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101. EXTH-44. ADDITION OF THE CARBONIC ANHYDRASE IX INHIBITOR SLC-0111 TO TEMOZOLOMIDE EXTENDS SURVIVAL OF MICE BEARING ORTHOTOPIC GLIOBLASTOMAS

Author

Paul C. McDonald, Victor M. Darley-Usmar, Anita B. Hjelmeland, Yancey Gillespie, Shoukat Dedhar, Nathaniel H. Boyd, Anh Tran, Mark O. Bevensee, Gloria A. Benavides, Kiera Walker, Burt Nabors, and James R. Hackney

Subjects
Cancer Research, Abstracts, Temozolomide, Oncology, Biochemistry, Chemistry, Cancer research, medicine, Neurology (clinical), Carbonic Anhydrase IX, medicine.drug
Abstract

Brain tumor microenvironments characterized by hypoxia, restricted glucose, and acidic stress contain a subset of neoplastic cells that thrive in these environments, identified as brain tumor initiating cells (BTICs). BTICs are resistant to chemo- and radiotherapy, providing a reservoir for tumor recurrence and a desirable target for glioma treatments. Standard of care for glioblastoma (GBM) includes surgical resection, radiation therapy, and the chemotherapeutic agent temozolomide, which prolongs life expectancy by months and is not curative. Prior studies suggested the efficacy of chemotherapies including temozolomide was increased by reducing expression of carbonic anhydrase 9 (CA9). CA9 is a hypoxia responsive gene elevated in tumors that is important for regulating intracellular pH and contributing to the acidic extracellular microenvironment. After confirming basal and hypoxia-induced expression of CA9 in GBM BTICs, we targeted CA9 activity with the small molecule inhibitor SLC-0111 alone or in combination with temozolomide. In multiple GBM BTIC lines, SLC-0111 reduced cell growth in vitro and showed additional benefit when used concurrently with temozolomide. Mechanistically, SLC-0111 treatment increased temozolomide DNA damage and resulted in changes to cellular metabolism and pH. SLC-0111 decreased the enrichment of BTICs after temozolomide treatment as determined via BTIC marker expression and functionally with neurosphere formation. SLC-0111 was detected in the brain after oral gavage administration of a formulation in Phase I clinical trials for breast cancer patients. SLC-0111 and temozolomide also significantly reduced the growth of subcutaneous and orthotopic models of a recurrent GBM greater than either drug alone. Together, our data suggest that SLC-0111 can sensitize GBM BTICs to the chemotherapy temozolomide and extend animal survival.

Published
2017

102. DDIS-01. INHIBITION OF BRAIN TUMOR INITIATING CELL GROWTH VIA NOVEL GLUCOSE TRANSPORTER ANTAGONISTS

Author

Arphaxad Otamias, Anita B. Hjelmeland, Gloria A. Benavides, Anh Tran, Sixue Zhang, Victor M. Darley-Usmar, Jianhua Zhang, Wei Zhang, Catherine J. Libby, Matthew Redmann, Mareck Napierla, and Yanjie Li

Subjects
Cancer Research, business.industry, Chemistry, Cell growth, Glucose transporter, Brain tumor, Pharmacology, medicine.disease, Abstracts, Text mining, Oncology, Biochemistry, medicine, Neurology (clinical), business
Abstract

The heterogeneous nature of glioblastoma has hampered the development of new effective therapeutic options. This heterogeneity is partially attributed to a subset of tumor cells known as brain tumor initiating cells (BTICs) that are highly tumorigenic and have some properties of neural stem cells. BTICs display metabolic plasticity, but, like many cancer cells, can have a reliance on aerobic glycolysis. Elevated expression of the glucose transporters GLUT1 and GLUT3 is present in many cancer types, with GLUT3 being preferentially expressed in BTICs to promote survival in low nutrient microenvironments. Through structure-based virtual screening, we identified potential novel GLUT inhibitors. The screening of 13 compounds identified two that can preferentially inhibit the growth of BTICs with minimal toxicity to non-neoplastic astrocytes and neurons. These compounds, SR37683 and SR37684, also inhibit glucose uptake and reduce glycolytic metabolism in Seahorse assays. We intend to identify a potential new therapeutic option targeting metabolic reprogramming for the treatment of glioblastoma, as well as other tumor types.

Published
2017

103. O-GlcNAc regulation of autophagy and α-synuclein homeostasis; implications for Parkinson’s disease

Author

Matthew Redmann, Victor M. Darley-Usmar, Gloria A. Benavides, John J. Shacka, Jianhua Zhang, Xiaosen Ouyang, Willayat Yousuf Wani, John C. Chatham, and Stacey S. Cofield

Subjects
0301 basic medicine, Parkinson's disease, Glycosylation, Mitochondrion, Biochemistry, lcsh:RC346-429, Rats, Sprague-Dawley, chemistry.chemical_compound, 0302 clinical medicine, O-GlcNAcylation, Homeostasis, Phosphorylation, Cells, Cultured, Temporal cortex, chemistry.chemical_classification, Neurons, 0303 health sciences, Glucosamine, TOR Serine-Threonine Kinases, Parkinson Disease, 3. Good health, Cell biology, Mitochondria, mTOR, alpha-Synuclein, Signal transduction, Signal Transduction, medicine.medical_specialty, Biology, Models, Biological, Cellular and Molecular Neuroscience, 03 medical and health sciences, α-synuclein, Internal medicine, Physiology (medical), medicine, Autophagy, Animals, Humans, Rapamycin, Molecular Biology, Protein kinase B, lcsh:Neurology. Diseases of the nervous system, PI3K/AKT/mTOR pathway, 030304 developmental biology, Pyrans, Alpha-synuclein, Sirolimus, Reactive oxygen species, Proteasome, Research, Akt, Thiamet G, Metabolism, medicine.disease, Thiazoles, 030104 developmental biology, Endocrinology, chemistry, Postmortem Changes, Parkinson’s disease, Proto-Oncogene Proteins c-akt, 030217 neurology & neurosurgery
Abstract

Post-translational modification on protein Ser/Thr residues by O-linked attachment of ß-N-acetyl-glucosamine (O-GlcNAcylation) is a key mechanism integrating redox signaling, metabolism and stress responses. One of the most common neurodegenerative diseases that exhibit aberrant redox signaling, metabolism and stress response is Parkinson’s disease, suggesting a potential role for O-GlcNAcylation in its pathology. To determine whether abnormal O-GlcNAcylation occurs in Parkinson’s disease, we analyzed lysates from the postmortem temporal cortex of Parkinson’s disease patients and compared them to age matched controls and found increased protein O-GlcNAcylation levels. To determine whether increased O-GlcNAcylation affects neuronal function and survival, we exposed rat primary cortical neurons to thiamet G, a highly selective inhibitor of the enzyme which removes the O-GlcNAc modification from target proteins, O-GlcNAcase (OGA). We found that inhibition of OGA by thiamet G at nanomolar concentrations significantly increased protein O-GlcNAcylation, activated MTOR, decreased autophagic flux, and increased α-synuclein accumulation, while sparing proteasomal activities. Inhibition of MTOR by rapamycin decreased basal levels of protein O-GlcNAcylation, decreased AKT activation and partially reversed the effect of thiamet G on α-synuclein monomer accumulation. Taken together we have provided evidence that excessive O-GlcNAcylation is detrimental to neurons by inhibition of autophagy and by increasing α-synuclein accumulation. Electronic supplementary material The online version of this article (doi:10.1186/s13041-017-0311-1) contains supplementary material, which is available to authorized users.

Published
2017

104. Addition of carbonic anhydrase 9 inhibitor SLC-0111 to temozolomide treatment delays glioblastoma growth in vivo

Author

Burt Nabors, Emily R Gordon, Victor M. Darley-Usmar, Corinne E. Griguer, Alessandra Audia, Gloria A. Benavides, Joshua Fried, Anita B. Hjelmeland, James R. Hackney, Raffaella Spina, Shoukat Dedhar, Catherine J. Libby, Susan Nozell, Anh Nhat Tran, Paul C. McDonald, Bo Xu, Krishna P. Bhat, Mark O. Bevensee, Eli E. Bar, Kiera Walker, Sarah E. Scott, Sara J. Cooper, Nathaniel H. Boyd, and G. Yancey Gillespie

Subjects
0301 basic medicine, medicine.medical_treatment, Cell, Mice, Nude, 03 medical and health sciences, In vivo, Neurosphere, Antineoplastic Combined Chemotherapy Protocols, medicine, Temozolomide, Animals, Humans, Cell Proliferation, Tumor microenvironment, Chemotherapy, Sulfonamides, Cell growth, Chemistry, Brain Neoplasms, Phenylurea Compounds, General Medicine, DNA, Neoplasm, Hydrogen-Ion Concentration, Xenograft Model Antitumor Assays, 030104 developmental biology, medicine.anatomical_structure, Cancer research, Neoplastic Stem Cells, Stem cell, Glioblastoma, medicine.drug, DNA Damage, Research Article
Abstract

Tumor microenvironments can promote stem cell maintenance, tumor growth, and therapeutic resistance, findings linked by the tumor-initiating cell hypothesis. Standard of care for glioblastoma (GBM) includes temozolomide chemotherapy, which is not curative, due, in part, to residual therapy-resistant brain tumor-initiating cells (BTICs). Temozolomide efficacy may be increased by targeting carbonic anhydrase 9 (CA9), a hypoxia-responsive gene important for maintaining the altered pH gradient of tumor cells. Using patient-derived GBM xenograft cells, we explored whether CA9 and CA12 inhibitor SLC-0111 could decrease GBM growth in combination with temozolomide or influence percentages of BTICs after chemotherapy. In multiple GBMs, SLC-0111 used concurrently with temozolomide reduced cell growth and induced cell cycle arrest via DNA damage in vitro. In addition, this treatment shifted tumor metabolism to a suppressed bioenergetic state in vivo. SLC-0111 also inhibited the enrichment of BTICs after temozolomide treatment determined via CD133 expression and neurosphere formation capacity. GBM xenografts treated with SLC-0111 in combination with temozolomide regressed significantly, and this effect was greater than that of temozolomide or SLC-0111 alone. We determined that SLC-0111 improves the efficacy of temozolomide to extend survival of GBM-bearing mice and should be explored as a treatment strategy in combination with current standard of care.

Published
2017

105. Endostatin inhibits androgen-independent prostate cancer growth by suppressing nuclear receptor-mediated oxidative stress

Author

Hong Wang, W. Timothy Garvey, Guru Sonpavde, Joo Hyoung Lee, Minsung Kang, Victor M. Darley-Usmar, Selvarangan Ponnazhagan, Gurudatta Naik, and James A. Mobley

Subjects
0301 basic medicine, Male, Thioredoxin-Disulfide Reductase, Thioredoxin reductase, Glutathione reductase, Down-Regulation, Antineoplastic Agents, Reductase, medicine.disease_cause, Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Receptors, Glucocorticoid, Cell Line, Tumor, Genetics, medicine, Humans, Molecular Biology, Cell Proliferation, NADPH-Ferrihemoprotein Reductase, chemistry.chemical_classification, Reactive oxygen species, Superoxide Dismutase, Research, Biliverdin reductase, Prostatic Neoplasms, Glutathione, Catalase, Glutathione synthetase, Endostatins, Oxidative Stress, 030104 developmental biology, Glutathione Reductase, chemistry, Receptors, Androgen, 030220 oncology & carcinogenesis, Cancer research, Oxidative stress, Biotechnology
Abstract

Androgen-deprivation therapy has been identified to induce oxidative stress in prostate cancer (PCa), leading to reactivation of androgen receptor (AR) signaling in a hormone-refractory manner. Thus, antioxidant therapies have gained attention as adjuvants for castration-resistant PCa. Here, we report for the first time that human endostatin (ES) prevents androgen-independent growth phenotype in PCa cells through its molecular targeting of AR and glucocorticoid receptor (GR) and downstream pro-oxidant signaling. This reversal after ES treatment significantly decreased PCa cell proliferation through down-regulation of GR and up-regulation of manganese superoxide dismutase and reduced glutathione levels. Proteome and biochemical analyses of ES-treated PCa cells further indicated a significant up-regulation of enzymes in the major reactive oxygen species (ROS) scavenging machinery, including catalase, glutathione synthetase, glutathione reductase, NADPH-cytochrome P450 reductase, biliverdin reductase, and thioredoxin reductase, resulting in a concomitant reduction of intracellular ROS. ES further augmented the antioxidant system through up-regulation of glucose influx, the pentose phosphate pathway, and NAD salvaging pathways. This shift in cancer cell redox homeostasis by ES significantly decreased the effect of protumorigenic oxidative machinery on androgen-independent PCa growth, suggesting that ES can suppress GR-induced resistant phenotype upon AR antagonism and that the dual targeting action of ES on AR and GR can be further translated to PCa therapy.-Lee, J. H., Kang, M., Wang, H., Naik, G., Mobley, J. A., Sonpavde, G., Garvey, W. T., Darley-Usmar, V. M., Ponnazhagan, S. Endostatin inhibits androgen-independent prostate cancer growth by suppressing nuclear receptor-mediated oxidative stress.

Published
2017

106. NADPH Oxidase 4 (Nox4) suppresses mitochondrial biogenesis and bioenergetics in lung fibroblasts via a nuclear factor erythroid-derived 2-like 2 (Nrf2)-dependent pathway

Author

Gloria A. Benavides, Victor M. Darley-Usmar, Victor J. Thannickal, Karen Bernard, A. Brent Carter, Jianhua Zhang, Verónica Miguel, Naomi J. Logsdon, and National Institutes of Health (US)

Subjects
0301 basic medicine, Voltage-dependent anion channel, NF-E2-Related Factor 2, Mitochondrion, Biochemistry, Mice, 03 medical and health sciences, Animals, Humans, Citrate synthase, Gene Silencing, RNA, Messenger, Lung, Molecular Biology, Mice, Knockout, Organelle Biogenesis, biology, High Mobility Group Proteins, NADPH Oxidases, Cell Biology, TFAM, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Cell biology, DNA-Binding Proteins, 030104 developmental biology, Mitochondrial biogenesis, NADPH Oxidase 4, biology.protein, DNAJA3, ATP–ADP translocase, PPARGC1A, Energy Metabolism
Abstract

Mitochondrial bioenergetics are critical for cellular homeostasis and stress responses. The reactive oxygen speciesgenerating enzyme, NADPH oxidase 4 (Nox4), regulates a number of physiological and pathological processes, including cellular differentiation, host defense, and tissue fibrosis. In this study we explored the role of constitutive Nox4 activity in regulating mitochondrial function. An increase in mitochondrial oxygen consumption and reserve capacity was observed in murine and human lung fibroblasts with genetic deficiency (or silencing) of Nox4. Inhibition of Nox4 expression/activity by genetic or pharmacological approaches resulted in stimulation of mitochondrial biogenesis, as evidenced by elevated mitochondrial-to-nuclear DNA ratio and increased expression of the mitochondrial markers transcription factor A (TFAM), citrate synthase, voltage-dependent anion channel (VDAC), and cytochrome c oxidase subunit 4 (COX IV). Induction of mitochondrial biogenesis was dependent on TFAM up-regulation but was independent of the activation of the peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α). The enhancement of mitochondrial bioenergetics as well as the increase in mitochondrial proteins in Nox4-deficient lung fibroblasts is inhibited by silencing of nuclear factor erythroid-derived 2-like 2 (Nrf2), supporting a key role for Nrf2 in control of mitochondrial biogenesis. Together, these results indicate a critical role for both Nox4 and Nrf2 in counter-regulation of mitochondrial biogenesis and metabolism., National Institutes of Health Grant P30AG050886)

Published
2017

107. Hemoglobin-associated Oxidative Stress in the Pericardial Compartment of Post-operative Cardiac Surgery Patients

Author

Tanecia Mitchell, Victor M. Darley-Usmar, Chad Steele, Spencer J. Melby, Alireza Arabshahi, David J. George, Philip A. Kramer, Louis J. Dell'Italia, Balu K. Chacko, James F. George, Saranya Ravi, Stephen Barnes, and Michelle S. Johnson

Subjects
medicine.medical_specialty, Neutrophils, 030204 cardiovascular system & hematology, medicine.disease_cause, Article, Mass Spectrometry, Pathology and Forensic Medicine, Protein Carbonylation, 03 medical and health sciences, Hemoglobins, 0302 clinical medicine, Postoperative Complications, Internal medicine, medicine, Rosaniline Dyes, Pericardium, Humans, Myocardial infarction, Sulfhydryl Compounds, Cardiac Surgical Procedures, Molecular Biology, 030304 developmental biology, 0303 health sciences, Analysis of Variance, F2-Isoprostanes, business.industry, valvular heart disease, Pericardial fluid, Extracellular Fluid, Cell Biology, Hydrogen Peroxide, medicine.disease, Flow Cytometry, 3. Good health, Cardiac surgery, Blood Cell Count, Oxidative Stress, medicine.anatomical_structure, Heart failure, Anesthesia, Cardiology, Electrophoresis, Polyacrylamide Gel, Lipid Peroxidation, business, Oxidation-Reduction, Oxidative stress, Artery
Abstract

Atherosclerosis and valvular heart disease often require treatment with corrective surgery to prevent future myocardial infarction, ischemic heart disease, and heart failure. Mechanisms underlying the development of the associated complications of surgery are multifactorial and have been linked to inflammation and oxidative stress, classically as measured in the blood or plasma of patients. Post-operative pericardial fluid (PO-PCF) has not been investigated in depth with respect to the potential to induce oxidative stress. This is important since cardiac surgery disrupts the integrity of the pericardial membrane surrounding the heart, and causes significant alterations in the composition of the pericardial fluid (PCF). This includes contamination with hemolyzed blood and high concentrations of oxidized hemoglobin, which suggests that cardiac surgery results in oxidative stress within the pericardial space. Accordingly, we tested the hypothesis that PO-PCF is highly pro-oxidant and that the potential interaction between inflammatory cell-derived hydrogen peroxide with hemoglobin is associated with oxidative stress. Blood and PCF were collected from 31 patients at the time of surgery and postoperatively from 4 to 48 hours after coronary artery bypass grafting, valve replacement, or valve repair (mitral or aortic). PO-PCF contained high concentrations of neutrophils and monocytes which are capable of generating elevated amounts of superoxide and hydrogen peroxide through the oxidative burst. In addition, PO-PCF primed naïve neutrophils resulting in an enhanced oxidative burst upon stimulation. The PO-PCF also contained increased concentrations of cell-free oxidized hemoglobin which was associated with elevated levels of F2α-isoprostanes and prostaglandins, consistent with both oxidative stress and activation of cyclooxygenase. Lastly, protein analysis of the PO-PCF revealed evidence of protein thiol oxidation and protein carbonylation. We conclude that PO-PCF is highly pro-oxidant and speculate that it may contribute to the risk of post-operative complications.

Published
2014

108. Mitophagy mechanisms and role in human diseases

Author

Victor M. Darley-Usmar, Matthew Dodson, Michaël Boyer-Guittaut, Matthew Redmann, and Jianhua Zhang

Subjects
Membrane Potential, Mitochondrial, Heart Diseases, Mitochondrial Turnover, Autophagy, Mitophagy, Mitochondrial Degradation, Parkinson Disease, Cell Biology, Mitochondrion, Biology, Biochemistry, Article, Cell biology, Neoplasms, Humans
Abstract

Mitophagy is a process of mitochondrial turnover through lysosomal mediated autophagy activities. This review will highlight recent studies that have identified mediators of mitophagy in response to starvation, loss of mitochondrial membrane potential or perturbation of mitochondrial integrity. Furthermore, we will review evidence of mitophagy dysfunction in various human diseases and discuss the potential for therapeutic interventions that target mitophagy processes.

Published
2014
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109. Redox regulation of antioxidants, autophagy, and the response to stress: Implications for electrophile therapeutics

Author

Victor M. Darley-Usmar, Bradford G. Hill, Emilia Kansanen, Jianhua Zhang, and Anna-Liisa Levonen

Subjects
Keap1, NF-E2-Related Factor 2, Biology, Mitochondrion, Electrophiles, Bioenergetics, medicine.disease_cause, Nitric Oxide, Biochemistry, Article, Nrf2, Antioxidants, Physiology (medical), medicine, Autophagy, Animals, Humans, Heat-Shock Proteins, Aldehydes, Kelch-Like ECH-Associated Protein 1, Intracellular Signaling Peptides and Proteins, Hydrogen Peroxide, 3. Good health, Cell biology, Oxidative Stress, Gene Expression Regulation, Second messenger system, Proteome, Unfolded protein response, Unfolded Protein Response, Signal transduction, Reactive Oxygen Species, Oxidative stress, Intracellular, Signal Transduction
Abstract

Redox networks in the cell integrate signaling pathways that control metabolism, energetics, cell survival, and death. The physiological second messengers that modulate these pathways include nitric oxide, hydrogen peroxide, and electrophiles. Electrophiles are produced in the cell via both enzymatic and nonenzymatic lipid peroxidation and are also relatively abundant constituents of the diet. These compounds bind covalently to families of cysteine-containing, redox-sensing proteins that constitute the electrophile-responsive proteome, the subproteomes of which are found in localized intracellular domains. These include those proteins controlling responses to oxidative stress in the cytosol—notably the Keap1-Nrf2 pathway, the autophagy-lysosomal pathway, and proteins in other compartments including mitochondria and endoplasmic reticulum. The signaling pathways through which electrophiles function have unique characteristics that could be exploited for novel therapeutic interventions; however, development of such therapeutic strategies has been challenging due to a lack of basic understanding of the mechanisms controlling this form of redox signaling. In this review, we discuss current knowledge of the basic mechanisms of thiol-electrophile signaling and its potential impact on the translation of this important field of redox biology to the clinic. Emerging understanding of thiol-electrophile interactions and redox signaling suggests replacement of the oxidative stress hypothesis with a new redox biology paradigm, which provides an exciting and influential framework for guiding translational research.

Published
2014
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110. The Bioenergetic Health Index: a new concept in mitochondrial translational research

Author

Victor M. Darley-Usmar, Brian P. Dranka, Saranya Ravi, Shannon M. Bailey, Robert W. Hardy, David A. Ferrick, Jianhua Zhang, Degui Zhi, Tanecia Mitchell, Scott W. Ballinger, Ashwani K. Singal, Balu K. Chacko, Philip A. Kramer, and Gloria A. Benavides

Subjects
haplotype, hepatotoxicity, Cell type, Bioenergetics, ETC, electron transport chain, Physiology, Translational research, S9, Disease, Biology, Mitochondrion, Bioinformatics, S4, Translational Research, Biomedical, RNS, reactive nitrogen species, neurodegenerative disease, ROS, reactive oxygen species, cardiovascular disease, Diabetes mellitus, reserve capacity, medicine, Animals, Humans, oxidative stress, OCR, oxygen consumption rate, HNE, hydroxynonenal, aging, Neurodegeneration, General Medicine, Hypothesis, medicine.disease, Mitochondria, mtDNA, mitochondrial DNA, 3. Good health, Biomarker (cell), FCCP, carbonyl cyanide p-trifluoromethoxyphenylhydrazone, BHI, Bioenergetic Health Index, Energy Metabolism, Biomarkers, LDA, linear discriminant analysis
Abstract

Bioenergetics has become central to our understanding of pathological mechanisms, the development of new therapeutic strategies and as a biomarker for disease progression in neurodegeneration, diabetes, cancer and cardiovascular disease. A key concept is that the mitochondrion can act as the ‘canary in the coal mine’ by serving as an early warning of bioenergetic crisis in patient populations. We propose that new clinical tests to monitor changes in bioenergetics in patient populations are needed to take advantage of the early and sensitive ability of bioenergetics to determine severity and progression in complex and multifactorial diseases. With the recent development of high-throughput assays to measure cellular energetic function in the small number of cells that can be isolated from human blood these clinical tests are now feasible. We have shown that the sequential addition of well-characterized inhibitors of oxidative phosphorylation allows a bioenergetic profile to be measured in cells isolated from normal or pathological samples. From these data we propose that a single value–the Bioenergetic Health Index (BHI)–can be calculated to represent the patient's composite mitochondrial profile for a selected cell type. In the present Hypothesis paper, we discuss how BHI could serve as a dynamic index of bioenergetic health and how it can be measured in platelets and leucocytes. We propose that, ultimately, BHI has the potential to be a new biomarker for assessing patient health with both prognostic and diagnostic value.

Published
2014
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111. The role of GABARAPL1/GEC1 in autophagic flux and mitochondrial quality control in MDA-MB-436 breast cancer cells

Author

Fatima-Zahra Chakrama, Gloria A. Benavides, Xiaosen Ouyang, Laura Poillet, Michèle Jouvenot, Michaël Boyer-Guittaut, Elodie Bole-Richard, Jianhua Zhang, Régis Delage-Mourroux, Gilles Despouy, Qiuli Liang, Victor M. Darley-Usmar, and Annick Fraichard

Subjects
Cell Survival, Breast Neoplasms, Biology, Mitochondrion, DNA, Mitochondrial, Small hairpin RNA, Cell Line, Tumor, Sequestosome-1 Protein, Mitophagy, Autophagy, Humans, Neoplasm Invasiveness, RNA, Messenger, RNA, Neoplasm, RNA, Small Interfering, Molecular Biology, Tumor Stem Cell Assay, Adaptor Proteins, Signal Transducing, Cell Proliferation, Membrane Potential, Mitochondrial, Aldehydes, LAMP1, Cell growth, Lysosome-Associated Membrane Glycoproteins, Membrane Proteins, Correction, Cell Biology, Cell biology, Gene Knockdown Techniques, Beclin-1, Female, Apoptosis Regulatory Proteins, Energy Metabolism, Lysosomes, Microtubule-Associated Proteins, Flux (metabolism), Intracellular, DNA Damage
Abstract

GABARAPL1/GEC1 is an early estrogen-induced gene which encodes a protein highly conserved from C. elegans to humans. Overexpressed GABARAPL1 interacts with GABAA or kappa opioid receptors, associates with autophagic vesicles, and inhibits breast cancer cell proliferation. However, the function of endogenous GABARAPL1 has not been extensively studied. We hypothesized that GABARAPL1 is required for maintaining normal autophagic flux, and plays an important role in regulating cellular bioenergetics and metabolism. To test this hypothesis, we knocked down GABARAPL1 expression in the breast cancer MDA-MB-436 cell line by shRNA. Decreased expression of GABARAPL1 activated procancer responses of the MDA-MB-436 cells including increased proliferation, colony formation, and invasion. In addition, cells with decreased expression of GABARAPL1 exhibited attenuated autophagic flux and a decreased number of lysosomes. Moreover, decreased GABARAPL1 expression led to cellular bioenergetic changes including increased basal oxygen consumption rate, increased intracellular ATP, increased total glutathione, and an accumulation of damaged mitochondria. Taken together, our results demonstrate that GABARAPL1 plays an important role in cell proliferation, invasion, and autophagic flux, as well as in mitochondrial homeostasis and cellular metabolic programs.

Published
2014
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112. A mitochondria-targeted mass spectrometry probe to detect glyoxals: implications for diabetes

Author

Angela Logan, Robin A.J. Smith, Ian M. Fearnley, Thomas Krieg, Katja E. Menger, Tracy A. Prime, Carmen Methner, G.D. Kishore Kumar, Sebastian Rogatti, Balu K. Chacko, Yvonne Collins, Pamela Boon Li Pun, Michelle S. Johnson, Andrew M. James, Michael P. Murphy, Guang W. Huang, Richard C. Hartley, David S. Larsen, Victor M. Darley-Usmar, and Lesley Larsen

Subjects
Free radicals, Mitochondria, Liver, Mitochondrion, Phenylenediamines, medicine.disease_cause, Biochemistry, Cell Line, Myoblasts, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Organophosphorus Compounds, In vivo, Glycation, Tandem Mass Spectrometry, Physiology (medical), Methylglyoxal, medicine, Animals, MitoG, 030304 developmental biology, Exomarker, 0303 health sciences, Endothelial Cells, Original Contribution, Glyoxal, Pyruvaldehyde, 3. Good health, Mitochondria, Rats, Disease Models, Animal, Oxidative Stress, Diabetes Mellitus, Type 1, chemistry, Cell culture, 030220 oncology & carcinogenesis, Hyperglycemia, Molecular Probes, Cattle, Oxidative stress, Intracellular, Chromatography, Liquid
Abstract

The glycation of protein and nucleic acids that occurs as a consequence of hyperglycemia disrupts cell function and contributes to many pathologies, including those associated with diabetes and aging. Intracellular glycation occurs after the generation of the reactive 1,2-dicarbonyls methylglyoxal and glyoxal, and disruption of mitochondrial function is associated with hyperglycemia. However, the contribution of these reactive dicarbonyls to mitochondrial damage in pathology is unclear owing to uncertainties about their levels within mitochondria in cells and in vivo. To address this we have developed a mitochondria-targeted reagent (MitoG) designed to assess the levels of mitochondrial dicarbonyls within cells. MitoG comprises a lipophilic triphenylphosphonium cationic function, which directs the molecules to mitochondria within cells, and an o-phenylenediamine moiety that reacts with dicarbonyls to give distinctive and stable products. The extent of accumulation of these diagnostic heterocyclic products can be readily and sensitively quantified by liquid chromatography–tandem mass spectrometry, enabling changes to be determined. Using the MitoG-based analysis we assessed the formation of methylglyoxal and glyoxal in response to hyperglycemia in cells in culture and in the Akita mouse model of diabetes in vivo. These findings indicated that the levels of methylglyoxal and glyoxal within mitochondria increase during hyperglycemia both in cells and in vivo, suggesting that they can contribute to the pathological mitochondrial dysfunction that occurs in diabetes and aging., Highlights • A mitochondria-targeted mass spectrometric probe, MitoG, has been developed to measure glyoxal and methylglyoxal. • Using MitoG we show that mitochondrial glyoxal and methylglyoxal can be measured in hyperglycemic cells. • MitoG can also be used in vivo to infer mitochondrial glyoxal and methylglyoxal production in a mouse model of type I diabetes. • These findings suggest that the accumulation of glyoxal and methylglyoxal within mitochondria may contribute to mitochondrial dysfunction in diabetes.

Published
2014
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113. A review of the mitochondrial and glycolytic metabolism in human platelets and leukocytes: Implications for their use as bioenergetic biomarkers

Author

Victor M. Darley-Usmar, Michelle S. Johnson, Saranya Ravi, Balu K. Chacko, and Philip A. Kramer

Subjects
Blood Platelets, Platelets, ROS/RNS, reactive oxygen species/reactive nitrogen species, Mini Review, Clinical Biochemistry, Inflammation, Oxidative phosphorylation, Biology, Mitochondrion, medicine.disease_cause, Biochemistry, Oxidative Phosphorylation, XF, extracellular flux analyzer, Adenosine Triphosphate, Neoplasms, medicine, Leukocytes, Animals, Humans, OCR, oxygen consumption rate, Glycolysis, Platelet, lcsh:QH301-705.5, Metabolic Syndrome, lcsh:R5-920, ECAR, extracellular acidification rate, Organic Chemistry, Neurodegeneration, Biomarker, Metabolic shift, Atherosclerosis, medicine.disease, Mitochondria, 3. Good health, Reserve capacity, lcsh:Biology (General), Oxidative stress, Immunology, Biomarker (medicine), medicine.symptom, Energy Metabolism, lcsh:Medicine (General), Biomarkers, Forecasting
Abstract

The assessment of metabolic function in cells isolated from human blood for treatment and diagnosis of disease is a new and important area of translational research. It is now becoming clear that a broad range of pathologies which present clinically with symptoms predominantly in one organ, such as the brain or kidney, also modulate mitochondrial energetics in platelets and leukocytes allowing these cells to serve as “the canary in the coal mine” for bioenergetic dysfunction. This opens up the possibility that circulating platelets and leukocytes can sense metabolic stress in patients and serve as biomarkers of mitochondrial dysfunction in human pathologies such as diabetes, neurodegeneration and cardiovascular disease. In this overview we will describe how the utilization of glycolysis and oxidative phosphorylation differs in platelets and leukocytes and discuss how they can be used in patient populations. Since it is clear that the metabolic programs between leukocytes and platelets are fundamentally distinct the measurement of mitochondrial function in distinct cell populations is necessary for translational research., Graphical abstract, Highlights • Monocytes, lymphocytes, neutrophils and platelets have distinct bioenergetic programs that regulate energy production. • Platelets and monocytes exhibit a high level of aerobic glycolysis and mitochondrial respiration. • Lymphocytes have a low glycolytic capacity while neutrophils have little or no detectable oxidative phosphorylation. • The levels of mitochondrial complex IV and III subunits differ substantially between lymphocytes, monocytes and platelets.

Published
2014

114. Autophagy as an essential cellular antioxidant pathway in neurodegenerative disease

Author

Samantha Giordano, Jianhua Zhang, and Victor M. Darley-Usmar

Subjects
Aging, Antioxidant, Redox signaling, MPP+, 1-methyl-4-phenylpyridinium, medicine.medical_treatment, PINK1, PTEN-induced putative kinase 1, Clinical Biochemistry, Drug Evaluation, Preclinical, HNE, 4-hydroxynonenal, Protein oxidation, medicine.disease_cause, Biochemistry, Antioxidants, Lipid peroxidation, Antiparkinson Agents, chemistry.chemical_compound, rasagiline, N-propargyl-1-(R)-aminoindan, Clinical trials, GSH, glutathione, Toxins, TFEB, transcription factor EB, lcsh:QH301-705.5, MitoQ, mitochondrially-targeted coenzyme Q, Neurons, Clinical Trials as Topic, MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydro pyridine, lcsh:R5-920, 6-OHDA, 6-hydroxydopamine, ROS/RNS, reactive oxygen and nitrogen species, Neurodegeneration, Brain, Neurodegenerative Diseases, curcumin, (1E,6E)-1,7-Bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione, LRRK2, leucine-rich repeat kinase 2, Animal models, Sirt1, NAD-dependent deacetylast sirtuin-1, Neuroprotective Agents, the ADAGIO study, the Attenuation of Disease Progression with Azilect Given Once-daily) study, Protein aggregation, Oxidoreductases, lcsh:Medicine (General), Oxidation-Reduction, DNA damage, CBZ, carbamazepine, Nerve Tissue Proteins, Biology, Nrf2, Nuclear factor (erythroid-derived 2)-like 2, Article, iPSC, induced pluripotent stem cells, Parkinsonian Disorders, Peroxynitrous Acid, SOD, superoxide dismutase, medicine, Autophagy, Animals, Humans, MnSOD, manganese superoxide dismutase, UPDRS, Unified Parkinson’s Disease Rating Scale, MDA, malondialdehyde, MitoQ, Organic Chemistry, the DATATOP Study, the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism Study, Selegiline, N-propargyl-methamphetamine, medicine.disease, UCHL1, ubiquitin carboxyl-terminal hydrolase L1, Disease Models, Animal, Oxidative Stress, chemistry, lcsh:Biology (General), the TEMPO Study, the TVP-1012 in Early Monotherapy for PD Outpatients Study, Parkinson’s disease, Anti-oxidants, Lipid Peroxidation, the NET-PD network, the NINDS Exploratory Trials in Parkinson’s Disease (NET-PD) network, Lysosomes, Mitochondrial dysfunction, Reactive oxygen species, EGCG, epigallocatechin gallate, Oxidative stress, HIF1α, hypoxia-inducible factor 1-alpha
Abstract

Oxidative stress including DNA damage, increased lipid and protein oxidation, are important features of aging and neurodegeneration suggesting that endogenous antioxidant protective pathways are inadequate or overwhelmed. Importantly, oxidative protein damage contributes to age-dependent accumulation of dysfunctional mitochondria or protein aggregates. In addition, environmental toxins such as rotenone and paraquat, which are risk factors for the pathogenesis of neurodegenerative diseases, also promote protein oxidation. The obvious approach of supplementing the primary antioxidant systems designed to suppress the initiation of oxidative stress has been tested in animal models and positive results were obtained. However, these findings have not been effectively translated to treating human patients, and clinical trials for antioxidant therapies using radical scavenging molecules such as α-tocopherol, ascorbate and coenzyme Q have met with limited success, highlighting several limitations to this approach. These could include: (1) radical scavenging antioxidants cannot reverse established damage to proteins and organelles; (2) radical scavenging antioxidants are oxidant specific, and can only be effective if the specific mechanism for neurodegeneration involves the reactive species to which they are targeted and (3) since reactive species play an important role in physiological signaling, suppression of endogenous oxidants maybe deleterious. Therefore, alternative approaches that can circumvent these limitations are needed. While not previously considered an antioxidant system we propose that the autophagy-lysosomal activities, may serve this essential function in neurodegenerative diseases by removing damaged or dysfunctional proteins and organelles., Graphical abstract, Highlights • Significant oxidative damage occurs in neurodegenerative disease brains. • Effective in animal models with single toxins, antioxidants are ineffective in clinical trials. • The failure of antioxidant therapy maybe due to propagation of cellular damage. • Autophagic clearance of diverse damaged molecules may provide antioxidant mechanisms. • Further mechanistic and translational studies on autophagy therapy are needed.

Published
2014

115. DDIS-04. COMPOUNDS IDENTIFIED BY STRUCTURE BASED VIRTUAL SCREENING DECREASE GBM BTIC GROWTH AND GLUCOSE UPTAKE

Author

Yanjie Li, Anita B. Hjelmeland, Sarah E. Scott, Victor M. Darley-Usmar, Arphaxad Otamias, Marek Napierala, Gloria A. Benavides, Catherine J. Libby, Sixue Zhang, Anh Nhat Tran, Corinne E. Augelli-Szafran, Wei Zhang, Matthew Redmann, Sajina Gc, Vibha Pathak, Omar Moukha-Chafiq, and Jianhua Zhang

Subjects
Abstracts, Cancer Research, Virtual screening, Oncology, Chemistry, Glucose uptake, Structure based, Neurology (clinical), Pharmacology
Abstract

Patient prognosis for individuals diagnosed with GBM remains incredibly poor with a median survival of only 15 months despite aggressive treatment with surgical tumor resection, chemotherapy, and radiation therapy. Therapeutic development to prolong survival has been hampered by a high degree of inter- and intra-tumoral heterogeneity. Contributing to tumor heterogeneity is a subset of highly tumorigenic cells, termed brain tumor initiating cells (BTICs), that can self-renew and have been shown to be highly invasive and resistant to therapy. BTICs can survive under nutrient poor conditions due to their increased expression of glucose transporter 3 (GLUT3). In a recently accepted study, we utilized structure based virtual screening (SBVS) using a GLUT3 homology model to identify two novel GLUT inhibitors. We are now generating a structure-activity relationship profile based on a highly efficacious compound (IC(50)= ~300 nM) with the same backbone structure identified in the initial screen and seek to improve the potency, selectivity and drug-like properties of the GLUT inhibitors. We have tested several novel analogs and identified four that have maintained efficacy against BTICs in vitro (IC(50)= 300–600 nM). Importantly, these analogs have displayed less toxicity to astrocytes than lead compounds in addition to improved stability in mouse liver microsomes. As proof of concept, we have begun to test the GLUT inhibitors alone and in combination with chemotherapy in vivo. Thus far, our work has demonstrated that targeting glucose transport is a promising therapeutic avenue to explore.

Published
2018
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116. Enhanced Keap1-Nrf2 signaling protects the myocardium from isoproterenol-induced pathological remodeling in mice

Author

Asokan Devarajan, Gobinath Shanmugam, Silvio H. Litovsky, Namakkal S. Rajasekaran, Dean P. Jones, Victor M. Darley-Usmar, Anil K. Challa, and Ding Wang

Subjects
0301 basic medicine, Clinical Biochemistry, Cardiovascular, medicine.disease_cause, environment and public health, Biochemistry, Antioxidants, Mice, 0302 clinical medicine, Fibrosis, lcsh:QH301-705.5, chemistry.chemical_classification, lcsh:R5-920, Kelch-Like ECH-Associated Protein 1, Chemistry, Heart, respiratory system, Glutathione, 3. Good health, Cell biology, Echocardiography, medicine.symptom, lcsh:Medicine (General), Oxidation-Reduction, Signal Transduction, NF-E2-Related Factor 2, Transgene, Mice, Transgenic, Inflammation, Protective Agents, digestive system, Nrf2, 03 medical and health sciences, medicine, Animals, Transcription factor, Cardiac remodeling, Reactive oxygen species, Myocardium, Organic Chemistry, Isoproterenol, medicine.disease, KEAP1, NFE2L2, Mice, Inbred C57BL, Oxidative Stress, 030104 developmental biology, lcsh:Biology (General), Reactive Oxygen Species, Biomarkers, 030217 neurology & neurosurgery, Oxidative stress
Abstract

Nuclear factor (erythroid-derived 2)-like 2 (NFE2L2/Nrf2) is an inducible transcription factor that is essential for maintenance of redox signaling in response to stress. This suggests that if Nrf2 expression response could be enhanced for a defined physiological pro-oxidant stress then it would be protective. This has important implications for the therapeutic manipulation of the Keap1/Nrf2 signaling pathway which is now gaining a lot of attention. We tested this hypothesis through the generation of Nrf2 transgene expression mouse model with and without isoproterenol-induced cardiac stress. Cardiac-specific mouse Nrf2 transgenic (mNrf2-TG) and non-transgenic (NTG) mice were subjected to isoproterenol (ISO) treatment and assessed for myocardial structure, function (echocardiography and electrocardiography), and glutathione redox state. Myocardial infarction and fibrosis along with increased inflammation leading to myocardial dysfunction was noted in NTG mice exposed to ISO, while mNrf2-TG hearts were resistant to the ISO insult. Preservation of myocardial structure and function in the mNrf2-TG mice was associated with the enhanced Nrf2 expression displayed in these hearts with an increased basal and post-treatment expression of redox modulatory genes and an overall enhanced antioxidant status. Of note, myocardium of ISO-treated TG mice displayed significantly increased stabilization of the KEAP1-NRF2 complex and enhanced release of NRF2 to the nucleus resulting in overall decreased pro-oxidant markers. Taken together, we suggest that a basal enhanced Nrf2 expression in mouse heart results in maintenance of redox homeostasis and counteracts ISO-induced oxidative stress, and suppresses pathological remodeling. These data suggest that an alternative therapeutic approach to enhance the efficacy of the Keap1-Nrf2 system is to stimulate basal expression of Nrf2., Graphical abstract Image 1, Highlights • Isoproterenol induces oxidative/inflammatory stresses and leading to myocardial remodeling. • Cardiac specific expression of Nrf2 augments Keap1-Nrf2 association, thereby timely responds to isoproterenol-induced stress. • Augmented levels of Keap1-Nrf2 signaling is crucial to combat isoproterenol toxicity in the heart. • Enhanced Nrf2-dependent antioxidant defense suppresses oxidative stress and prevents pathological cardiac remodeling. • A controlled activation of global antioxidant signaling is vital for myocardial protection in stress conditions.

Published
2019
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117. Mitochondria in precision medicine; linking bioenergetics and metabolomics in platelets

Author

Karan Uppal, Gloria A. Benavides, Matthew R. Smith, Dean P. Jones, Sruti Shiva, Victor M. Darley-Usmar, Jyotsna Pilli, Young-Mi Go, Matilda Lillian Culp, Balu K. Chacko, and Michelle S. Johnson

Subjects
Adult, Blood Platelets, Male, 0301 basic medicine, Adolescent, Bioenergetics, Clinical Biochemistry, Cell, Mitochondrion, Biology, Biochemistry, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Metabolomics, medicine, Metabolome, Humans, Precision Medicine, lcsh:QH301-705.5, lcsh:R5-920, Organic Chemistry, Computational Biology, Metabolism, Middle Aged, Mitochondria, 3. Good health, Cell biology, 030104 developmental biology, medicine.anatomical_structure, lcsh:Biology (General), chemistry, Female, lcsh:Medicine (General), Xenobiotic, Metabolic Networks and Pathways, 030217 neurology & neurosurgery, Function (biology), Research Paper
Abstract

Mitochondria possess reserve bioenergetic capacity, supporting protection and resilience in the face of disease. Approaches are limited to understand factors that impact mitochondrial functional reserve in humans. We applied the mitochondrial stress test (MST) to platelets from healthy subjects and found correlations between energetic parameters and mitochondrial function. These parameters were not correlated with mitochondrial complex I-IV activities, however, suggesting that other factors affect mitochondrial bioenergetics and metabolism. Platelets from African American patients with sickle cell disease also differed from controls, further showing that other factors impact mitochondrial bioenergetics and metabolism. To test for correlations of platelet metabolites with energetic parameters, we performed an integrated analysis of metabolomics and MST parameters. Subsets of metabolites, including fatty acids and xenobiotics correlated with mitochondrial parameters. The results establish platelets as a platform to integrate bioenergetics and metabolism for analysis of mitochondrial function in precision medicine., Graphical abstract Image 1, Highlights • Variations in platelet bioenergetics can be ascribed to the metabolic plasticity required for physiological metabolism. • Bioenergetic parameters in normal subjects are related. These relationships deteriorate in Sickle Cell disease patients. • Untargeted metabolomics reveals over 100 potential metabolites that underlie the mitochondrial stress test. • Among the metabolites associated with platelet bioenergetic parameters are environmental toxins and natural products.

Published
2019
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118. Inhibition of glycolysis attenuates 4-hydroxynonenal-dependent autophagy and exacerbates apoptosis in differentiated SH-SY5Y neuroblastoma cells

Author

Matthew Dodson, Qiuli Liang, Naomi Fineberg, Matthew Redmann, Victor M. Darley-Usmar, Jianhua Zhang, and Michelle S. Johnson

Subjects
Programmed cell death, Cellular differentiation, Down-Regulation, Apoptosis, Caspase 3, Deoxyglucose, medicine.disease_cause, 4-Hydroxynonenal, chemistry.chemical_compound, Adenosine Triphosphate, Cell Line, Tumor, Autophagy, medicine, Humans, Molecular Biology, Glyceraldehyde 3-phosphate dehydrogenase, Neurons, Aldehydes, Dose-Response Relationship, Drug, biology, Cell Differentiation, Cell Biology, Glutathione, Basic Research Paper, Cell biology, Oxidative Stress, chemistry, biology.protein, Glycolysis, Oxidative stress
Abstract

How cellular metabolic activities regulate autophagy and determine the susceptibility to oxidative stress and ultimately cell death in neuronal cells is not well understood. An important example of oxidative stress is 4-hydroxynonenal (HNE), which is a lipid peroxidation product that is formed during oxidative stress, and accumulates in neurodegenerative diseases causing damage. The accumulation of toxic oxidation products such as HNE, is a prevalent feature of neurodegenerative diseases, and can promote organelle and protein damage leading to induction of autophagy. In this study, we used differentiated SH-SY5Y neuroblastoma cells to investigate the mechanisms and regulation of cellular susceptibility to HNE toxicity and the relationship to cellular metabolism. We found that autophagy is immediately stimulated by HNE at a sublethal concentration. Within the same time frame, HNE induces concentration dependent CASP3/caspase 3 activation and cell death. Interestingly, both basal and HNE-activated autophagy, were regulated by glucose metabolism. Inhibition of glucose metabolism by 2-deoxyglucose (2DG), at a concentration that inhibited autophagic flux, further exacerbated CASP3 activation and cell death in response to HNE. Cell death was attenuated by the pan-caspase inhibitor Z-VAD-FMK. Specific inhibition of glycolysis using koningic acid, a GAPDH inhibitor, inhibited autophagic flux and exacerbated HNE-induced cell death similarly to 2DG. The effects of 2DG on autophagy and HNE-induced cell death could not be reversed by addition of mannose, suggesting an ER stress-independent mechanism. 2DG decreased LAMP1 and increased BCL2 levels suggesting that its effects on autophagy may be mediated by more than one mechanism. Furthermore, 2DG decreased cellular ATP, and 2DG and HNE combined treatment decreased mitochondrial membrane potential. We conclude that glucose-dependent autophagy serves as a protective mechanism in response to HNE.

Published
2013
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119. Cellular metabolic and autophagic pathways: Traffic control by redox signaling

Author

Victor M. Darley-Usmar, Matthew Dodson, and Jianhua Zhang

Subjects
Cell signaling, Apoptosis, Oxidative phosphorylation, Mitochondrion, Biology, medicine.disease_cause, Biochemistry, Article, Antioxidants, chemistry.chemical_compound, Physiology (medical), Mitophagy, Autophagy, medicine, Humans, Reactive nitrogen species, NAD, Mitochondria, Cell biology, Oxidative Stress, Metabolic pathway, Cytosol, Glucose, chemistry, Lysosomes, Reactive Oxygen Species, Oxidation-Reduction, Metabolic Networks and Pathways, Oxidative stress
Abstract

It has been established that the key metabolic pathways of glycolysis and oxidative phosphorylation are intimately related to redox biology through control of cell signaling. Under physiological conditions glucose metabolism is linked to control of the NADH/NAD redox couple, as well as providing the major reductant, NADPH, for thiol-dependent antioxidant defenses. Retrograde signaling from the mitochondrion to the nucleus or cytosol controls cell growth and differentiation. Under pathological conditions mitochondria are targets for reactive oxygen and nitrogen species and are critical in controlling apoptotic cell death. At the interface of these metabolic pathways, the autophagy-lysosomal pathway functions to maintain mitochondrial quality, and generally serves an important cytoprotective function. In this review we will discuss the autophagic response to reactive oxygen and nitrogen species that are generated from perturbations of cellular glucose metabolism and bioenergetic function.

Published
2013
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120. Mitochondrial genetic background modulates bioenergetics and susceptibility to acute cardiac volume overload

Author

Louis J. Dell'Italia, Jessica L. Fetterman, Douglas R. Moellering, Chih-Chang Wei, Wayne E. Bradley, Scott W. Ballinger, Victor M. Darley-Usmar, Melissa J Sammy, Jinju Zhang, Danny R. Welch, Blake R. Zelickson, Balu K. Chacko, Xuemei Cao, Larry W. Johnson, Kimberly J. Dunham-Snary, Michelle S. Johnson, Robert A. Kesterson, Melissa Pompilius, David G. Westbrook, and Theodore G. Schurr

Subjects
Mitochondrial ROS, Mitochondrial DNA, Bioenergetics, DNA damage, Cardiac Volume, Volume overload, Mitochondrion, Biology, medicine.disease_cause, DNA, Mitochondrial, Biochemistry, Article, Mice, Microscopy, Electron, Transmission, medicine, Animals, Genetic Predisposition to Disease, Molecular Biology, Genetics, chemistry.chemical_classification, Mice, Inbred C3H, Reactive oxygen species, NADH Dehydrogenase, Cell Biology, Mitochondria, Mice, Inbred C57BL, Oxidative Stress, chemistry, Energy Metabolism, Reactive Oxygen Species, Oxidative stress, DNA Damage
Abstract

Dysfunctional bioenergetics has emerged as a key feature in many chronic pathologies such as diabetes and cardiovascular disease. This has led to the mitochondrial paradigm in which it has been proposed that mitochondrial DNA (mtDNA) sequence variation contributes to disease susceptibility. In this study we present a novel animal model of mtDNA polymorphisms, the mitochondrial nuclear exchange mouse (MNX), in which the mtDNA from C3H/HeN mouse has been inserted onto the C57/BL6 nuclear background and vice versa to test this concept. Our data show a major contribution of the C57/BL6 mtDNA to the susceptibility to the pathological stress of cardiac volume overload which is independent of the nuclear background. Mitochondria harboring the C57/BL6J mtDNA generate more reactive oxygen species (ROS) and have a higher mitochondrial membrane potential relative to those having the C3H/HeN mtDNA, independent of nuclear background. We propose this is the primary mechanism associated with increased bioenergetic dysfunction in response to volume overload. In summary, these studies support the “mitochondrial paradigm” for the development of disease susceptibility, and show that the mtDNA modulates, cellular bioenergetics, mitochondrial reactive oxygen species generation and susceptibility to cardiac stress.

Published
2013
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121. Dysfunctional mitochondrial bioenergetics and oxidative stress in Akita+/Ins2-derived β-cells

Author

Balu K. Chacko, Akio Koizumi, Victor M. Darley-Usmar, D. Ray Moore, Jianhua Zhang, Michelle S. Johnson, Ying Gai, Xiaoyong Lei, Sasanka Ramanadham, Tanecia Mitchell, Stephen Barnes, Kasturi Mitra, and Xiaosen Ouyang

Subjects
Male, endocrine system, medicine.medical_specialty, Thapsigargin, endocrine system diseases, Physiology, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Blotting, Western, Mitochondrion, Biology, Real-Time Polymerase Chain Reaction, medicine.disease_cause, DNA, Mitochondrial, Diabetes Mellitus, Experimental, Mice, chemistry.chemical_compound, Cell Line, Tumor, Insulin-Secreting Cells, Physiology (medical), Internal medicine, Mitophagy, Autophagy, medicine, Animals, Insulin, Glucose homeostasis, Superoxide Dismutase, Endoplasmic reticulum, Articles, Endoplasmic Reticulum Stress, Mitochondria, Mice, Inbred C57BL, Oxidative Stress, Endocrinology, chemistry, Unfolded protein response, Energy Metabolism, Oxidative stress
Abstract

Insulin release from pancreatic β-cells plays a critical role in blood glucose homeostasis, and β-cell dysfunction leads to the development of diabetes mellitus. In cases of monogenic type 1 diabetes mellitus (T1DM) that involve mutations in the insulin gene, we hypothesized that misfolding of insulin could result in endoplasmic reticulum (ER) stress, oxidant production, and mitochondrial damage. To address this, we used the Akita+/Ins2T1DM model in which misfolding of the insulin 2 gene leads to ER stress-mediated β-cell death and thapsigargin to induce ER stress in two different β-cell lines and in intact mouse islets. Using transformed pancreatic β-cell lines generated from wild-type Ins2+/+(WT) and Akita+/Ins2mice, we evaluated cellular bioenergetics, oxidative stress, mitochondrial protein levels, and autophagic flux to determine whether changes in these processes contribute to β-cell dysfunction. In addition, we induced ER stress pharmacologically using thapsigargin in WT β-cells, INS-1 cells, and intact mouse islets to examine the effects of ER stress on mitochondrial function. Our data reveal that Akita+/Ins2-derived β-cells have increased mitochondrial dysfunction, oxidant production, mtDNA damage, and alterations in mitochondrial protein levels that are not corrected by autophagy. Together, these findings suggest that deterioration in mitochondrial function due to an oxidative environment and ER stress contributes to β-cell dysfunction and could contribute to T1DM in which mutations in insulin occur.

Published
2013
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122. Mitochondria-targeted heme oxygenase-1 decreases oxidative stress in renal epithelial cells

Author

Anupam Agarwal, Karina C. Ricart, Stephen Barnes, Victor M. Darley-Usmar, Ravindra Boddu, Gloria A. Benavides, Abolfazl Zarjou, Subhashini Bolisetty, Michelle S. Johnson, Amie M. Traylor, Ray Moore, and Aimee Landar

Subjects
Hemeprotein, Voltage-dependent anion channel, Cell Survival, Physiology, Blotting, Western, Citric Acid Cycle, Citrate (si)-Synthase, Mitochondrion, Biology, Kidney, Klinikai orvostudományok, medicine.disease_cause, Electron Transport Complex IV, chemistry.chemical_compound, medicine, Humans, Voltage-Dependent Anion Channels, Heme, Membrane Potential, Mitochondrial, chemistry.chemical_classification, Reactive oxygen species, Cytochromes c, Epithelial Cells, Orvostudományok, Immunohistochemistry, Aerobiosis, Mitochondria, Cell biology, Heme oxygenase, Oxidative Stress, Cytosol, HEK293 Cells, chemistry, Biochemistry, Call for Papers, biology.protein, Heme Oxygenase-1, Oxidative stress, Plasmids
Abstract

Mitochondria are both a source and target of the actions of reactive oxygen species and possess a complex system of inter-related antioxidants that control redox signaling and protect against oxidative stress. Interestingly, the antioxidant enzyme heme oxygenase-1 (HO-1) is not present in the mitochondria despite the fact that the organelle is the site of heme synthesis and contains multiple heme proteins. Detoxification of heme is an important protective mechanism since the reaction of heme with hydrogen peroxide generates pro-oxidant ferryl species capable of propagating oxidative stress and ultimately cell death. We therefore hypothesized that a mitochondrially localized HO-1 would be cytoprotective. To test this, we generated a mitochondria-targeted HO-1 cell line by transfecting HEK293 cells with a plasmid construct containing the manganese superoxide dismutase mitochondria leader sequence fused to HO-1 cDNA (Mito-HO-1). Nontargeted HO-1-overexpressing cells were generated by transfecting HO-1 cDNA (HO-1) or empty vector (Vector). Mitochondrial localization of HO-1 with increased HO activity in the mitochondrial fraction of Mito-HO-1 cells was observed, but a significant decrease in the expression of heme-containing proteins occurred in these cells. Both cytosolic HO-1- and Mito-HO-1-expressing cells were protected against hypoxia-dependent cell death and loss of mitochondrial membrane potential, but these effects were more pronounced with Mito-HO-1. Furthermore, decrement in production of tricarboxylic acid cycle intermediates following hypoxia was significantly mitigated in Mito-HO-1 cells. These data suggest that specific mitochondrially targeted HO-1 under acute pathological conditions may have beneficial effects, but the selective advantage of long-term expression is constrained by a negative impact on the synthesis of heme-containing mitochondrial proteins.

Published
2013
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123. Utilization of fluorescent probes for the quantification and identification of subcellular proteomes and biological processes regulated by lipid peroxidation products

Author

Ashlee N. Higdon, Balu K. Chacko, Louis J. Dell'Italia, Jianhua Zhang, Philip A. Kramer, Victor M. Darley-Usmar, Joshua K. Salabei, Timothy D. Cummins, Bradford G. Hill, and Daniel W. Riggs

Subjects
Proteome, Autophagy, Mitochondrion, medicine.disease_cause, Biochemistry, Article, 4-Hydroxynonenal, Lipid peroxidation, Oxidative Stress, chemistry.chemical_compound, chemistry, Lipid oxidation, Physiology (medical), Organelle, medicine, Lipid Peroxidation, Oxidative stress, Fluorescent Dyes
Abstract

Oxidative modifications to cellular proteins are critical in mediating redox-sensitive processes such as autophagy, the antioxidant response, and apoptosis. The proteins that become modified by reactive species are often compartmentalized to specific organelles or regions of the cell. Here, we detail protocols for identifying the subcellular protein targets of lipid oxidation and for linking protein modifications with biological responses such as autophagy. Fluorophores such as BODIPY-labeled arachidonic acid or BODIPY-conjugated electrophiles can be paired with organelle-specific probes to identify specific biological processes and signaling pathways activated in response to oxidative stress. In particular, we demonstrate “negative” and “positive” labeling methods using BODIPY-tagged reagents for examining oxidative modifications to protein nucleophiles. The protocol describes the use of these probes in slot immunoblotting, quantitative Western blotting, in-gel fluorescence, and confocal microscopy techniques. In particular, the use of the BODIPY fluorophore with organelle- or biological process-specific dyes and chromophores is highlighted. These methods can be used in multiple cell types as well as isolated organelles to interrogate the role of oxidative modifications in regulating biological responses to oxidative stress.

Published
2013
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124. Convergent mechanisms for dysregulation of mitochondrial quality control in metabolic disease: implications for mitochondrial therapeutics

Author

Shannon M. Bailey, Scott W. Ballinger, Jianhua Zhang, Balu K. Chacko, Victor M. Darley-Usmar, and Tanecia Mitchell

Subjects
Quality Control, Alcoholic liver disease, Bioenergetics, Context (language use), Oxidative phosphorylation, Biology, Mitochondrion, Bioinformatics, medicine.disease, medicine.disease_cause, Biochemistry, Article, Mitochondria, Oxidative Stress, Metabolic Diseases, Mitophagy, medicine, Humans, Precision Medicine, Steatosis, Oxidative stress, Signal Transduction
Abstract

Mitochondrial dysfunction is associated with a broad range of pathologies including diabetes, ethanol toxicity, metabolic syndrome and cardiac failure. It is now becoming clear that maintaining mitochondrial quality through a balance between biogenesis, reserve capacity and mitophagy is critical in determining the response to metabolic or xenobiotic stress. In diseases associated with metabolic stress, such as Type II diabetes and non-alcoholic and alcoholic steatosis, the mitochondria are subjected to multiple ‘hits’ such as hypoxia and oxidative and nitrative stress, which can overwhelm the mitochondrial quality control pathways. In addition, the underlying mitochondrial genetics that evolved to accommodate high-energy demand, low-calorie supply environments may now be maladapted to modern lifestyles (low-energy demand, high-calorie environments). The pro-oxidant and pro-inflammatory environment of a sedentary western lifestyle has been associated with modified redox cell signalling pathways such as steatosis, hypoxic signalling, inflammation and fibrosis. These data suggest that loss of mitochondrial quality control is intimately associated with the aberrant activation of redox cell signalling pathways under pathological conditions. In the present short review, we discuss evidence from alcoholic liver disease supporting this concept, the insights obtained from experimental models and the application of bioenergetic-based therapeutics in the context of maintaining mitochondrial quality.

Published
2013
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125. Mitochondrially targeted compounds and their impact on cellular bioenergetics

Author

Michael P. Murphy, Colin Reily, Victor M. Darley-Usmar, Tanecia Mitchell, Balu K. Chacko, and Gloria A. Benavides

Subjects
Antioxidant, medicine.medical_treatment, Clinical Biochemistry, Mitochondrion, MitoQ, Biochemistry, Oligo, Oligomycin, chemistry.chemical_compound, 0302 clinical medicine, BTPP, butyl triphenylphosphonium, OCR, oxygen consumption rate, lcsh:QH301-705.5, chemistry.chemical_classification, lcsh:R5-920, 0303 health sciences, Respiration, Mitochondria, 3. Good health, MitoE, Mito Vitamin E, FCCP, carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone, 030220 oncology & carcinogenesis, MitoQ, Mitoquinone, lcsh:Medicine (General), Research Paper, Cell signaling, Extracellular flux, Oxidative phosphorylation, Biology, RNS, reactive nitrogen species, Redox, 03 medical and health sciences, ROS, reactive oxygen species, medicine, MES-13, murine mesangial cells, 030304 developmental biology, DTPP, decyl triphenylphosphonium, Reactive oxygen species, ECAR, extracellular acidification rate, Organic Chemistry, TPP+, triphenylphosphonium, TPP+ derivatives, AA, Antimycin A, TPMP, triphenylmethylphosphonium, In vitro, lcsh:Biology (General), chemistry, Cell culture, Mitochondrial targeted compounds
Abstract

Mitochondria are recognized as critical sites of localized injury in a number of chronic pathologies which has led to the development of organelle directed therapeutics. One of the approaches employed to target molecules to the mitochondrion is to conjugate a delocalized cation such as triphenylphosphonium (TPP+) to various redox active compounds. Mitochondrially targeted antioxidants have also been used in numerous cell culture based studies as probes of the contribution of the mitochondrial generation of reactive oxygen species on cell signaling events. However, concentrations used in vitro are typically 10–100 times greater than those generated from oral dosing in a wide range of animal models and in humans. In the present study, we determined the effects of mitochondrial targeted antioxidants, MitoQ, MitoTempol, and MitoE on cellular bioenergetics of mesangial cells in culture and compared these to TPP+ conjugated compounds which lack the antioxidant functional group. We found that all TPP+ compounds inhibited oxidative phosphorylation to different extents independent of the antioxidant functional groups. These findings show that the TPP+ moiety can disrupt mitochondrial function at concentrations frequently observed in cell culture and this behavior is dependent on the linker group and independent of antioxidant properties. Moreover, the TPP+ moiety alone is unlikely to achieve the concentrations needed to contribute to the protective mechanisms of the mitochondrially targeted compounds that have been reported in vivo., Graphical abstract Highlights ► Mitochondrial targeted antioxidants are conjugated to a triphenylphosphonium cation (TPP+) moiety that allows the compound to accumulate within the mitochondria. ► The effect of MitoQ, MitoTempol, and MitoE and their TPP+ carrier groups on oxidative phosphorylation was examined. ► Higher concentrations of TPP+ conjugated compounds alter cellular bioenergetics independent of the functional antioxidant group. ► Many of the effects ascribed to mitochondrial oxidant scavenging by these compounds in cell culture may be nonspecific effects of the carrier molecule.

Published
2013
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126. O-GlcNAcylation and neurodegeneration

Author

Willayat Yousuf Wani, Lori L. McMahon, John C. Chatham, Jianhua Zhang, and Victor M. Darley-Usmar

Subjects
0301 basic medicine, Huntingtin, Glycosylation, Glycoside Hydrolases, Acylation, Biology, N-Acetylglucosaminyltransferases, Neuroprotection, Article, Acetylglucosamine, Serine, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Alzheimer Disease, medicine, Animals, Humans, General Neuroscience, Neurodegeneration, Brain, Proteins, Neurodegenerative Diseases, medicine.disease, Transmembrane protein, beta-N-Acetylhexosaminidases, carbohydrates (lipids), 030104 developmental biology, Biochemistry, chemistry, Synuclein, Phosphorylation, Protein Processing, Post-Translational, 030217 neurology & neurosurgery
Abstract

O-GlcNAcylation is a dynamic form of protein glycosylation which involves the addition of β-d-N-acetylglucosamine (GlcNAc) via an O-linkage to serine or threonine residues of nuclear, cytoplasmic, mitochondrial and transmembrane proteins. The two enzymes responsible for O-GlcNAc cycling are O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA); their expression and activities in brain are age dependent. More than 1000 O-GlcNAc protein targets have been identified which play critical roles in many cellular processes. In mammalian brain, O-GlcNAc modification of Tau decreases its phosphorylation and toxicity, suggesting a neuroprotective role of pharmacological elevation of brain O-GlcNAc for Alzheimer's disease treatment. Other observations suggest that elevating O-GlcNAc levels may decrease protein clearance or induce apoptosis. This review highlights some of the key findings regarding O-GlcNAcylation in models of neurodegenerative diseases.

Published
2016

127. Redox Biology and the Interface Between Bioenergetics, Autophagy and Circadian Control of Metabolism

Author

Jianhua Zhang, Martin E. Young, Adam R. Wende, Victor M. Darley-Usmar, John C. Chatham, and Namakkal S. Rajasekaran

Subjects
0301 basic medicine, Bioenergetics, Circadian clock, Metabolic network, PINK1, Biology, medicine.disease_cause, Biochemistry, Article, Acetylglucosamine, 03 medical and health sciences, Physiology (medical), Circadian Clocks, medicine, Autophagy, Animals, Humans, Kelch-Like ECH-Associated Protein 1, Cell biology, Mitochondria, Metabolic pathway, Oxidative Stress, 030104 developmental biology, Metabolic control analysis, Energy Metabolism, Oxidation-Reduction, Protein Processing, Post-Translational, Oxidative stress, Signal Transduction
Abstract

Understanding molecular mechanisms that underlie the recent emergence of metabolic diseases such as diabetes and heart failure has revealed the need for a multi-disciplinary research integrating the key metabolic pathways which change the susceptibility to environmental or pathologic stress. At the physiological level these include the circadian control of metabolism which aligns metabolism with temporal demand. The mitochondria play an important role in integrating the redox signals and metabolic flux in response to the changing activities associated with chronobiology, exercise and diet. At the molecular level this involves dynamic post-translational modifications regulating transcription, metabolism and autophagy. In this review we will discuss different examples of mechanisms which link these processes together. An important pathway capable of linking signaling to metabolism is the post-translational modification of proteins by O-linked N-acetylglucosamine (O-GlcNAc). This is a nutrient regulated protein modification that plays an important role in impaired cellular stress responses. Circadian clocks have also emerged as critical regulators of numerous cardiometabolic processes, including glucose/lipid homeostasis, hormone secretion, redox status and cardiovascular function. Central to these pathways are the response of autophagy, bioenergetics to oxidative stress, regulated by Keap1/Nrf2 and mechanisms of metabolic control. The extension of these ideas to the emerging concept of bioenergetic health will be discussed.

Published
2016

128. Assessing Cardiac Metabolism A Scientific Statement From the American Heart Association

Author

E. Dale Abel, Victor M. Darley-Usmar, Stefan Neubauer, Fabio A. Recchia, Heinrich Taegtmeyer, Martin E. Young, Craig R. Malloy, Michael A. Portman, Linda R. Peterson, Jan F. C. Glatz, Robert J. Gropler, Gary D. Lopaschuk, Christine Des Rosiers, Robert E. Gerszten, Jennifer E. Van Eyk, Julian L. Griffin, Thomas J. Wang, Jorge R. Kizer, E. Douglas Lewandowski, Henri Brunengraber, Hermann Georg Holzhuetter, RS: CARIM - R2.06 - Intermediate cardiac metabolism, Moleculaire Genetica, and Genetica & Celbiologie

Subjects
0301 basic medicine, Dynamic field, cardiac, Physiology, Energy transfer, Systems biology, Cardiovascular research, Cardiac metabolism, Computational biology, 030204 cardiovascular system & hematology, Biology, 03 medical and health sciences, 0302 clinical medicine, Animals, Humans, metabolic pathways, molecular biology, Radionuclide imaging, radionuclide imaging, Myocardium, metabolism, cardiac, Computational Biology, systems biology, American Heart Association, United States, AHA Scientific Statements, Cardiac Imaging Techniques, 030104 developmental biology, Cardiovascular Diseases, Cardiology and Cardiovascular Medicine, metabolism
Abstract

In a complex system of interrelated reactions, the heart converts chemical energy to mechanical energy. Energy transfer is achieved through coordinated activation of enzymes, ion channels, and contractile elements, as well as structural and membrane proteins. The heart's needs for energy are difficult to overestimate. At a time when the cardiovascular research community is discovering a plethora of new molecular methods to assess cardiac metabolism, the methods remain scattered in the literature. The present statement on "Assessing Cardiac Metabolism" seeks to provide a collective and curated resource on methods and models used to investigate established and emerging aspects of cardiac metabolism. Some of those methods are refinements of classic biochemical tools, whereas most others are recent additions from the powerful tools of molecular biology. The aim of this statement is to be useful to many and to do justice to a dynamic field of great complexity. ? 2016 American Heart Association, Inc.

Published
2016

129. Abrogation of Nrf2 impairs antioxidant signaling and promotes atrial hypertrophy in response to high-intensity exercise stress

Author

Sethu Palaniappan, Gobinath Shanmugam, Namakkal S. Rajasekaran, Asokan Devarajan, Ganesh V. Halade, Jennifer Hong, John R. Hoidal, Madhusudhanan Narasimhan, Jianhua Zhang, Victor M. Darley-Usmar, and Radhakrishnan Rajesh Kumar

Subjects
0301 basic medicine, Aging, medicine.medical_specialty, GPX1, Transcription, Genetic, NF-E2-Related Factor 2, Down-Regulation, Fluorescent Antibody Technique, Bioinformatics, medicine.disease_cause, Models, Biological, Antioxidants, General Biochemistry, Genetics and Molecular Biology, Muscle hypertrophy, 03 medical and health sciences, Stress, Physiological, Physical Conditioning, Animal, Internal medicine, Gene expression, Autophagy, medicine, Animals, Heart Atria, Medicine(all), chemistry.chemical_classification, Reactive oxygen species, Biochemistry, Genetics and Molecular Biology(all), Nrf2 knockout, business.industry, Research, Hypertrophy, General Medicine, Glutathione, Ubiquitinated Proteins, Mice, Inbred C57BL, Oxidative Stress, 030104 developmental biology, Endocrinology, GCLC, chemistry, Atrial hypertrophy, Lipid Peroxidation, Signal transduction, Reactive Oxygen Species, business, Gene Deletion, Oxidative stress, Signal Transduction
Abstract

Background Anomalies in myocardial structure involving myocyte growth, hypertrophy, differentiation, apoptosis, necrosis etc. affects its function and render cardiac tissue more vulnerable to the development of heart failure. Although oxidative stress has a well-established role in cardiac remodeling and dysfunction, the mechanisms linking redox state to atrial cardiomyocyte hypertrophic changes are poorly understood. Here, we investigated the role of nuclear erythroid-2 like factor-2 (Nrf2), a central transcriptional mediator, in redox signaling under high intensity exercise stress (HIES) in atria. Methods Age and sex-matched wild-type (WT) and Nrf2−/− mice at >20 months of age were subjected to HIES for 6 weeks. Gene markers of hypertrophy and antioxidant enzymes were determined in the atria of WT and Nrf2–/– mice by real-time qPCR analyses. Detection and quantification of antioxidants, 4-hydroxy-nonenal (4-HNE), poly-ubiquitination and autophagy proteins in WT and Nrf2−/− mice were performed by immunofluorescence analysis. The level of oxidative stress was measured by microscopical examination of di-hydro-ethidium (DHE) fluorescence. Results Under the sedentary state, Nrf2 abrogation resulted in a moderate down regulation of some of the atrial antioxidant gene expression (Gsr, Gclc, Gstα and Gstµ) despite having a normal redox state. In response to HIES, enlarged atrial myocytes along with significantly increased gene expression of cardiomyocyte hypertrophy markers (Anf, Bnf and β-Mhc) were observed in Nrf2−/− when compared to WT mice. Further, the transcript levels of Gclc, Gsr and Gstµ and protein levels of NQO1, catalase, GPX1 were profoundly downregulated along with GSH depletion and increased oxidative stress in Nrf2−/− mice when compared to its WT counterparts after HIES. Impaired antioxidant state and profound oxidative stress were associated with enhanced atrial expression of LC3 and ATG7 along with increased ubiquitination of ATG7 in Nrf2−/− mice subjected to HIES. Conclusions Loss of Nrf2 describes an altered biochemical phenotype associated with dysregulation in genes related to redox state, ubiquitination and autophagy in HIES that result in atrial hypertrophy. Therefore, our findings direct that preserving Nrf2-related antioxidant function would be one of the effective strategies to safeguard atrial health.

Published
2016
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130. Erratum

Author

Sascha Martens, Masashi Narita, Rajkumar Cheluvappa, Kevin A. Roth, Ta Yuan Chang, Kartik Venkatachalam, Chang-Shen Lin, Sharon G. Adler, Flaminia Pavone, Dianwen Ju, Michelle A. Ozbun, Michael R. Duchen, Shu Feng Zhou, Wei-Guo Zhu, Aaron Di Antonio, Defeng Wu, Taixing Cui, Xu Guang Guo, Zhiping Xie, Lorena García Nannig, Eloy Bejarano, Stéphane D. Lemaire, Petro Starokadomskyy, Hyung Ryong Kim, Mario Pinar, Rebecca T. Marquez, Zvenyslava Husak, Anthony R. White, Joanna Poulton, Antonis S. Zervos, Shweta Sharma, Jochen Walter, Nicholas T. Ktistakis, Christopher H.K. Cheng, Sunhee Lee, Yuen Li Chung, Howard O. Fearnhead, Young J. Oh, Ivano Amelio, Guillermo A. Blanco, Jan Simak, Junfang Wu, Yingying Lu, Mary Kate McBrayer, Soo Han Bae, Ichizo Nishino, Hong-Ming Hu, Benjamin R. Underwood, Tomonori Kimura, Zexian Liu, Savithrama P. Dinesh-Kumar, Qian Yang, Andreas Kern, Hsing Jien Kung, Jan B. Parys, Cam Patterson, Celine Perier, Toshiro Okazaki, Daisuke Koya, Avinash Sonawane, Cédric Cleyrat, Robert I. Richards, Kai Y. Soo, Rodrigo Mora-Rodriguez, Gigi N.C. Chiu, Moon Moo Kim, Vladimir N. Uversky, Shengfang Ge, Matthew T. V. Chan, Irene Kyrmizi, Lara Gibellini, Ángela M. Valverde, Erik Norberg, Fan Zhang, Jan C. Koch, Alec C. Kimmelman, Jingfang Ju, Jie Bai, Lei Duan, Paulina Ordonez, Shuwen Liu, Wolfdieter Springer, Eric Deutsch, Elena Ortona, Jose M. Seguí-Simarro, Vinay Choubey, Leonidas Stefanis, Robert G. Hawley, Claudia Bincoletto, Xian-Hui He, Zhifen Yang, Thomas M. Durcan, Martine Biard-Piechaczyk, Kui Lin, Hongming Pan, Konstantinos Kambas, Cristina Muñoz-Pinedo, Marta Magariños, Yoshinori Takahashi, Adrienne M. Gorman, Philippe Gailly, Takahiko Akematsu, Justine D. Mintern, Liang Xu, Tetsuo Shioi, Luis M. Botana, Yule Liu, Yong Yeon Cho, Jinzhi Lei, Eung Kweon Kim, Alakananda Basu, Vikash Kumar Dubey, Candelaria Gomez-Manzano, Avital Eisenberg-Lerner, Chuan-Ming Xie, Wenjie Dai, Pedro Gonzalez-Alegre, Maria Condello, Zheng-Hong Qin, Zhi-Min Yuan, Catherine Andreadi, Anna Rita Migliaccio, Chong Liu, Michaël Boyer-Guittaut, Melanie Denizot, Esperanza Arias, Greet Van den Berghe, Guomei Tang, Timothy P. Devarenne, Xianyong Sheng, Louis R. Lapierre, J. Wade Harper, Zuzana Storchova, Aileen R. Ariosa, Sug Hyung Lee, Qi Zeng, Godefridus J. Peters, Daniela L. Papademetrio, Alexandre Arcaro, Zhiyuan Yao, Pablo Iribarren, Mario Chiariello, Maria Rosaria Torrisi, Parimal Karmakar, Yong Huang, Sebastiano Sciarretta, Nathalie Andrieu-Abadie, László Fésüs, Patricia Boya, Ruediger Rudolf, Leonor Miller-Fleming, Vasilis J. Promponas, Juan Segura-Aguilar, Paula Daza, Shiow Ju Lee, Songshu Meng, Paul K. Herman, Ludwig Eichinger, Ye-Guang Chen, Kay F. Macleod, Thomas Simmet, Cristina Corral-Ramos, Claudio Brancolini, Jun Ren, Ying Jiang, Benoît Derrien, Xiao Fang Yu, Qing Zhong, Zong Wan Mao, Xingcong Ren, Armando A. Genazzani, Marina Pierdominici, Sanbing Shen, Sandra Moreno, Hana Algül, Maurizio Renna, Ricardo Sánchez-Prieto, Ashok K. Saluja, Yasuo Uchiyama, Pope L. Moseley, Victor E. Dosenko, Chun-Feng Liu, Bakhos A. Tannous, Efthimios Sivridis, Baharia Mograbi, Michiko Shintani, Amanda S. Bess, Rodrigo Portes Ureshino, Avnika A. Ruparelia, Paul Hofman, Eric Chevet, Martha M. Monick, Hong Gang Wang, Daping Fan, Jorge Moscat, Giuseppe Matarese, Consiglia Pacelli, Young Seok Cho, Miriam Cnop, Stefan Böckler, Nikolai V. Gorbunov, Christina J. Sigurdson, Hang T.T. Nguyen, Aurélie François, Katarina Kågedal, Sam Gandy, Silvia Campello, Alain Bruhat, Filomena Fiorito, Hua Feng, Man Tian Mi, Gian Maria Fimia, Masaki Tanaka, Guofei Zhou, José L. Crespo, Heinz Jungbluth, Anna Chiara Nascimbeni, Arianne L. Theiss, Svetlana Dokudovskaya, Mar Lorente, Sergio Lavandero, Yu Xia Zhao, Fangming Lin, Yuchen Feng, Gad Galili, Silvia Cetrullo, Paula I. Moreira, Dhyan Chandra, Dimitrios J. Stravopodis, Roberta A. Gottlieb, Gregory A. Taylor, Longping Wen, Faqiang Li, Marco Sardiello, Umesh K. Jinwal, Francesca Belleudi, Lan Tan, Livia Di Renzo, Tamas Korcsmaros, Xinbing Sui, Douglas R. Green, Guillermo Mazzolini, Hervé Le Stunff, Kelly S. Doran, Mary E. Choi, Carlos S. Subauste, Natalia Rodriguez-Muela, Nicholas J. Talbot, Marta Palmieri, Sonia Hernández-Tiedra, Ligia C. Gomes, Irving M. Shapiro, Makoto Ubukata, Mario P. Tschan, Baris Bingol, Benjamin Loos, Terry Kwok, Luca M. Neri, Sreejayan Nair, Michele Wolfe Bianchi, Ralf Erdmann, Alexander Greenhough, Neeraj Vij, Jeong Hun Kim, Satoaki Matoba, Bo Liu, George R. Beck, Michael Moore, Vrajesh V. Parekh, Kyle A. Bauckman, Li-Lin Du, Mikihiro Fujiya, Yan G. Zhao, Renaud Legouis, Jiangwei Zhang, Kailiang Jia, Nadezda Apostolova, Sehamuddin Galadari, Khosrow Adeli, Ming Yong Zhang, Carmela Fusco, Angel Ortega, Anna Pensalfini, Zsuzsanna Szatmári, Marco Tafani, Isabella Ceccherini, Anne Hamacher-Brady, Kuen Jer Tsai, Anita C. Truttmann, Franco Fortunato, Keisuke Miyazawa, Chunhai Fan, Berge A. Minassian, Jian Zhang, Frank A. Anania, Heesun Cheong, Amal O. Amer, Ing Swie Goping, Won-Ki Huh, Anita Solhaug, Joan Cl ria, Laurent Le Cam, Seungmin Hwang, Karen L. Wright, Antonella De Matteis, Troy T. Rohn, Ivana Bjedov, Subbiah Pugazhenthi, Hal E. Broxmeyer, Xue Yuan Bai, Koenraad Norga, Minnie M. Sarwal, Daniel F. Schorderet, Ioannis P. Nezis, Mei Qing Wang, Jun Hee Lee, Yong J. Lee, David A. Tumbarello, Fernando Macian, Joern Dengjel, Dmitry V. Bulavin, Andrew J. Halayko, Ben Berkhout, Aseem Pandey, Santosh Kesari, Karin Przyklenk, Elena V. Tchetina, Matthew L. Albert, Laura Segatori, Joel N. Meyer, Mustapha Rouis, Éva Margittai, Ashish Jain, David Hahn, Thomas Vaccari, Lori R. Covey, Ghanshyam Swarup, Kuo Yang Huang, Gennaro Napolitano, Sam W. Lee, Seong Who Kim, Alberto Anel, Vladimir V. Rogov, Laura A. Carleton, Amine Belaid, Byoung Kuk Jang, Sheng-Han Kuo, Patricia L. Yeyati, Jae U. Jung, Teresa Zoladek, Sabrina Di Bartolomeo, Clémence Richetta, Peixin Yang, Daniela Trisciuoglio, Hye Seung Jung, Katsumi Higaki, Eui-Bae Jeung, Ivan Topisirovic, Isabella Caniggia, Susan E. Logue, Issidora S. Papassideri, Lynda A. Morrison, Caihong Wang, Graeme Sargent, Beth Levine, Mingxiang Ye, David M. Sabatini, Consuelo Amantini, Julio A. Aguirre-Ghiso, Lawrence H. Boise, Patricia Silvia Romano, Sean T. Sweeney, Takayuki Tsukuba, Reinhard Dechant, Benoit Barbeau, Marta Martinez-Vicente, Kuo How Huang, Edésio José Tenório de Melo, Faustino Mollinedo, José M. Fuentes, Joaquín Jordán, Dong-Hyung Cho, Dexian Zheng, Jeroen J.M. Hoozemans, Zhong Chen, Waleska Kerllen Martins, Abraham Acevedo Arozena, Marcos P. Thomé, Gordon C. Shore, Fabienne C. Fiesel, Teng Jiang, Feng Han, Marc Poirot, Anne Sophie Nicot, Eileen White, Olivier Feron, Arthur I. Cederbaum, Wen Bin Qian, Yingjie Sun, Rejko Krüger, Shingo Kajimura, Jianzhen Xu, Shang Der Chen, Maximiliano G. Gutierrez, Zhengping Yu, Jiaren Sun, Utpal Sen, Giovanna Galliciotti, Hilde Nilsen, Benjamin T. Kopp, Benedikt Westermann, Inmaculada Galindo, Eeva-Liisa Eskelinen, Rubem F. S. Menna-Barreto, Guillermo Mariño, Andrea Ballabio, Izabela Poprawa, Yanjin Zhang, Clay F. Semenkovich, Martin E. Fernandez-Zapico, Helin Vakifahmetoglu-Norberg, Hongchi Jiang, Eugenia Morselli, Angelo A. Manfredi, Marianne Boes, Han-Jung Chae, Covadonga Alonso, Min Chen, Safia Costes, David Kessel, Rakesh Kumar, Yang Zhang, Reinhild Prange, Vassiliki E. Mpakou, Laura Santambrogio, Javier E. Irazoqui, Anna Skwarska, Junichi Sadoshima, Rika Umemiya-Shirafuji, Michael I. Koukourakis, Norma Maugeri, Yuqing Wang, Pedro R. Cutillas, Jiqin Lian, Jiri Stulik, Takashi Ueno, Craig Montell, Rena Balzan, Meiyan Jin, Mara C. Duncan, Cathleen R. Carlin, Yasuo Yanagi, Maite G. Fernandez-Barrena, Yuyan Xiong, Martin Graef, Wei Yuan Yang, Renato V. Iozzo, Mark Screen, Patrick Brest, Haichao Wang, Ming Tan, Werner J. Kovacs, Weili Shen, Alessandro Fraldi, Paul Saftig, Alberto Faggioni, Krisna Prak, Christos E. Zois, Timothy E. Weaver, Marc Lecuit, Yu-Ying He, Michele Caraglia, Walter Balduini, M. Isabel G. Roncero, B. Schneider, Monika Cahova, Mathias Faure, Chihiro Sasakawa, Simon Michaeli, Sandy Giuliano, Dario C. Altieri, Eun-Kyeong Jo, Myung-Shik Lee, Carol Imbriano, John H. Brumell, Gustavo H. Goldman, Yan Wang, Junyan Shi, Quan Chen, Jayanta Debnath, Yonggeun Hong, Mohamed Amessou, Richard W. Wong, Robert E. Burke, Mauro De Santi, Trevor G. Shepherd, Anna Maria Joseph, Wouter G. van Doorn, Erkang Fei, Huey Lan Huang, F. Gisou van der Goot, Xinfeng Liu, Alexandru Almasan, Akiko Maeda, Yu Qiu, Yaohua Wu, Annie Sittler, Wen-Xing Ding, Wenhua Zhu, Hung-Jen Liu, Moisés Martínez-Velázquez, Jeffery S. Cox, Seung Yong Yoon, Concepcio Marin, Wilian A. Silveira, Fulvio Chiacchiera, W. Douglas Fairlie, Jian Xin Gao, Shuilong Leng, Nathan R. Brady, Josef M. Penninger, Puran Singh Sijwali, Florian Gruber, Tibor Vellai, Jiunn-Liang Ko, Laura Korhonen, Slimane Ait-Si-Ali, Hirokazu Arimoto, Alberto M. Martelli, Teresa L. M. Thurston, Chuanshan Xu, Kathrin Pallauf, Eduardo Couve, Shweta Saran, Lionel Blanc, Maylin Almonte-Beceril, Yong-Keun Jung, Lena Lavie, Junsoo Park, Camilla Palumbo, Claire H. Mitchell, Sophie Pattingre, Guillermo Velasco, Steve S.-L. Chen, Xiu-Fen Ming, Xin Qi, Vania Gelmetti, Nicolas Dupont, Soraya S. Smaili, Chinnaswamy Jagannath, Uta Dahmen, Daolin Tang, Rodrigo Franco, John H. Kehrl, Xiaonan Dong, Carsten Sachse, Jeff Kuret, Genzou Takemura, Supawadee Sukseree, Joëlle Botti, W. Haung Yu, Aurelia Lugea, Scott J. Bultman, Divaker Choubey, Frank A. Sinicrope, You-Wen He, Jian Wu, Yoshitaka Isaka, Geert Bultynck, Giuseppe Merla, Luigi Maiuri, Sonia Melino, Hannelore Maes, Daniele Lettieri Barbato, Ian G. Ganley, Zhihong Yang, Daniel Hofius, Kimberly McCall, Peiwen Chen, Istvan Lekli, Alicia Rosello, Eric Ghigo, Atsushi Kuno, Iman Tavassoly, Chris Albanese, Agustín Aranda, Salvatore Pepe, Hong Jiang, Henri Batoko, Giovanna Elvira Granato, Vincent Zecchini, Stephen E. Girardin, Maria T. Diaz-Meco, Philippe Marambaud, G. Amadoro, Sangeeta Khare, Christelle Koechlin-Ramonatxo, Emery H. Bresnick, Christian Behl, Mikio Nishimura, Julien Puyal, Wenjie Guo, Hsinyu Lee, Carolyn M. Sue, Derrick Gibbings, Alina Maloyan, Philippe Pierre, Serge N. Manié, Gerry Melino, Elizabeth A. Woodcock, Roberto Ciarcia, Liwen Jiang, Michael C. Kruer, Vladimir Trajkovic, Yunjiao Zhang, Nina Raben, Beata Pajak, Michael J. Ragusa, Riccardo Autelli, Kelly Jean Thomas, Suzana Gispert, Wei Li Zhao, Cheol Hyeon Kim, Pothana Saikumar, Arsenio Fernández-López, Juliano Machado, Valentina Iovane, Cai Ping Tan, Carmine Settembre, Neelam Azad, Yohta Shimada, Shivendra V. Singh, Hai Rao, Hirosato Mashima, Michael T. Stang, Yasuhito Sakuraba, Gemma Fabriàs, Tuck Wah Soong, Didac Carmona-Gutierrez, Ilse Vanhorebeek, F. Javier Oliver, Mondira Kundu, Alfonso Schiavi, Dan Lindholm, José L. Revuelta, Jason S. King, Susana Castro-Obregón, Paul Digard, Hua Zhu, Komal Raina, Yun Dai, Ruben K. Dagda, Nuria Martinez-Lopez, Andrea A. Gust, Lucia Notterpek, Robert Clarke, Manon E. Wildenberg, Mingzhou Chen, Leticia Reyes, Laura Berliocchi, John J. McMahon, Hongzhuan Chen, E.M. Nolte, Stefan W. Ryter, Fulvio Reggiori, Jiefei Geng, Michael A. Mandell, John H. Fingert, Holger Prokisch, Marina Jendrach, Søren R. Paludan, Elizabeth P. Henske, Ricardo Gargini, Wei-Xing Zong, Susmita Kaushik, Michael Overholtzer, Paul W. Sylvester, Daniel E. Voth, Canhua Huang, Andrea Boman, Gérard Lizard, Rut Valdor, Marc Flajolet, Graham S. Taylor, Nicola Di Daniele, Leonardo H. Travassos, Ying Yang, Anumantha G. Kanthasamy, Hasan Mukhtar, Yuhua Zhu, Noor Gammoh, Ignacio Vega-Naredo, Victoria Ryabovol, Sara W. Bird, Gang Min Hur, Qun-Ying Lei, Fan Yi, Laura Caberlotto, Maria F. Galindo, Bilal Piperdi, Leonidas C. Platanias, P. Hande Özdinler, Régis Delage-Mourroux, Julio Madrigal-Matute, Xu Liu, Nagio Takigawa, Aurora Pujol, Marta Margeta, Hee Jeong Kong, Christian Behrends, Michael Thumm, Shirley Luckhart, Emilio Clementi, John W. Steele, Liliana Schaefer, Philip L. Lorenzi, Chao-Yu Miao, She Min Lu, Jane E. Ishmael, Jin Hyoung Kim, V. Izzo, Yanming Wang, Balindiwe J.N. Sishi, Vincent Galy, Andras Perl, Shouqing Luo, Giovanni Vitale, Yongsheng Che, Rodrigo Troncoso, Liu Yang, Thomas J. Begley, Sebastien G. Bouret, Elizete Rizzo, James M. Piret, Junjun Wang, Herman P. Spaink, Thomas S. Jacques, Robin F. B. Turner, Young H. Lee, Eva Szegezdi, Daphne R. Goring, Manish K. Aghi, Rui Kang, Bart Staels, Midori Umekawa, Delia Goletti, Robert J. Bryson-Richardson, Ubaldo E. Martinez-Outschoorn, Luisa Dalla Valle, Giovanni Luca Gravina, Emad S. Alnemri, Maria Kaparakis-Liaskos, Konstantinos Ritis, Shalmoli Bhattacharyya, Alessandra Bolino, Xiaonan Zhao, Yoshihisa Watanabe, Christian Ungermann, Juan L. Iovanna, Katherine Williams, Ken Shirabe, Teresa S. Hawley, Sara Cherry, Ryuichiro Atarashi, Kozo Hamada, Seamus J. Martin, Shigeru Oshima, Mario Pende, Illana Gozes, Michel A. Duchosal, John J. Shacka, Shunhei Yamashina, Kithiganahalli Narayanaswamy Balaji, Richard L. Proia, Besim Ogretmen, Fang Hua, Koichi Araki, Charles Grose, Jia Luo, Helen K. W. Law, Charles Swanton, Liat Drucker, Guo Zhang, Zhizhuang J. Zhao, Anne K. Kenworthy, Javier A. Menendez, Gary Grant, Stig U. Andersen, Frank Lafont, Aparna Lakkaraju, Taijoon Chung, Leticia A.M. Carneiro, Monique Bernard, Gang Chen, Stephen W.G. Tait, Aimee L. Edinger, Jeffrey P. MacKeigan, Paul A. Ney, Mireia Niso-Santano, Valeria Crippa, Andreas S. Reichert, Isabelle Dugail, Jon D. Lane, Farida V. Minibayeva, Gianluca Tettamanti, Scott Pattison, Péter Lõrincz, Kamal Chowdhury, Ulrich E. Schaible, Maria Agnello, Paolo Pinton, Niels Jessen, Lei Guo, Kwang-Huei Lin, David N. Zacks, Ying Jan Wang, Simone Fulda, John J. Lemasters, Andrea Viale, Anna Maria Marconi, Valerie Askanas, Yoshitaka Nagai, François M. Vallette, Joan K. Heath, Srinivasan Dasarathy, Soo-Youl Kim, Günter U. Höglinger, Tamara Kravic-Stevovic, Iraide Alloza, Tiago F. Outeiro, Ana Serrano-Puebla, Elena A. Minina, Terrence M. Donohue, Ming Guo, Alexandra Giatromanolaki, Abdel Halim Harrath, Ken Sato, Anne Elisabeth Theron, Usha P. Andley, Claudio Cardinali, Maija Pesonen, Penny E. Lovat, Chanhee Kang, Sabah N. A. Hussain, Lisa A. Brennan, Jose A. Tapia, Christoph Becker, Huixin Yu, Pei-Yu Wang, Bertrand Joseph, Zhen Yan, Georgia Minakaki, Ricardo Escalante, Ralph A. Nixon, Katsuhiko Asanuma, M. Helena Vasconcelos, David J. Reiner, Shengkan Jin, David Dávila, Theo Rein, Balakrishna L. Lokeshwar, Antonio Miranda-Vizuete, Carl Ward, Vito Turk, Frederick D. Quinn, Katja Köhler, Masaru Harada, Kathleen Boesze-Battaglia, Fraser P. Coxon, Paulo R. Jannig, Miguel A. Peñalva, Manjula Kalia, Marco Corazzari, Chunjuan Song, Xianghua Yan, Lilach Toker, Benjamin Pineda, Vanessa Ginet, Ye Xu, Chun Jung Chen, Roberto Towns, Amy A. Kiger, Rajagopal Ramesh, Maria Rita Rippo, Joseph A. Hill, Boris Zhivotovsky, Peter Speck, Ya Hua, Peter J. Roach, Fabio Penna, Kasper M.A. Rouschop, Jeng-Jer Shieh, Maria Angeles Mena, Mei Zhao, Sonia Rocha, Xin Wen, Sylvain Lefort, Michael Scharl, Ramnik J. Xavier, Alan Cheng, Marion Bouchecareilh, Stella Y. Lee, Maria Xilouri, Qi Chen, Claudia Spies, Pengfei Ge, Natascia Ventura, Luca Galluzzi, Yau Hung Chen, Jing Pu Zhang, Diego Albani, Dingzhong Tang, Nikolai Engedal, Stefania Meschini, Maria Lyngaas Torgersen, Shibu M. Poulose, Jean-Paul Decuypere, Ziheng Xu, Jocelyn Laporte, Thierry Arnould, Albert Haas, Ida J. van der Klei, Agustín Hernández, Dong Wook Shin, Per E. Stromhaug, Valentín Ceña, Ugo Pagnini, Karolina Pakos-Zebrucka, Blagovesta Popova, Lisa M Lindqvist, Sangita C. Sinha, Yuguang Shi, Zvonimir Marelja, Robin Candau, Xin Wang, Evelina Gatti, Olatz Pampliega, Michael P. Lisanti, Elena Tamagno, Mei Lan Tan, Gary Warnes, Zdena Palková, Shigeomi Shimizu, Ingo Schmitz, Tino Kurz, Soledad Matus, Gopal Chakrabarti, Joseph J.Y. Sung, Beáta G. Vértessy, Giuliana Cassinelli, Giovanni Benard, Yin Chen, Emma Colucci-Guyon, Craig Blackstone, Lizhi Cao, Sebastian Schuck, Qingqiu Gong, Theocharis Panaretakis, Jayoung Choi, Sven R. Carlsson, Libuše Váchová, Raymond Chuen-Chung Chang, Yang Liu, Zheng Dong, Qinghua Shi, Hélène Duez, Tiziana Bachetti, Axel H. Schönthal, Sumit Sahni, Bo Wang, Naomichi Matsumoto, Markus Rehm, Liliana Torosantucci, Toren Finkel, Yi Hsin Tseng, Hsiang Cheng Chi, Fang Lin, Tony George Jacob, Ju-Xian Song, Alessandro Fanzani, Marc Tatar, Paola Costelli, Rubén Gómez-Sánchez, Yunfei Wen, Juha J. Hulmi, Francesca V. Mariani, Min Zeng, Chiung Chyi Shen, Carine Michiels, Yan Burelle, Andreas L. Serra, Goran Petrovski, Kwang Woon Kim, Paula Ludovico, Darius Ebrahimi-Fakhari, Yee Joo Tan, Luisa De Martino, Alvaro Glavic, Pierre Lapaquette, Edmund B. Rucker, Andreas Mayer, Shigeko Yamashiro, Scott K. Powers, Robert M. Gogal, Ebru Goncu, Yuichiro J. Suzuki, Anna Maria Giammarioli, Claudio Hetz, Eric H. Baehrecke, Cheryl L. Walker, Cinzia Lanzi, Deepti S. Wilkinson, Ralph Feuer, Long Yi, Virawudh Soontornniyomkij, Nektarios Tavernarakis, Nobuyuki Nukina, Elisabetta Ferraro, Thomas Wollert, Vassiliki Karantza, Simon Wilkinson, Yong Tae Kwon, Panagiotis D. Velentzas, Jong-In Park, Huu Phuc Nguyen, Miriam J. Schönenberger, Marcello Chieppa, Thomas A. Ferguson, Behzad Yeganeh, Saurabh Chatterjee, Anika Nagelkerke, Ju Hong Jeon, David W. Russ, Jeff W. Chen, Verónica I. Dumit, Chuangui Wang, Stephen C. Pak, Georgios Chamilos, Vijittra Leardkamolkarn, L. Ashley Cowart, Miguel A. Martín-Acebes, Andrea Cossarizza, László Orosz, X. Charlie Dong, Kei Watase, Yasuko Rikihisa, Santiago Rodríguez de Córdoba, Yu Jen Chen, Andrew P. Lieberman, Peter G.H. Clarke, Guylène Page, Babak Razani, Franziska Wild, Guang Zhou Zhou, Tsui-Fen Chou, Gen Sheng Wu, Daniel Johnson, Jiwu Wei, Rani Ojha, Marco Molinari, Manolis Fanto, Yongjun Jiang, Nadine Camougrand, Rong-Rong He, Ivan Dikic, Candece L. Gladson, Naoki Suzuki, Shiming Liu, Felipe X. Pimentel-Muiños, Alicia Meléndez, José Antonio Sánchez-Alcázar, Maho Hamasaki, Carmen Ruiz-Roldán, Hana Schmeisser, Margarita Villar, Vinod Sundaramoorthy, Maria Beatrice Morelli, Naweed I. Naqvi, Jochen Klucken, Nirmala Parajuli, Rodney J. Devenish, Mari L. Shinohara, J. Lindsay Whitton, Marie-Josée Boucher, Jeroen Roelofs, Xiao Hong Liu, Saverio Minucci, Germán Bou, Katie R. Martin, Hermann M. Schätzl, Suresh C. Tyagi, Shengzhou Wu, Michael T. Lotze, Albert R. La Spada, Channing J. Der, Gabriela Roca, Lucile Espert, Elisabeth Corcelle-Termeau, Zhenyu Yue, Sabine Hilfiker, Evripidis Gavathiotis, Truong Lam, Tobias M. Rasse, Kumaravel Somasundaram, Chih-Wen Shu, Tamotsu Yoshimori, Daniel T. Starczynowski, Oliver Florey, Vladimir Kirkin, Dan T. Vogl, Peter Vandenabeele, Allan Tsung, Renwick C. J. Dobson, Serge Mostowy, Nelly Godefroy, Maria Teresa Viscomi, Young Ho Koh, Caroline Mauvezin, Keiji Tanaka, Juan Fueyo, Lih-Shen Chin, Jingjing Cai, Laura D. Osellame, Maurizio Battino, Małgorzata Gajewska, Maria I. Vaccaro, Darius J.R. Lane, Yuji Ogura, Ian G. Mills, Gil Leibowitz, Joan Villarroya, Yu-Chen Hu, Maria Teresa Batista, Vojo Deretic, Manoj B. Menon, Zhenyi Ma, Dawit A. P. Gonçalves, Iban Seiliez, Enzo Emanuele, Ho Shin Gwak, Arnim Pause, Francesca Palladino, Cristiano Simone, Angelica M. Merlot, Peng Wang, Liang Ge, Kenneth Maiese, Ken Cadwell, Sally S. Atherton, Deepak Shukla, Thomas Neill, Jean-François Beaulieu, Barry Jutten, Cristina P.R. Xavier, James Murray, Tatsuya Saitoh, Roberto Chiarelli, Benedetto Grimaldi, Antonio Giordano, Yanjun Kou, Cathy Tournier, Romana T. Netea-Maier, Rui Li, Jason L. Eriksen, Colin D. Weekes, Esther Barreiro, Denis Mottet, Derek P. Narendra, Karl Swärd, Stephanie E. Wohlgemuth, Gary A. Silverman, Yukitoshi Nagahara, Mark J. Walker, Roland Malli, Diane M. Ward, Ling Hua Meng, John D. MacMicking, Cinzia Fabrizi, Marco Tucci, Tomasz M. Stepkowski, Wannian Yang, Yi Zhen Deng, Daret K. St. Clair, Darren J. Moore, Michael Lee, Katia Aquilano, Norbert Frey, Tibor Kovács, Ru Jeng Teng, Federico Pietrocola, Alfredo Criollo, Nadia Jaber, Walter T. Klimecki, Xiaohong Zhuang, Beata Sikorska, Inmaculada Tasset-Cuevas, Iwona A. Ciechomska, Robert C. Dickson, Haruo Kanno, Hua She, Xiaolei Xu, Maria Laura Avantaggiati, Isei Tanida, Jun Li, Diego Pérez-Rodríguez, Agnieszka Bagniewska-Zadworna, Viktor I. Korolchuk, Thirumala-Devi Kanneganti, Simone Nardin Weis, Thorsten Nürnberger, Guanghui Wang, Luigi Puglielli, Valina L. Dawson, Santosh Chauhan, Carole Kretz-Remy, Po-Yuan Ke, Haijun Bao, Patrícia Sampaio Tavares Veras, Sharad Kumar, Guo-Qiang Chen, Congfeng Xu, Annie M. Joubert, Diego L. Medina, Andrea Hamann, Christian Münz, Hongchuan Jin, Zhen Chen, Cristina López-Vicario, Seung Il Choi, Ivanka Markovic, Ronit Pinkas-Kramarski, Lei Jin, Yonghyun Kim, Michael J. Clague, James D. Johnson, Areti Pantazopoulou, Mohamed Al-Rubeai, Si Chen, Anne Spang, Matteo Bordi, Xiaowei Wang, Stefanie Pöggeler, Terrence M. Donohue-Jr, Aldrin V. Gomes, Jawahar L. Mehta, Yuuki Fujiwara, Mihai G. Netea, Ezra E.W. Cohen, Yunfei Huang, Do Hyung Kim, Guido Lenz, Qian Cai, Chenran Wang, Anna Katharina Simon, Barbara Del Bello, Robert Layfield, Taehoon Chun, Margit Burmeister, Wei Liu, Peter D. Adams, C. K.James Shen, Iva Slaninová, Kathleen W. Scotto, Erinna F. Lee, Mireille Verdier, Fernando J. Peña, Nicola Brunetti-Pierri, Eun-Kyoung Choi, Aleksandra Isakovic, Ju-Hyun Lee, Swapan K. Ray, Ming Chang Hu, Stephen Baghdiguian, Davide Cervia, Brent R. Stockwell, Maurizio Sorice, Andreas Till, Victor M. Darley-Usmar, Horng-Dar Wang, Ken H. Young, Yibin Feng, Néstor L. Uzcátegui, Andreja Erman, Manuela Antonioli, Alicia Torriglia, Michael D. Kim, Kazuyuki Kuchitsu, Fabio Di Domenico, Claudia Giampietri, Fuyong Song, Kevin E. Behrns, Craig Stevens, A. Sue Menko, Joana Liberal, Antonio Di Pietro, Xuejun Jiang, Joseph D. Mancias, Maria Tiziana Corasaniti, Frédéric Gros, Fuxin Wang, Jeremy Thorner, Areechun Sotthibundhu, Gijs R. van den Brink, Andrei S. Chagin, Rossella Menghini, Francesca Bernassola, Chi Li, Sung Gil Chi, Enrico Milan, Jean M. Mulcahy Levy, A. Murat Kaynar, Maria João Sousa, Olga Corti, Simone Cenci, Ting-Fang Wang, Carlos Hernández, Sucheta Telang, Zun-Ji Ke, Atsuo Amano, Lihuan Du, Meera Nanjundan, Lin Zhang, Matthias Gaestel, Bertrand Kaeffer, Andrey S. Tsvetkov, Silvia Carloni, Kazuhisa Hasui, Rosa Puertollano, Vladimir Bumbasirevic, Yongchao Zhao, Carolyn B. Coyne, Allan Caplan, Per Ottar Seglen, Kotb Abdelmohsen, Andreas Buch Møller, Jenny P.-Y. Ting, Raquel Muñoz-Moreno, Markus A. Rüegg, Monica Hagedorn, Hao Zhang, Tomotake Kanki, Edoardo M. Airoldi, Melanie Schwarten, Alfred J. Meijer, Anne Bertolotti, Matteo Bergami, Joëlle Wiels, Claudia Cerella, Eric Asselin, Z. H. An, Spencer B. Gibson, Chunlai Wu, Kai Kaarniranta, Paloma B. Liton, Feng Jun Li, Roberta Nardacci, Ernst J. Wolvetang, Robert C. Bast, Mark S. Cragg, Quentin Liu, Massimo Federici, Hyun Kyu Song, Hua Bai, Xiaotao Li, Nils J. Færgeman, Jason Chesney, Shrawan Kumar Singh, Marcello D'Amelio, Mark Prescott, Georg Auburger, Shazib Pervaiz, Allen Taylor, Diane C. Bassham, Lei Wan, Michinaga Ogawa, Emilia Maellaro, Cynthia Y. He, Chris Jones, Paolo Grumati, Jun-Lin Guan, Hiroyasu Nakano, Eric A. Schon, Roswitha Krick, Yoshihiro Shidoji, Jaime L. Schneider, Dusica Maysinger, Thomas Thum, Paul G. Thomes, Edo Vellenga, Liang Liu, Giuseppe Filomeni, Niramol Savaraj, Rudolf A. Kley, Wei Jung Chen, Bradley L. Baumgarner, Victor H. Villar, Steven Finkbeiner, Kapil Sirohi, Francesco Cecconi, Steven S. Witkin, Steve Jean, André du Toit, Rossella Russo, Irina Petrache, Randy Schekman, Keisuke Hino, Wei Chen, Basil J. Petrof, Daniel E. Frigo, Gyun Min Lee, Paul N. Span, Megumi Inomata, Ivica Arsov, Zhi-Xiang Xu, Saeid Ghavami, Tania C. Felizardo, Konstanze F. Winklhofer, Weidong Han, Jianhua Zhang, Eva Maria Mandelkow, Lydia Alvarez-Erviti, Wanderley de Souza, Pawel P. Liberski, Yang Sun, Cornelia M. Weyand, William D. Hill, Eric J. Brown, Christopher M. Adams, Felix Randow, Jose Luis Rosa, Ivan R. Nabi, Patricia V. Aguilar, Laure Aurelian, Jae-sung Bae, Gábor Juhász, Hing Y. Leung, Karla Kirkegaard, Peter J. O'Dwyer, Daniele Bergamaschi, Thomas Farkas, Tsunenori Saito, Laura Knuppertz, Leyuan Liu, Dongxu Fu, Liesu Meng, Alon Kahana, Viktor Billes, Shohreh Issazadeh-Navikas, Ljubica Harhaji-Trajkovic, Xiangguo Liu, Takahiro Yamada, Ciro Isidoro, Huiping Zhou, William A. Dunn, Takeshi Into, Giampietro Viola, Eumorphia G. Konstantakou, G. William Wong, Peter W. Szlosarek, Jeffrey S. Isenberg, Mikkel H. Vendelbo, Zuzana Papackova, Carlos B. Gonzalez, Hong Zhang, Alkesh Jani, Heidi Kiil Blomhoff, Wen-Li Chen, Simon Sedej, François Bertrand Favier, Marina K. Holz, Mitsunori Fukuda, Gudmundur Vignir Helgason, Fu-Cheng Lin, Inés Díaz-Laviada, Stefaan J. Soenen, Chao Yung Wang, Chee Yin Chai, Pierre-André Bédard, Xiaoxiang Zheng, Peter V. Bozhkov, Han-Ming Shen, Hazel M. Davey, Pedro A. Lazo, Haoxing Xu, Fengtian He, Jean Max Pasquet, Benoit Pasquier, William T. Jackson, Stéphane Duvezin-Caubet, Bertrand Mollereau, Tomohiro Kabuta, Maria Rosa Ciriolo, Peter Hasselblatt, Nihar Ranjan Jana, Jane L. Armstrong, Elisa Giovannetti, Fang Lin Sun, Zhenyu Yao, Shuji Kishi, Pei-Hui Lin, Yingmei Zhang, Limor Avrahami, Kenichi Shibuya, Guillaume Dalmasso, Radovan Vasko, Sharon Prince, Valerie B. O'Donnell, Gordon B. Mills, Hiroshi Aoki, Maryam Mehrpour, Muniswamy Madesh, Guillermo Díaz-Araya, Susan L. Cotman, Marius K. Lemberg, Tilman Grune, Jing Lan Liu, Richard C. Wang, Sandro Goruppi, Hongmin Wang, Robert A. Heinzen, Xiangmei Chen, Nihal Altan-Bonnet, Sung Sik Lee, Hai Jie Wang, Catherine Dargemont, Jie Du, Sofie Claerhout, Edmond Chan, Yi Sun, Xiangbo Wan, Paul Lingor, Shilpa Buch, Gerald M. McInerney, Zhenlong Wu, Guo Chang Zhang, Iain A. McNeish, Suresh Awale, Mark P. Mattson, Srinivasa Subramaniam, Wuhan Xiao, Katsuhiko Mikoshiba, Giancarlo Parenti, Bruno Miguel Neves, Benjamin Dehay, Fatima Teixeira-Clerc, Patricia Huebbe, Calvin K. Yip, Ryan J. Schulze, Pallabi Sarkar, Vladimir I. Titorenko, Johanna Laukkarinen, Martin E. Gleave, Veronika Stoka, Pascal Genschik, Karen Brown, Zhaoliang Su, Walter Malorni, Arlette Darfeuille-Michaud, Vincent C. O. Njar, Jeffrey E. Pessin, Thomas Wileman, Alexander J. Whitworth, Stefano Santaguida, Gustavo A. Nader, Gláucia Maria Machado-Santelli, Marie-Josée Hébert, Skye C. McIver, Scott A. Soleimanpour, Jia-Hong Lu, Fei Liu, Yu Wang, Elisa Motori, Chad A. Dickey, Andrej Udelnow, Ahmed Hamaï, Junying Yuan, Jan Paul Medema, Michelangelo Campanella, Abhishek D. Garg, Pallavi Chandra, Marco Mongillo, Bonnie Bartel, Thomas Weide, Yong Joon Chwae, Nancy Y. Ip, Yoshiaki Kamada, Hikmet Budak, Jian Xiao, Mario D. Cordero, Wei Li, Muzamil Majid Khan, He Jin Lee, Meng-Chao Yao, Zu-Hang Sheng, Perrine Castets, Dongsheng Cai, Morten Petersen, Javier Díaz-Nido, Yong Lin, Kaio Kitazato, Yotaro Izumi, Beatrice Y.J.T. Yue, Des R. Richardson, Chunsun Dai, Michael Hensel, Ronit Sagi-Eisenberg, Chan Ding, Christian Sell, Idil Orhon, Wilhelm Krek, Qutayba Hamid, Salem Chouaib, Rajkumar Banerjee, Hsing Yu Tuan, Eyleen J. O’Rourke, Fathia Mami-Chouaib, Ryo Ushioda, Hidekazu Suzuki, Jie Fan, Anders H. Lund, Urban Emmenegger, Brigit E. Riley, Andrew Thorburn, Kailash Gulshan, Karol Dokladny, José M. Cuezva, Daniel T. Ruan, Salik Hussain, Mohamed Rahmani, Maria Teresa Bassi, Miquel Vila, Pavel Strnad, Terry H. Landowski, Christiaan Leeuwenburgh, Hagit Eldar-Finkelman, Francesco Fornai, Vincent Kam Wai Wong, Hengyi Xiao, Massimo Nabissi, Luciano Merlini, Chris Williams, Jatin M. Vyas, Motoko Sasaki, Chwen Ming Shih, Saveria Aquila, Marina Garcia-Macía, Po Wu Gean, Yasuo Kitajima, Gian Luigi Russo, Tania Zaglia, Arnaud Moris, Alessandra Stacchiotti, Elaine Gutierrez, Iain D. C. Fraser, Paolo Salomoni, Ramón Corbalán, Dave Bridges, Juan P. Liuzzi, Rosanna Parlato, Sandrine Silvente-Poirot, Carl G. Maki, Patty J. Lee, Paulo Pereira, Vitaliy O. Kaminskyy, Rajaraman Eri, Bertha Brodin, Tobias Eisenberg, Rong Yu Liu, Yide Mei, Pearl P.Y. Lie, Bradford G. Hill, Yoshio Fujitani, Angelika A. Noegel, Nadarajah Vigneswaran, Muriel Mari, Steven Grant, Davide Romanelli, Lee Ann MacMillan-Crow, Anna-Lena Ström, David Sulzer, Aditya Murthy, Lisa B. Frankel, Yong Ma, Ok-Nam Bae, Pablo Wappner, Chun Hei Antonio Cheung, Young Hyun Yoo, Andreas Linkermann, Kirill V. Rosen, Orsolya Kapuy, Simone Di Paola, Thomas J. Evans, Rosa A. González-Polo, Jin H. Son, Kinya Otsu, Tracey R. O’Donovan, Nicolas Pallet, Stefano Toldo, Wafik S. El-Deiry, Allen Kaasik, Jin Tai Yu, Susu M. Zughaier, Gordon W. Laurie, Barbara Guerra, Taeg Kyu Kwon, Priyamvada Dua, Stephen A. Spector, Yingyu Chen, Ayesha N. Shajahan-Haq, Wei Pan, Matthew Campbell, Leo A. B. Joosten, J. Paul Taylor, Julian J. Lum, Matthew J. Justice, Clarissa von Haefen, William K.K. Wu, Gerald Rimbach, Peter Polčic, Jens Schmidt, Saverio Bettuzzi, Xian De Liu, Satoru Kobayashi, Yan Zhang, Ling Tian, Péter Nagy, Mercedes Pozuelo-Rubio, Cheng Jin, Marek Los, Hiroyuki Ishida, Yuji Moriyasu, Maria Teresa Cruz, Jingjing Liu, Anil K. Sood, Roberto Mateo, Antonio Facchiano, J. Mark Cooper, Xiaofeng Yao, Pei Ming Yang, Eli Arama, Marc Diederich, Luc J. W. van der Laan, Robin Ketteler, James Harris, Eui Ju Choi, Grant R. Campbell, Julie D. Atkin, Janos Kriston-Vizi, Sharon L. McKenna, Mila Ljujic, Hirotaka Watada, Harry Ischiropoulos, Shile Huang, Udo Hasler, Ke Li, Josefina Casas, Ken-ichi Isobe, Min Li, Muriel Priault, Vincenzo De Tata, Monique Gannagé, Sakineh Kazemi Noureini, Isao Ishii, Sasanka Ramanadham, Valérie Pierrefite-Carle, Chengyu Liang, Louise Deldicque, Gabriella Cavallini, Afshin Samali, Angelika Amon, Kah-Leong Lim, Lavinia Cantoni, Demetrios G. Vavvas, James E. Haber, Alireza R. Rezaie, Regina Celia Bressan Queiroz de Figueiredo, Cynthia D. Cooper, Masaaki Komatsu, Silvia Alvarez, Gemma Triola, Dong-Yun Ouyang, Razaul Karim, Kostyantyn V. Dmytruk, Bassam Janji, Peter Bütikofer, Indira U. Mysorekar, Hana Popelka, E. Marion Schneider, Carlos Guillén, Gaël Roué, Seung-Hoon Baek, Patrick Auberger, Jun Araya, Sandra M. Cardoso, Gu He, Eduardo C. Filippi-Chiela, Patrick A. Lewis, Wei-Pang Huang, Eric Reits, Cécile Vindis, Trond Lamark, Mehrdad Alirezaei, Takao Setoguchi, Alberto Bartolomé, Chih Peng Chang, Andriy A. Sibirny, Mauro Piacentini, Jing Wang, Kuninori Suzuki, Ludo Van Den Bosch, Kevin N. Dalby, Keiran S.M. Smalley, David K. Ann, Luis F. Moita, Anthony Sanchez, Chin Hsu, Guillermo M. Albaiceta, Vassilis Stratoulias, Attila L. Kovács, Charleen T. Chu, Tewin Tencomnao, Audrey H. Poon, Steve Lancel, José C. Fernández-Checa, Hannah Rabinowich, Heinz D. Osiewacz, Sami Dridi, Kate E. Keller, Thorsten Hoppe, Crispin R. Dass, Jekaterina Erenpreisa, Akira Matsuura, Donna D. Zhang, Ying Zhao, Luisa Coletto, Roy Parker, Georg M. N. Behrens, Alessia Di Nardo, Mian Wu, Alberto Jiménez, Magdalena Rost-Roszkowska, Christopher J. H. Elliott, Pamela J. Yao, Damián Gatica, Rafael Linden, Helena L. A. Vieira, Anand K. Ganesan, Wim Martinet, Frank Madeo, Juliann G. Kiang, Helmut Kramer, Lorrie A. Kirshenbaum, Salvador Ventura, Clemens Steegborn, Zahra Zakeri, Marco Antonio Meraz-Ríos, Masaki Ohmuraya, Michael A. Riehle, Congcong He, Federica Sotgia, Shi-Mei Zhuang, Paul Dent, Jürgen Bosch, Xuejun Wang, Kuan-Chih Chow, Carlos Gorbea, Lisa Gerner, Yuzuru Imai, Jan Gunst, Duncan R. Smith, María Esther Pérez-Pérez, N. Tony Eissa, Michel Roberge, Carmen García-Ruiz, Irfan J. Lodhi, Hongjiao Ouyang, Mustapha Kandouz, Alessio Papini, Jun Sun, Takanobu Otomo, David H. Perlmutter, Jae-Sung Kim, Feng Gao, Åsa B. Gustafsson, Paul M. Salvaterra, Michael Klinkenberg, Or Kakhlon, Abhinav Diwan, Takahiro Shintani, Paola Matarrese, Marc D. Meneghini, Jinsheng Zeng, Xu-jie Zhou, Linda S. Yasui, Rui Sheng, Shiqian Huang, Elizabeth Delorme-Axford, Amélie Bernard, Kevin M. Ryan, Cecília M. P. Rodrigues, Jonathan M. Backer, Harald Stenmark, Hiroaki Adachi, Koichi Sakakura, Fatima Mechta-Grigoriou, Zhi Nong Wang, Ramesh Natarajan, Tian Xia, Marco Folini, Robert A. Screaton, Jane J. Yu, Xian Wang, Gerhard H. Braus, Min Wu, John A. Hanover, Anuj Kumar, Charbel Moussa, Shailendra Anoopkumar-Dukie, Edward A. Fon, Ted Powers, Thomas H. Kawula, Zhe Liu, Jennifer Martinez, Orian S. Shirihai, Mara Cirone, Fen Wang, Machiko Sakoh-Nakatogawa, Yong Xia, Durga Nand Tripathi, James T. Handa, Nadia Zaffaroni, Esther Wong, Carlos López-Otín, Michael E. Cheetham, Harm H. Kampinga, Leopold Eckhart, Paul de Figueiredo, Xueqin Liu, Michael S. Goligorsky, Valentina Sica, Marco Sandri, Wen Qiang Chen, Szabolcs Takáts, Lilach O. Lerman, Akio Kihara, Constantinos Koumenis, Sergio Comincini, Antoinette Lemoine, Marc Bitoun, Zhuo-Wei Hu, Yu Xiong Su, Jeremy C. Mottram, Miguel A. Sanjuan, Richard D. Vierstra, Angelo De Milito, Marjolein van Egmond, Xi-Long Zheng, Kun-Liang Guan, Katrin Juenemann, Ohkmae K. Park, Eisuke Itakura, Bo Yan, Tim Lahm, Yongshun Chen, Kenneth L. van Golen, Federica Rizzi, Guochang Hu, Volker Doetsch, Chengtao Her, Conrad C. Weihl, Jing Hsiung James Ou, Chiou Feng Lin, Dun-Sheng Yang, Bozena Gabryel, Xiao Feng Zhu, Jackie de Belleroche, Charles L. Edelstein, Julie Gavard, Miklós Sass, Maria Chiara Maiuri, Zhendong Zhao, Pu Duann, Julián Pardo, Atsuhiro Ichihara, Lester M. Davids, Swamynathan Ganesan, Shengyun Fang, Hernando Gomez, Yun Chau Long, Mark J. Czaja, Arnaud Echard, Pilar Gonzalez-Cabo, Chuanyong Guo, Katherine L. Cook, Isabel Varela-Nieto, Li Yu, Yi Ran Huang, Binfeng Lu, Athanassios D. Velentzas, Koji Yamanaka, Giuseppe Russo, Ester M. Hammond, Kelsey B. Law, Sheng Li, Samisubbu R. Naidu, Michael E. Boulton, Anna-Mart Engelbrecht, Ba-Bie Teng, Zixu Mao, Vania M.M. Braga, Núria S. Coll, Eliana M. Coccia, Akihisa Abe, V. Ashutosh Rao, Nava Segev, Regina Menezes, Zufeng Ding, Hyman M. Schipper, Álvaro F. Fernández, Peter K. Kim, Lucia Micale, Biplab Dasgupta, Nazzy Pakpour, Janna L. Morrison, Yue Qin Chen, Rolf J. Craven, Zvulun Elazar, Anders Aune Tveita, Lian Li, Hsueh Fen Juan, Ulrich Koenig, Qiang Shi, Harald W. Platta, Michele S. Swanson, Olga V. Voitsekhovskaja, Bruce H. Reed, Malene Hansen, Paola Lenzi, Sandra Cottet, Yacine Graba, Christian Frezza, Bernd Schröder, Helene Knævelsrud, Li Chung Hsu, Hyunjung Jade Lim, Michael T. Greenwood, Parco M. Siu, Kyu Lim, Dolores Pérez-Sala, Patrice Codogno, Yi Yang, Frank Lezoualc'h, Ida Perrotta, Elaine A. Dunlop, Jörg H W Distler, Ken Ichi Yoshida, Dominic P. Del Re, Luigina Romani, Hye Young Kim, Eric Jonasch, Rajesh Agarwal, Wei Song, Ai Yamamoto, Zully Pedrozo, Steffan T. Nawrocki, María Salazar-Roa, Jorrit M. Enserink, Dong Wang, Flaviano Giorgini, Takayuki Ohshima, Boris Turk, Anastasia S. Mihailidou, Rosa Salvioli, Anne Simonsen, Caroline Biagosch, Glauber Costa Brito, Junko Oshima, Gail V.W. Johnson, Emmanuel Taillebourg, Sovan Sarkar, Shane Deegan, Eldad Zacksenhaus, Laura Avagliano, Byung-Hoon Lee, Weiliang Xia, Paolo Paganetti, Timothy J. Lyons, Christine M. Stellrecht, Jane E.B. Reusch, Raquel T. Lima, Feng Xu, James M. Phang, Hongwei Xu, Claudio Luparello, Mohammad Ishaq, Maureen E. Murphy, Isabelle Coppens, Luc Dupuis, Elio Ziparo, Patrick J. Bednarski, Svetlana Saveljeva, Ashok Kumar, Hongxin Zhu, Tobias B. Huber, Günther Weindl, Claudine Kraft, Dhiraj Kumar, Sara Marinelli, Karin von Schwarzenberg, Lijun Jia, Tiziana Crepaldi, Ke Liu, Eleonora García Véscovi, Qing Lu, Cláudia N. Santos, Bertrand H. Rihn, Jun Yu, Fen-Biao Gao, Flavio Flamigni, Jason E. Gestwicki, Dong-Hun Bae, Gustavo C. MacIntosh, David A. Leib, Giorgio Santoni, Chin Yuan Hsu, Abdelhaq Rami, Joseph Satriano, Matthew J. LaVoie, Paloma Martín-Sanz, Daniela De Zio, Sharon M. Gorski, Yu Tian Wang, Shuyan Lu, Clara L. Oeste, Andrew R. Tee, Koji Itahana, Xuesong Yang, Shuiping Tu, Malathi Krishnamurthy, Anne M. Strohecker, Gui Xian Xia, Helena Orozco, Sujit K. Bhutia, Hongbo Hu, Rupert Beale, Ying-Ray Lee, Kai Mao, Pierre-Emmanuel Rautou, Jean Francois Groulx, James A. Mastrianni, Victoria El-Khoury, Koji Okamoto, Mark J. Taylor, Arianna L. Kim, José M. Izquierdo, Dalibor Mijaljica, Björn Stork, Thomas Schwarz, Savita Bhalla, Menno van Lookeren Campagne, Long Zhang, Elizabeth S. Yeh, Li Zhang, Tae Cheon Kang, Frederic Luciano, Shusaku Shibutani, Luciana Dini, Valentina Cianfanelli, Sara Calatayud, Yong-Sun Kim, Maurizio Molinari, Graham H. Coombs, Takeshi Noda, Angelo Poletti, Silvia Palumbo, Dhan V. Kalvakolanu, Valérie Vouret-Craviari, Volodymyr Y. Nazarko, Salvatore Florio, Noboru Mizushima, Arthur Kaser, Shigeki Miyamoto, Patric J. Jansson, Thomas I-Sheng Hwang, Daniel J. Jackson, Adrian L. Harris, Srikanta Dash, Yeong Min Yoo, David Colecchia, Ute C. Meier, Yi Ma, Tadashi Suzuki, Anand Krishnan V. Iyer, Flavia Radogna, Paul S. Brookes, Deepak Kumar, Gabriella D'Orazi, Barry Yedvobnick, David R. Soto-Pantoja, Christian Waeber, Craig McCormick, Dong Hu, Sarron Randall-Demllo, Gustavo J.S. Pereira, Emil Rudolf, Scott L. Friedman, Paolo Bonaldo, Oliana Carnevali, Guido R.Y. De Meyer, Alice Carrier, Yipeng Wang, Serena Montagnaro, Nadeem O. Kaakoush, José de la Fuente, Devrim Gozuacik, Edward D. Plowey, Alastair M. Buchan, John C. Chatham, Daniel J. Klionsky, Cecilia Gotor, Isabelle Hamer, Katarzyna Mnich, Paola Rusmini, Chengshu Wang, Per Nilsson, Lorena Esteban-Martínez, Raúl V. Durán, Dieter Willbold, Hye Won Chung, Janet D. Sparks, John M. Lucocq, Blake B. Rasmussen, Takeshi Matsuzawa, Hagai Abeliovich, Wiep Scheper, Sung Joon Lee, Jennifer S. Carew, Serena Carra, Michael J. Morgan, Nikolai Slavov, Guy Berchem, Tiziana Cocco, Simone Engelender, Jianbo Yue, Yujie Chen, Mario Fabri, Maria F. Czyzyk-Krzeska, Hua Niu, Roger J. Davis, Peter J. Adhihetty, Kishore B.S. Pasumarthi, Jongsook Kim Kemper, Sharon A. Tooze, Antonio Zorzano, Jin Cheon Kim, Jian Xu, Andreas Meryk, Kristina Vuori, Jongdae Lee, Patrizia Agostinis, Diego Ruano, Wim Vandenberghe, Julia I-Ju Leu, Céline Gongora, Bernadette Carroll, Vinoth Kumar Megraj Khandelwal, Bo Lu, Marja Jäättelä, Lorenzo Galluzzi, Ioannis P. Trougakos, Tatsuya Maeda, Marie-Agnès Bringer, Mario Chiong, Hans-Uwe Simon, Lance A. Liotta, Ruth S. Slack, Ina Oehme, Umamaheswar Duvvuri, Shaun Martin, Augustine M.K. Choi, Michel Vidal, Ying Wang, Isis do Carmo Kettelhut, Mojgan Djavaheri-Mergny, Jörn Coers, Massimo Donadelli, Jesus Aldudo, Miyuki Sato, Jianxun Liu, Jörg Höhfeld, Luc Van Kaer, Andrei I. Ivanov, Dohun Pyeon, José M. Bravo-San-Pedro, Jianxin Peng, Xiaoyan Jiang, Dimitri Krainc, Yangqing Xu, Arnaud François, P. Robin Hiesinger, Sagar Lonial, William C. Cho, Caty Casas, Betty Yuen Kwan Law, Hongbing Zhang, Tor Erik Rusten, Erwin Knecht, Honglin Luo, Shi Xiao, Hiromi Sesaki, Enza Maria Valente, Verónica Pérez de la Cruz, Marta M. Lipinski, David A. Hood, Shi-Yong Sun, Luiz Carlos Carvalho Navegantes, Joynal Abedin, Shino Goto-Yamada, Gustavo Maegawa, Takehiko Matsushita, Vitor A. Lira, Clara I. Rodríguez, Ekihiro Seki, Qiang Li, Karin Öllinger, Ted M. Dawson, Ssang-Goo Cho, Wan-Wan Lin, Pramod Kumar Garg, Jeffrey Robbins, Peter R. Williamson, Michael Sacher, Carlo Follo, Bulent Ozpolat, Xiao Jia Wang, Na Man, Hua Cheng, Bing Yan, Tsung-Hsien Chuang, Paul B. Fisher, Rajat Singh, Edward A. Ratovitski, Katsuhiko Kitamoto, Jung Jin Hwang, Shinji Hadano, Che Hsin Lee, Shuo Wang, Einar M. Sigurdsson, Camille Martinand-Mari, Agnieszka Sirko, Katherine R. Parzych, Etienne Morel, Yasushi Kitaoka, Hassan Chaachouay, Patricia Chakur Brum, Dexin Kong, Jerome Tamburini, Kuppan Gokulan, Stefan Olsson, Bilon Khambu, Lea M.D. Delbridge, Daniel P. Orban, David A. Gewirtz, Zhonglin Xie, Joe Quadrilatero, Kunikazu Tanji, Simin Mohseni, Gábor Bánhegyi, Jin Ming Yang, Jinxian Xu, Carmen Veríssima Ferreira-Halder, Addanki P. Kumar, Deok Ryong Kim, Jianjie Ma, Sang Won Suh, Guido Kroemer, Klára Megyeri, Michael N. Sack, Heinrich Taegtmeyer, Gilles Pagès, Gabriella Marfe, Gregg L. Semenza, Karine G. Le Roch, Marisa Brini, Marina Bouché, Oliver Kepp, Vinay V. Eapen, J. David Beckham, Stephan T. Stern, Xudong Zhang, Marcello Pinti, Xiangnan Zhang, Jae Keun Lee, Ana Coto-Montes, Assaf Rudich, Laura D. Attardi, Debabrata Ghosh, Philip Rosenstiel, Sébastien Besteiro, Maria Rosa Sarrias, R. Andres Floto, Xiao Ming Yin, Nicholas W. Lukacs, Hermann Pavenstädt, Matias Simons, Hitoshi Nakatogawa, Sandro Alves, Krisztina Takács-Vellai, Masato Koike, Debasish Sinha, Shoji Notomi, Faraj Terro, Maria Carmela Roccheri, Santiago Ambrosio, K. Ulrich Bayer, Yumin Li, Terje Johansen, Christian Kuhn, Yee Shin Lin, David C. Rubinsztein, Ziwei Qu, Ronit Shiri-Sverdlov, Emmanuel T. Akporiaye, Galila Agam, Hui Ling Chiang, Seung-Jae Lee, Yu Xue, Francesca Giampieri, Markus Damme, Tassula Proikas-Cezanne, Tianwei Lin, Marc Kantorow, Guang-Chao Chen, Qiangrong Liang, Claudia Manzoni, Joan S. Steffan, Emilio Boada-Romero, Damien Freyssenet, Sepp D. Kohlwein, Maria D. Barrachina, Yulin Liao, Jiankang Chen, Erika Isono, Hugo Seca, Mei Wang, Taras Y. Nazarko, Yannick Bailly, Nadya V. Koshkina, Tapas K. Maiti, Bärbel Rohrer, Karin Nowikovsky, James H. Hurley, Gerald W. Dorn, Nils C. Gassen, Kazuhiro Nagata, Eiki Kominami, A. Ivana Scovassi, Ana Maria Cuervo, Adi Kimchi, Minghua Yang, Sylviane Muller, Life Sciences Institute and Department of Molecular, Cellular, and Developmental Biology and Biological Chemistry, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Defense in Plant-Pathogen Interactions [Nagoya, Japan], Nagoya University-Graduate School of Bioagricultural Sciences [Nagoya, Japan], Facultad de Quimica [Santiago], Pontificia Universidad Católica de Chile (UC), Institute of Cancer Sciences [Glasgow, UK] (CR-UK Beatson Institute), University of Glasgow, Cell Death Research & Therapy (CDRT) Lab, Université Catholique de Louvain, Harvard University Statistics Department, Harvard University [Cambridge], Centre épigénétique et destin cellulaire (EDC (UMR_7216)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Conway Institute of Biomolecular and Biomedical Research and School of Chemical and Bioprocess Engineering, University College Dublin [Dublin] (UCD), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Biochemistry and Molecular Biology, Thomas Jefferson University-Sidney Kimmel Cancer Center, Jefferson (Philadelphia University + Thomas Jefferson University)-Jefferson (Philadelphia University + Thomas Jefferson University), Centro de Estudios Farmacológicos y Botánicos [Buenos Aires] (CEFYBO), Consejo Nacional de Investigaciones Científicas y Técnicas [Buenos Aires] (CONICET)-Facultad de Medicina [Buenos Aires], Universidad de Buenos Aires [Buenos Aires] (UBA)-Universidad de Buenos Aires [Buenos Aires] (UBA), Thérapie génique, Génomique et Epigénomique (U 1169), Université Paris-Saclay-Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Sud - Paris 11 (UP11), Department of Experimental Medicine and Public Health, University of Camerino, MRC Toxicology Unit, University of Leicester, Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Departamento de Bioquímica y Biología Molecular y Celular, University of Zaragoza - Universidad de Zaragoza [Zaragoza], Department of Pharmaco-Biology, Università della Calabria [Arcavacata di Rende] (Unical), Department of Molecular Genetics [Rehovot, Israël], Weizmann Institute of Science, Fondation Universitaire Notre Dame de la Paix (FUNDP), Facultés Universitaires Notre-Dame de la Paix, Département Advanced Research And Techniques For Multidimensional Imaging Systems (ARTEMIS), Institut Mines-Télécom [Paris] (IMT)-Télécom SudParis (TSP), USC Neuromuscular Center, Department of Neurology, University of Southern California (USC), Centre méditérannéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Giannina Gaslini Institute, Department of Molecular Pharmacology, Albert Einstein College of Medicine, Department of Cancer Biology, University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS)-University of Massachusetts System (UMASS), Institut des Sciences de l'Evolution de Montpellier (UMR ISEM), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École pratique des hautes études (EPHE)-Université de Montpellier (UM)-Institut de recherche pour le développement [IRD] : UR226-Centre National de la Recherche Scientifique (CNRS), Inner Mongolia Agricultural University (IMAU), Franche-Comté Électronique Mécanique, Thermique et Optique - Sciences et Technologies (UMR 6174) (FEMTO-ST), Université de Franche-Comté (UFC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Technologie de Belfort-Montbeliard (UTBM), Indian Institute of Science [Bangalore] (IISc Bangalore), Politecnico di Milano [Milan] (POLIMI), Département des Sciences Biologiques [Montréal], Université du Québec à Montréal (UQAM), Laboratory of Molecular Biology, Scientific Institute E. Medea, Université Catholique de Louvain (UCL), Univ Ancona, Politecn Marche, University of Toronto, Munich Cluster for systems neurology [Munich] (SyNergy), Technische Universität München [München] (TUM)-Ludwig-Maximilians-Universität München (LMU), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA), Department of Clinical and Molecular Medicine, Università degli Studi di Roma 'La Sapienza' [Rome]-Réseau International des Instituts Pasteur (RIIP)-Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP), Physiopathologie du système nerveux central - Institut François Magendie, Université Bordeaux Segalen - Bordeaux 2-IFR8-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Hémato-Cancérologie Expérimentale, CRP-Santé, Dpt of Neuroscience and Brain Technologies [Genova], NeuroEngineering & bio-arTificial Synergic SystemS Laboratory [Genova] (NetS3 Lab), Istituto Italiano di Tecnologia (IIT)-Istituto Italiano di Tecnologia (IIT), Center for Infection and Immunity Amsterdam (CINIMA), Laboratoire de biogenèse membranaire (LBM), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Régulation de l'expression génétique (REG), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris)-École normale supérieure - Paris (ENS Paris)-Centre National de la Recherche Scientifique (CNRS), Dynamique des interactions membranaires normales et pathologiques (DIMNP), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Department of Microbiology and Immunology, Stanford University School of Medicine [CA, USA], Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Department of Dermatology, Brigham and Women's Hospital [Boston], San Raffaele Scientific Institute, Milan, Italy, Laboratory of Molecular Neuroembryology, University of Rome 'Tor Vergeta'-Clinical and Behavioral Neurology - Neuroscienze e riabilitazione, IRCCS Fondazione Santa Lucia [Roma]-Dulbecco Telethon Institute, Department of Pharmacology, Universidade de Santiago de Compostela, Glycobiologie et signalisation cellulaire, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Complexo Hospitalario Universitario A Coruña, Mécanismes moléculaires de l'angiogénèse, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Florida [Gainesville], Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U1172 Inserm), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, Centro de Investigaciones Biológicas (CSIC), Consejo Superior de Investigaciones Científicas [Spain] (CSIC), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (HOTE GREFFON), Université de Franche-Comté (UFC)-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Infection bactérienne, inflammation, et carcinogenèse digestive, Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Universita degli Studi di Padova, University of British Columbia (UBC), University of Edinburgh, Unité de Nutrition Humaine - Clermont Auvergne (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne (UCA), Australian Regenerative Medicine Institute, Monash University, Clayton, 3800, VIC, Australia, Faculty of Engineering and Natural Sciences, Sabanci University [Istanbul], Department of Biological Sciences [Stanford], Stanford University [Stanford], Université de Montréal (UdeM), Department of Human Genetics, Department of Psychiatry, University of Michigan System-University of Michigan System-Molecular and Behavioral Neuroscience Institute, Centre for Computational and Systems Biology (COSBI), Department of Computer Science [Tsukuba], Graduate School of Systems and Information Engineering [Tsukuba], University of Tsukuba-University of Tsukuba, Institut de biochimie et génétique cellulaires (IBGC), University of Western Ontario (UWO), Genetics, Dynamique Musculaire et Métabolisme (DMEM), Institut National de la Recherche Agronomique (INRA)-Université de Montpellier (UM), Department of Biochemistry and Biophysics, University of Naples Federico II, Lund University [Lund], Institute of Molecular Biosciences, Karl-Franzens University Graz, (IMB), Karl-Franzens-Universität Graz, Polytechnic University of Marche, Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Cell Biology, Physiology and Immunology, Research Unit on BioActive Molecules, Departamento de Química Orgánica Biológica, Instituto de Investigaciones Quimicas y Ambientales de Barcelona, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Physiopathologie et thérapie du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), The Buck Institute for Age Research, University of Pisa - Università di Pisa, Laboratorio di Genetica Molecolare, Istituto Gaslini, Universidad de Castilla-La Mancha (UCLM), Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, University of Crete [Heraklion] (UOC), Division of Molecular and Cellular Pathology [Birmingham], Department of Medical Research, Taichung Veterans General Hospital, Modélisation et Simulation Numérique en Mécanique et Génie des Procédés (MSNMGP), Université de la Méditerranée - Aix-Marseille 2-Université Paul Cézanne - Aix-Marseille 3-Université de Provence - Aix-Marseille 1-Centre National de la Recherche Scientifique (CNRS), University of Queensland [Brisbane], Dept of Mathematics, Purdue University, Purdue University [West Lafayette], Virologie et Pathologie Humaine (VirPath), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Zhejiang University, Équipe Micro et nanosystèmes HyperFréquences Fluidiques (LAAS-MH2F), Laboratoire d'analyse et d'architecture des systèmes (LAAS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse 1 Capitole (UT1)-Université Toulouse - Jean Jaurès (UT2J)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse 1 Capitole (UT1)-Université Toulouse - Jean Jaurès (UT2J), King Abdullah University of Science and Technology (KAUST), Southern University of Science and Technology of China (SUSTech), OASE, National University of Tainan, Taiwan (OASE), National Taiwan University [Taiwan] (NTU), Weifang Bureau of Land Resources [Weifang], Department of cardiology [Guy's and St. Thomas ' hospitals] [London], Guy's and St Thomas' Hospital [London]-Guy's Hospital [London], University of Pennsylvania [Philadelphia], CRLCC Eugène Marquis (CRLCC), Emory University School of Medicine, Emory University [Atlanta, GA], Korea University, Cytokines et Immunologie des Tumeurs Humaines (U753), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Pharmacology [Tartu, Estonie], Institute of Biomedicine and Translational Medicine [Tartu, Estonie], University of Tartu-University of Tartu, Max-Planck-Institut für Biophysikalische Chemie - Max Planck Institute for Biophysical Chemistry [Göttingen], Max-Planck-Gesellschaft, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), University of Cincinnati (UC), Réponses immunes : régulation et développement, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Experimental Medicine, Oxford University, University of Oxford [Oxford], Division of regenerative Medicine, San Raffaele Scientific Institute, The University of New Mexico [Albuquerque], Université Libre de Bruxelles [Bruxelles] (ULB), Macrophages et Développement de l'Immunité, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health [Baltimore], Johns Hopkins University (JHU)-Johns Hopkins University (JHU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Dipartimento di Scienze Biomediche, Università degli Studi di Modena e Reggio Emilia (UNIMORE), Department of Experimental Medicine and Oncology, University of Turin, Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), CNV, University of Valparaiso, Institut Gustave Roussy (IGR), Universidad Autonoma de Madrid (UAM), Cell Signalling & Proteomics Group [Londres, Royayme-Uni], Barts Cancer Institute [Londres, Royayme-Uni], Queen Mary University of London (QMUL)-Queen Mary University of London (QMUL), Department of General, Visceral and Vascular Surgery [Jena], Friedrich-Schiller-Universität Jena, Department of Biomedical Engineering, The University of Texas at Austin, University of Texas at Austin, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte - Clermont Auvergne (M2iSH), Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne), Fondazione Santa Lucia (IRCCS), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Jacques Monod (IJM (UMR_7592)), Institute of Biological, Environmental and Rural Sciences (IBERS), Aberystwyth University, Department of Biology, Johns Hopkins University (JHU), Neurogenetics Group, Instituto de Investigación en Recursos Cinegéticos (IREC), Laboratório de Ultraestrutura Celular Hertha Meyer (IBCCF), Universidade Federal do Rio de Janeiro [Rio de Janeiro] (UFRJ), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology in Zürich [Zürich] (ETH Zürich), Molecular and Cellular Biology, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), National University of Ireland [Galway] (NUI Galway), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Freiburg Institute for Advanced Studies-LifeNet, Albert-Ludwigs-Universität Freiburg, Groupe de Recherche en Immunopathologies et maladies infectueuses (GRI), Université de La Réunion (UR)-Centre hospitalier Félix-Guyon [Saint-Denis, La Réunion], Brunel University London [Uxbridge], Unité Propre de Recherche 2357, Institution de Biologie Moléculaire des Plantes, Radiothérapie moléculaire (UMR 1030), Department of Chemistry, University of Kentucky, Universidad de Córdoba [Cordoba], Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Università degli Studi di Roma 'La Sapienza' [Rome], Facultad de Ciencias Químicas y Farmacéuticas, Centro de Estudios Moleculares de la Célula, Biochemistry and Molecular Biology, Goethe-University Frankfurt am Main, Department of Biological and Environmental Sciences and Technologies (DiSTeBA), Università del Salento, Institut Bergonié - Département de médecine, Université Bordeaux Segalen - Bordeaux 2-Centre régional de lutte contre le cancer [CRLCC], Institut National Polytechnique de Lorraine (INPL), Récepteurs nucléaires, maladies cardiovasculaires et diabète (EGID), Université de Lille, Droit et Santé-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU), Institut de recherches sur la catalyse et l'environnement de Lyon (IRCELYON), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Laboratoire de signalisation moléculaire et neurodégénerescence, Université Louis Pasteur - Strasbourg I-IFR37-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Européen de Chimie et Biologie (IECB), Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Trafic membranaire et Division cellulaire, Landesbetrieb Hessisches Landeslabor, Hematology-Oncology Division, Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], University of Pavia, Instituto de Investigaciones Biotecnológicas [San Martín] (IIB-INTECH), Universidad Nacional de San Martin (UNSAM)-Consejo Nacional de Investigaciones Científicas y Técnicas [Buenos Aires] (CONICET), University of Helsinki, School of Physics and Astronomy [Exeter], University of Exeter, Department of Biomedicinal Chemistry (CSIC), Institut de Química Avançada de Catalunya, Laboratory of Vascular Pathology (IDI-IRCCS), Istituto Dermopatico dell'Immacolata, Peking University [Beijing], MRC Centre for Developmental Neurobiology, University of Brescia, Immunobiologie fondamentale et clinique, Université de Lyon-Université de Lyon-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC régional épidémiologie clinique/essais cliniques - Ile de la Réunion (CIC-EC), University of Rome 'Tor Vergeta', Universidad de Oviedo [Oviedo], Laboratoire des signaux et systèmes (L2S), Université Paris-Sud - Paris 11 (UP11)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Dulbecco Telethon Institute/Department of Biology, Istituto Nazionale di Malattie Infettive 'Lazzaro Spallanzani' (INMI), Rockefeller University [New York], The Babraham Institute, Kansas State University, McGill University, Service d'Anatomie et Cytologie Pathologique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Laboratoire Interuniversitaire de Biologie de la Motricité (LIBM ), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), Department of Medicine [New York], Icahn School of Medicine at Mount Sinai [New York] (MSSM), ATOS Origin, Department of Developmental Biology and Neurosciences, Graduate School of Life Sciences-Tohoku University [Sendai], Goethe-University, Goethe-Universität Frankfurt am Main, Institute of physiological chemistry, Hannover Medical School [Hannover] (MHH), Department of Physiology, Department of Plant and Environmental Sciences, Apoptose, cancer et immunité (U848), Laboratoire de Biologie du Développement (LBD), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Departments of Neurology and Psychiatry, Alzheimer's Disease Research Center, Institute of Experimental Immunology - IEI [Zürich, Switzerland], Université de Zurich [Switzerland], Digital Enterprise Research Institute (DERI-NUIG), Spanish National Research Council (CSIC), Cell Death Research and Therapy Unit [Leuven, Belgium] ( Department of Cellular and Molecular Medicine), Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Signaling in Oncogenesis, Angiogenesis and Permeability - SOAP (CRCINA - Département ONCO - Equipe 15), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers (CRCINA), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Department of Medicine [San Francisco], University of California [San Francisco] (UCSF), University of California-University of California, Fondazione Santa Lucia [IRCCS], Clinical and Behavioral Neurology [IRCCS Santa Lucia], Institut de biologie moléculaire des plantes (IBMP), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes (URMITE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR48, INSB-INSB-Centre National de la Recherche Scientifique (CNRS), Department of Anatomy, Histology, Forensic Medicine and Orthopedic, N.A., Division of Pharmacology and Chemotherapy, Department of Internal Medicine, Pathogénie Microbienne Moléculaire, University of Chile [Santiago], Université de Montpellier (UM), Faculdade de Ciências Farmacêuticas de Ribeirão Preto [São Paulo], Universidade de São Paulo (USP), Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1), Catalan Institute of Oncology, Department of Cell Biology, National Institute for Basic Biology [Okazaki], Instituto de Bioquímica Vegetal y Fotosíntesis (IBVF), Universidad de Sevilla-Centro de Investigaciones Científicas Isla de la Cartuja, The Adams Super Center for Brain Studies, Tel Aviv University [Tel Aviv], Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF)-Centre National de la Recherche Scientifique (CNRS), Department of Pharmacology and biochemistry, Virginia Commonwealth University (VCU), Department of Immunology, St Jude Children's Research Hospital, Department of Biology and Biotechnologies 'Charles Darwin', Lettres, Idées, Savoir (LIS), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institute of Biological Chemistry and Nutrition, University of Hohenheim, China Seismological Bureau, Massachusetts Institute of Technology (MIT), Rosenstiel Basic Medical Sciences Research Center [Waltham], Brandeis University, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA), Meakins-Christie Laboratories, Sanford Burnham Medical Research Institute, La Jolla, National Institute of Advanced Industrial Science and Technology (AIST), ORIENT ET MÉDITERRANÉE : Textes, Archéologie, Histoire (OM), Université Panthéon-Sorbonne (UP1)-École pratique des hautes études (EPHE)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Centro de Investigacion y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV), Biochemistry and Molecular Biology I, Department of Immunology and Infectious Diseases, Harvard School of Public Health, aDepartment of Plant Biology, Uppsala BioCenter, Swedish University of Agricultural Sciences (SLU), Philipps University of Marburg, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Renal Division, University Medical Center Freiburg, Freiburg, Germany, Rural Health Academic Centre, University of Melbourne-Rural Clinical School, Department of Pathology, University of Veterinary and Animal Sciences, Dipartimento di Scienze della Vita [Modena, Italy], Stress Cellulaire, Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Pathology, Anatomy & Cell Biology [Philadelphia, Pennsylvania, USA], Thomas Jefferson University, Department of Molecular Neuroscience, Departamento de Bioquimica Clinica, Facultad de Ciencias Quimicas, Centro de Investigación en Bioquímica Clínica e Inmunología (CONICET), Universidad Nacional de Córdoba, Córdoba, Argentina, Neuroinflammation Unit, Biotech Research and Innovation Centre-University of Copenhagen = Københavns Universitet (KU), Mathematics and Computing in Automatic Control and Optimization for the User (MIAOU), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Danish Cancer Society, Institute of Cancer Biology, UCL-Institute of Child Health (ICH), Institute of Child Health-Great Ormond Street Hospital for Children [London] (GOSH), Division of Renal Diseases and Hypertension, University of Colorado [Boulder], Institut de biologie et chimie des protéines [Lyon] (IBCP), Joslin Diabetes Center, Universität Ulm - Ulm University [Ulm, Allemagne], Qingdao Institute of Marine Geology, China Geological Survey, Qingdao 266071, China, Université Paris Diderot - Paris 7 (UPD7), Institute of Software, Chinese Academy of Sciences [Beijing] (CAS), Metabolic Engineering Group, Departamento de Microbiologia y Genetica, Edificio Departamental, Campus Miguel de Unamuno, Universidad de Salamanca, University of Minnesota [Twin Cities], University of Minnesota System, Department of Cellular and Molecular Physiology, Yale University School of Medicine, The Arctic University of Norway, Department of Biological Sciences, The Open University [Milton Keynes] (OU), Summit Analytical, CALRG, Institute of Educational Technology, Institute for Neurologic Disabilities Research, Faculty of Health Sciences-University of Pretoria [South Africa], Department of Paediatric Neurology, Guy's and St Thomas' Hospital [London]-Evelina Children's Hospital, Physiologie des Adaptations Nutritionnelles [UMR_A1280] (PhAN), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), Dana-Farber Cancer Institute and the Department of Cell Biology, Harward Medical School, Translational Health Science and Technology Institute [Faridabad] (THSTI), Department of Biomedical Sciences of Cells and Systems, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands, School of Reliability and Systems Engineering [Beijing], Beihang University, Oxford Centre for Integrative Systems Biology, Center for Membrane and Cell Physiology [Charlottesville, VA, USA] (School of Medicine), University of Virginia [Charlottesville], Apoptose, cancer et immunité (Equipe labellisée Ligue contre le cancer - CRC - Inserm U1138), Institut Gustave Roussy (IGR)-Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Karlsruher Institut für Technologie (KIT), Faculty of Pharmaceutical Sciences, Hokkaido University, École normale supérieure - Paris (ENS Paris), School of Electrical Engineering [Seoul] (Korea University), Department of Mathematics and Statistics [Guelph], University of Guelph, Department of Molecular Genetics, Department of Genetics [Stanford, CA, États-Unis], Institute of Immunology, University Hospital Schleswig-Holstein, Arizona Respiratory Center, Okazaki Institute for Integrative Bioscience, ToxAlim (ToxAlim), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Newcastle University [Newcastle], JRC Institute for Transuranium Elements [Karlsruhe] (ITU ), European Commission - Joint Research Centre [Karlsruhe] (JRC), Department of Neuroscience, University of Texas Southwestern Medical Center [Dallas], Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Laboratory of Functional Neurogenomics [Tuebingen, Germany], University of Tuebingen-Center of Neurology and Hertie-Institute for Clinical Brain Research [Tuebingen, Germany], Indian Institute of Technology Bombay (IIT Bombay), European Organization for Nuclear Research (CERN), Harvard Medical School [Boston] (HMS), Indian School of Mines, Department of Computer Science [UIUC] (UIUC), University of Illinois at Urbana-Champaign [Urbana], University of Illinois System-University of Illinois System, Centre for Cancer Biology, Hanson Institute, Adelaide, University of California [San Diego] (UC San Diego), University of California, Centre d’Infection et d’Immunité de Lille (CIIL) - U1019 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Department of Biochemistry, University of Bristol, Organisation Nucléaire et Oncogenèse, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), FONDAP Center CEMC Estudios Moleculares de la Célula, Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Centre d'infectiologie Necker-Pasteur [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Chungnam National Univesity School of Medicine, Taejon, Korea, Chungnam National Univesity School of Medicine, Micro & Nanobiotechnologies, Institut des Sciences Analytiques (ISA), Centre National de la Recherche Scientifique (CNRS)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-École normale supérieure - Lyon (ENS Lyon), Centre de Recherche en Cancérologie de Lyon (CRCL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de génétique moléculaire (CGM), Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Center for Applied Mathematics, Tsinghua University [Beijing], University of Connecticut School of Medicine, University of Connecticut (UCONN), Laboratoire de Biologie Moléculaire et Cellulaire des Eucaryotes (LBMCE), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Microenvironnement et Physiopathologie de la Differenciation, Division of Nephrology and Hypertension, Mayo Clinic, Beatson Institute for Cancer Research, Beatson institute for cancer research, Howard Hughes Medical Institute, Howard Hugues Medical Institute, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute of Computing Technology [Beijing] (ICT), Chinese Academy of Sciences [Changchun Branch] (CAS), School of Electronics and Computer Science (ECS), University of Southampton, Third Hospital, Department of Anesthesiology, Cognitive Interaction Technology [Bielefeld] (CITEC), Universität Bielefeld = Bielefeld University, Procédés, Matériaux et Energie Solaire (PROMES), Université de Perpignan Via Domitia (UPVD)-Centre National de la Recherche Scientifique (CNRS), Faculty of Pharmacy- University of Coimbra, National Neuroscience Institute, Key Laboratory of Molecular Virology & Immunology (LMVI), Institut Pasteur de Shanghai, Académie des Sciences de Chine - Chinese Academy of Sciences (IPS-CAS), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Coll Life Sci, Beijing Normal University, Delft University of Technology (TU Delft), Christian-Albrechts-Universität zu Kiel (CAU), Department of Molecular Pathology and Microbiology, Center for Applied Proteomics and Molecular Medicine-George Mason University [Fairfax], Sidney Kimmel Cancer Center, Jefferson (Philadelphia University + Thomas Jefferson University), Institut des Sciences Chimiques de Rennes (ISCR), Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Rennes-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES), Department of Chemistry, University of Pittsburgh, University of Pittsburg, Tianjin University of Science and Technology (TUST), Hunan University of Science and Technology [Xiangtan], Laboratoire de Génie Civil et Génie Mécanique (LGCGM), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), China Agricultural University (CAU), Acad Disaster Reduct and Emergency Management, Minist Civil Affairs, Minist Educ, Beijing, Peoples R China, affiliation inconnue, Département Technologie des Polymères et Composites & Ingénierie Mécanique (TPCIM), École des Mines de Douai (Mines Douai EMD), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Ministère de l'Economie, des Finances et de l'Industrie, MOE Key Laboratory of Bioinformatics, Centre for Plant Biology, School of Life Sciences, Laboratoire d'Informatique Gaspard-Monge (ligm), Université Paris-Est Marne-la-Vallée (UPEM)-École des Ponts ParisTech (ENPC)-ESIEE Paris-Fédération de Recherche Bézout-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biochimie Moléculaire et Cellulaire (LBMC), Université de Bourgogne (UB), Center for International Blood and Marrow Transplant Research (CIBMTR), Emory University [Atlanta, GA]-Medical College of Wisconsin, Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Illman Cancer Center, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Ingénierie des Matériaux Polymères (IMP), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet [Saint-Étienne] (UJM)-Centre National de la Recherche Scientifique (CNRS), Université Côte d'Azur (UCA), Department of Medical Microbiology and Immunology, University of California [Davis] (UC Davis), School of Health Sciences, University of Minho [Braga], Équipe Calcul Distribué et Asynchronisme (LAAS-CDA), University of California [Riverside] (UCR), Ohio State University [Columbus] (OSU), Laboratory of Systems Biology, Van Andel Institute [Grand Rapids], Division of Genetics and Cell Biology, National Center for Gender-Specific Medicine, Istituto Superiore di Sanità, Oregon Health and Science University [Portland] (OHSU), Dendrite Differenciation Group [DZNE - Bonn], German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Equipe 12, Génétique moléculaire, signalisation et cancer (GMSC), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre de Recherche en Cancérologie de Lyon (CRCL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University Medical Center [Utrecht], Institut d'Investigacions Biomèdiques August Pi I Sunyer [Barcelona, Spain] (Hospital Clinic ), Department of Genetics, Trinity College Dublin, Fisiopatologia de los procesos inflamatorios, Vall d'Hebron Research Institute, Institució Catalana de Recerca i Estudis Avançats (ICREA), Department of Human Genetics, Nagasaki University, Transduction du signal et oncogénèse, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie, Center for Experimental and Molecular Medicine, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA), Department of medical Biochemistry, University of Amsterdam [Amsterdam] (UvA), IDI-IRCCS Biochemistry Laboratory, Università degli Studi di Roma Tor Vergata [Roma], Program Against Cancer Therapeutic Resistance/Metabolism & Cancer Group [Catalonia, Spain] (ProCURE), Catalan Institute of Oncology-Girona (ICO-Girona), Instituto de Tecnologia Química e Biológica António Xavier (ITQB), Universidade Nova de Lisboa (NOVA), Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza Hospital, CNR, Consiglio Nazionale delle Ricerche (CNR), Biochimie et Physiologie Moléculaire des Plantes (BPMP), Université de Montpellier (UM)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Laboratory for Developmental Neurobiology, RIKEN Brain Science Institute, The Hospital for sick children [Toronto] (SickKids), Universidad de Sevilla, Immunité muqueuse et vaccination, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR50-Université Nice Sophia Antipolis (... - 2019) (UNS), DIMS, University of Trento [Trento], Laboratoire de Biologie Moléculaire de la Cellule (LBMC), Department of Cellular and Molecular Medicine [Madrid, Spain], Laboratory of Cell Death and Cancer Therapy [Madrid, Spain], Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC) -Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Plymouth Marine Laboratory, Prospect Place, The Hoe, Plymouth PL1 3HD, UK, Centre d'Immunologie et de Maladies Infectieuses (CIMI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Dpt. of Cancer & Cell Biology, Interactions Bactéries-Cellules (UIBC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]-Institut National de la Recherche Agronomique (INRA), Max planck Institute for Biology of Ageing [Cologne], Euromov (EuroMov), Wellcome Trust Centre for Molecular Parasitology [Glasgow, UK], University of Glasgow- Institute of Infection, Immunity and Inflammation [Glasgow, UK], Immunologie et chimie thérapeutiques (ICT), Cancéropôle du Grand Est-Centre National de la Recherche Scientifique (CNRS), UMR 1599, Centre National de la Recherche Scientifique (CNRS), EA 4100, Histoire culturelle et sociale de l'art (HiCSA), Université Panthéon-Sorbonne (UP1)-Université Panthéon-Sorbonne (UP1), Centre for Astrophysics and Supercomputing (Centre for Astrophysics and Supercomputing), Swinburne University of Technology [Melbourne], Department of Cellular and Physiological Sciences [Vancouver, BC, Canada] (Life Sciences Institute), University of British Columbia (UBC)-Life Sciences Institute [Vancouver, BC, Canada], School of Pharmacy, Department of Experimental Medicine, Dept. Neurosciences, Department of Internal Medicine, Radboud University Medical Center [Nijmegen], Institute of Medical Genetics and Applied Genomics, Radiation Physics, School of Life Science, Department of Basic Biology, The Graduate University for Advanced Studies, CIBER de Enfermedades Neurodegenerativas (CIBERNED), Doshisha University, National Cancer Research Center [Tokyo, Japan], University of Washington [Seattle], Department of Experimental Neurodegeneration [Göttingen, Germany], University Medical Center Göttingen (UMG), Cibles moléculaires et thérapeutiques de la maladie d'Alzheimer (CIMoTHeMA), Université de Poitiers, Laboratoire de Probabilités et Modèles Aléatoires (LPMA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), BioCeV-Institute of Microbiology, Médecine Personnalisée, Pharmacogénomique, Optimisation Thérapeutique (MEPPOT - U1147), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Istituto di chimica biologica, Università degli Studi di Verona, Département Image et Traitement Information (ITI), Institut Mines-Télécom [Paris] (IMT)-Université européenne de Bretagne - European University of Brittany (UEB)-Télécom Bretagne, Department of Cell Biology and Biophysics, Università degli Studi di Firenze [Firenze], Cell Immunity in Cancer, Inflammation and infection Group [Zaragoza, Spain] (Biomedical Research Center), Nanoscience Institute of Aragon - INA [Zaragoza, Spain]-Fundación Agencia Aragonesa para la Investigación y el Desarrollo - ARAID [Zaragoza, Spain]-University of Zaragoza - Universidad de Zaragoza [Zaragoza], Department of Pediatrics, Università degli studi di Napoli Federico II, Transfert de Genes a Visee Therapeutique Dans les Cellules Souches, Developpement Normal et Pathologique du Système Immunitaire, Signalisation et physiopathologie des cellules épithéliales, Facultad de Medicina, Universidad de Santiago de Chile [Santiago] (USACH), Departamento de Farmacobiología, Cinvestav-Sede Sur, Centre de recherche Croissance et signalisation (UMR_S 845), College of Life Sciences, Central China Normal University, Institute of Molecular Biotechnology, Austrian Academy of Sciences (OeAW), Laboratory of Cardiac Surgical Research, Monash University [Clayton], Universidade do Minho, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Neurodegenerative Diseases Research Group (CIBERNED), Vall d'Hebron Research Institute-Center for Networked Biomedical Research on Neurodegenerative Diseases, Barcelona, Department of medicine, Syracuse, NY, USA, State University of New York (SUNY), National University of Singapore (NUS)-Yong Loo Lin School of Medicine-Graduate School for Integrative Sciences and Engineering, McGill University Health Center [Montreal] (MUHC), National Institute for Infectious Diseases, Transporteurs en Imagerie et Radiothérapie en Oncologie (TIRO - UMR E4320), Service Hospitalier Frédéric Joliot (SHFJ), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-UMR E4320 (TIRO-MATOs), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Nice Sophia Antipolis (... - 2019) (UNS), Institut Gustave Roussy (IGR)-Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Biomedical Sciences, Department of Genetics of Eukaryotic Microorganisms, Georg-August-University [Göttingen]-Institute of Microbiology and Genetics, Sterol metabolism and therapeutic innovations in oncology, Institut Claudius Regaud, CRLCC Institut Claudius Regaud-CRLCC Institut Claudius Regaud-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Department of Molecular, Cellular and Developmental Biology, Señalización Celular 4, Institute of integrative biology (Liverpool), University of Liverpool, Department of Human Biology, University of Cape Town, National Institute of Diabetes and Digestive and Kidney Diseases [Bethesda], Department of Molecular Biology, Eberhard Karls Universität Tübingen, Technical University of Munich (TUM), Biophysics and Bioinformatics Laboratory, Department of Cell Biology and Morphology, Université de Lausanne (UNIL), Shenyang Institute of Automation, the Chinese Academy of Sciences (SIA), Key Laboratory of Thermo-Fluid Science and Engineering of Ministry of Education, Xi'an Jiaotong University (Xjtu), Dipartimento di Biologia, Mechanics laboratory , UniversityAmar Telidji, 3000 Laghouat, Algéria., Mechanics laboratory , University Amar Telidji, sans affiliation, Service d'hépatologie [Hôpital Beaujon], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), University of Waterloo, Waterloo, ON, Canada, Institute of Cell Biology and Immunology, University of Stuttgart, Chaperones Research Group, Institute of Biosciences and Technology [Houston, TX, États-Unis] (IBT), Texas A&M Health Science Center [Houston, TX, États-Unis] (TAMHSC), Texas A&M University Health Science Center-Texas A&M University Health Science Center, Aquatic and Crop Resource Development, National Research Council of Canada (NRC), Cibles thérapeutiques, formulation et expertise pré-clinique du médicament (CITHEFOR), Université de Lorraine (UL), Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche [Ancona] (UNIVPM), Department of Biochemistry and Molecular Biology [Indianapolis, IN, USA], Indiana University School of Medicine, Indiana University System-Indiana University System, Wellcome Trust Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, iMed.UL, Faculty of Pharmacy, University of Lisbon, CESAM & Biology Department, Universidade de Aveiro, Celullar and Molecular Medicine, Università degli Studi di Perugia (UNIPG), Institute of Clinical Molecular Biology, Kiel University, Apoptose et Système Immunitaire (ASI), Vieillissement Cellulaire Intégré et Inflammation (VCII), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Mathematical Sciences [Aalborg], Aalborg University [Denmark] (AAU), Cambridge Institute for Medical Research (CIMR), University of Cambridge [UK] (CAM), Biozentrum, University of Basel (Unibas), Structural and Computational Biology Unit, European Molecular Biology Laboratory [Grenoble] (EMBL), Rutgers New Jersey Medical School (NJMS), Rutgers University System (Rutgers), Université de Perpignan Via Domitia (UPVD), Universidad Pablo de Olavide [Sevilla] (UPO), Department of Neurosciences, Agronomes et Vétérinaires Sans Frontières (AVSF), AVSF, Department of Mathematics [Gakushuin], Gakushuin University, Department of Internal Medicine [Münster, Germany], University of Münster, Neurogenetics laboratory, University Medicine Goettingen, Institut de biologie structurale (IBS - UMR 5075), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS), Université d'Uruguay, Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération (LBCMCP), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Institute for Conservation & Improvement of Valentian Agrodiversity (COMAV), Universitat Politecnica de Valencia (UPV), ICBM, University of Chile [Santiago]-Faculty of Medicine, Nutrition, Métabolisme, Aquaculture (NuMéA), Institut National de la Recherche Agronomique (INRA)-Université de Pau et des Pays de l'Adour (UPPA), Department of Cell Biology, Baltimore, Johns Hopkins University School of Medicine, Baylor College of Medicine (BCM), Baylor University, University of Minnesota Medical School, Beijing Candid soft Technology Co. Ltd, Nanjing University of Information Science and Technology, Department of Hepatobiliary and Pancreatic Surgery [Maebashi, Japan], Gunma University Graduate Schoolof Medicine [Maebashi, Japan], Department of Molecular Genetics [Maastricht, The Netherlands], Maastricht University [The Netherlands], Institute of Cell Biology and Genetic Engineering, National Academy of Sciences of Ukraine (NASU), Institute of Pharmacology of Natural Products and Clinical Pharmacology, Institute of Pharmacology, University of Bern, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Wilmer Eye Institute, Mayo Clinic and Mayo College of Medicine, Rochester, Institute of Biochemistry and Biophysics, Polska Akademia Nauk (PAN)-Sciences, Department of Electrical and Computer Engineering [Waterloo] (ECE), University of Waterloo [Waterloo], Department of Chemistry and Toxicology, Norwegian Veterinary Institute, Department of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center [Houston], University of Minho, Friedrich Miescher Laboratory (FML), Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Department of Biomedical Sciences and Biotechnologies, Brescia University, Department of Physiological Chemistry [Bochum], Ruhr-Universität Bochum [Bochum], University of Oslo (UiO), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Facultés Universitaires Notre Dame de la Paix (FUNDP), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), École pratique des hautes études (EPHE)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut de recherche pour le développement [IRD] : UR226, Université du Québec à Montréal = University of Québec in Montréal (UQAM), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Université Lille 2 - Faculté de Médecine -Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Université de Franche-Comté (UFC), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon), Institut de Chimie de Toulouse (ICT-FR 2599), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Toulouse 1 Capitole (UT1)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse 1 Capitole (UT1)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Université Fédérale Toulouse Midi-Pyrénées, Université libre de Bruxelles (ULB), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Universidade Federal do Rio de Janeiro (UFRJ), Institut Bergonié [Bordeaux], UNICANCER, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Trafic membranaire et Division cellulaire - Membrane Traffic and Cell Division, Centre National de la Recherche Scientifique (CNRS)-CentraleSupélec-Université Paris-Sud - Paris 11 (UP11), McGill University = Université McGill [Montréal, Canada], Service d'Anatomie et Cytologie Pathologique [CHU Rouen], Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Signaling in Oncogenesis, Angiogenesis and Permeability (CRCINA-ÉQUIPE 15), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Universidad de Chile = University of Chile [Santiago] (UCHILE), Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III (ISC), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS), Université Panthéon-Sorbonne (UP1)-École pratique des hautes études (EPHE)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Collège de France (CdF (institution)), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Great Ormond Street Hospital for Children [London] (GOSH)-Institute of Child Health, Hokkaido University [Sapporo, Japan], Université Paris sciences et lettres (PSL), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université de Lyon-Université de Lyon, Centre d’Infection et d’Immunité de Lille (CIIL) - INSERM U1019 - UMR 9017 (CIIL), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Organisation Nucléaire et Oncogenèse - Nuclear Organization and Oncogenesis, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon], Centre National de la Recherche Scientifique (CNRS)-Institut de biologie physico-chimique (IBPC (FR_550)), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU), The Beatson Institute for Cancer Research, Beijing Normal University (BNU), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Fédération de Recherche Bézout-ESIEE Paris-École des Ponts ParisTech (ENPC)-Université Paris-Est Marne-la-Vallée (UPEM), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA), Université de Lyon-Université de Lyon-Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre Léon Bérard [Lyon], Vall d’Hebron Research Institute (VHIR), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Universidade Nova de Lisboa = NOVA University of Lisboa (NOVA), Université de Montpellier (UM)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Doshisha University [Kyoto], Université européenne de Bretagne - European University of Brittany (UEB)-Télécom Bretagne-Institut Mines-Télécom [Paris] (IMT), Università degli Studi di Firenze = University of Florence [Firenze], University of Zaragoza - Universidad de Zaragoza [Zaragoza]-Nanoscience Institute of Aragon - INA [Zaragoza, Spain]-Fundación Agencia Aragonesa para la Investigación y el Desarrollo - ARAID [Zaragoza, Spain], Central China Normal University [Wuhan, China], Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-UMR E4320 (TIRO-MATOs), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut Claudius Regaud, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de biologie structurale [1992-2019] (IBS - UMR 5075 [1992-2019]), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Nanjing University of Information Science and Technology (NUIST), Facultad de Medicina [Buenos Aires], Universidad de Buenos Aires [Buenos Aires] (UBA)-Universidad de Buenos Aires [Buenos Aires] (UBA)-Consejo Nacional de Investigaciones Científicas y Técnicas [Buenos Aires] (CONICET), Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Clermont Auvergne (UCA)-Institut National de la Recherche Agronomique (INRA), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Consejo Nacional de Investigaciones Científicas y Técnicas [Buenos Aires] (CONICET)-Universidad Nacional de San Martin (UNSAM), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, George Mason University [Fairfax]-Center for Applied Proteomics and Molecular Medicine, Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Institute of Infection, Immunity and Inflammation [Glasgow, UK]-University of Glasgow, Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Settore BIO/06, biology, Cell Biology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, biology.organism_classification, Cell biology, Interpretation (model theory), 03 medical and health sciences, Arama, 030104 developmental biology, Molecular Biology, Humanities, ComputingMilieux_MISCELLANEOUS
Abstract

Author(s): Klionsky, DJ; Abdelmohsen, K; Abe, A; Abedin, MJ; Abeliovich, H; Arozena, AA; Adachi, H; Adams, CM; Adams, PD; Adeli, K; Adhihetty, PJ; Adler, SG; Agam, G; Agarwal, R; Aghi, MK; Agnello, M; Agostinis, P; Aguilar, PV; Aguirre-Ghiso, J; Airoldi, EM; Ait-Si-Ali, S; Akematsu, T; Akporiaye, ET; Al-Rubeai, M; Albaiceta, GM; Albanese, C; Albani, D; Albert, ML; Aldudo, J; Algul, H; Alirezaei, M; Alloza, I; Almasan, A; Almonte-Beceril, M; Alnemri, ES; Alonso, C; Altan-Bonnet, N; Altieri, DC; Alvarez, S; Alvarez-Erviti, L; Alves, S; Amadoro, G; Amano, A; Amantini, C; Ambrosio, S; Amelio, I; Amer, AO; Amessou, M; Amon, A; An, Z; Anania, FA; Andersen, SU; Andley, UP; Andreadi, CK; Andrieu-Abadie, N; Anel, A; Ann, DK; Anoopkumar-Dukie, S; Antonioli, M; Aoki, H; Apostolova, N; Aquila, S; Aquilano, K; Araki, K; Arama, E; Aranda, A; Araya, J; Arcaro, A; Arias, E; Arimoto, H; Ariosa, AR; Armstrong, JL; Arnould, T; Arsov, I; Asanuma, K; Askanas, V; Asselin, E; Atarashi, R; Atherton, SS; Atkin, JD; Attardi, LD; Auberger, P; Auburger, G; Aurelian, L; Autelli, R

Published
2016
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131. Integration of cellular bioenergetics with mitochondrial quality control and autophagy

Author

Scott W. Ballinger, Gloria A. Benavides, Jack R. Lancaster, Zhang Jianhua, Bradford G. Hill, Lou Dell'Italia, and Victor M. Darley-Usmar

Subjects
Mitochondrial DNA, Bioenergetics, Clinical Biochemistry, Population, Respiratory chain, Mitochondrion, Biology, DNA, Mitochondrial, Biochemistry, Article, Diabetes mellitus genetics, Mitophagy, Autophagy, Diabetes Mellitus, Animals, Humans, Obesity, education, Molecular Biology, education.field_of_study, Neurodegenerative Diseases, Mitochondria, Cell biology, Cardiovascular Diseases, Energy Metabolism, DNA Damage
Abstract

Bioenergetic dysfunction is emerging as a cornerstone for establishing a framework for understanding the pathophysiology of cardiovascular disease, diabetes, cancer and neurodegeneration. Recent advances in cellular bioenergetics have shown that many cells maintain a substantial bioenergetic reserve capacity, which is a prospective index of ‘healthy’ mitochondrial populations. The bioenergetics of the cell are likely regulated by energy requirements and substrate availability. Additionally, the overall quality of the mitochondrial population and the relative abundance of mitochondria in cells and tissues also impinge on overall bioenergetic capacity and resistance to stress. Because mitochondria are susceptible to damage mediated by reactive oxygen/nitrogen and lipid species, maintaining a ‘healthy’ population of mitochondria through quality control mechanisms appears to be essential for cell survival under conditions of pathological stress. Accumulating evidence suggest that mitophagy is particularly important for preventing amplification of initial oxidative insults, which otherwise would further impair the respiratory chain or promote mutations in mitochondrial DNA (mtDNA). The processes underlying the regulation of mitophagy depend on several factors, including the integrity of mtDNA, electron transport chain activity, and the interaction and regulation of the autophagic machinery. The integration and interpretation of cellular bioenergetics in the context of mitochondrial quality control and genetics is the theme of this review.

Published
2012
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132. Cell signalling by reactive lipid species: new concepts and molecular mechanisms

Author

Joo Yeun Oh, Victor M. Darley-Usmar, Anne R. Diers, Ashlee N. Higdon, and Aimee Landar

Subjects
HNE, 4-hydroxynonenal, Review Article, Biochemistry, Hsp, heat-shock protein, EpRE, electrophilic-response element, Lipid peroxidation, chemistry.chemical_compound, 0302 clinical medicine, GST, glutathione transferase, nuclear factor-erythroid 2 related factor (Nrf2), Nrf2, nuclear factor-erythroid 2-related factor, BLT, leukotriene B receptor, LOX, lipoxygenase, chemistry.chemical_classification, 0303 health sciences, Cell Death, electrophile-responsive proteome, HO-1, haem oxygenase-1, lipid peroxidation, Cell biology, Amino acid, Keap1, Kelch-like ECH-associated protein 1, Signal transduction, 15d-PGJ2, 15-deoxyprostaglandin J2, Oxidation-Reduction, Signal Transduction, Cell signaling, LT, leukotriene, Biology, protein modification, RNS, reactive nitrogen species, COX, cyclo-oxygenase, 03 medical and health sciences, ROS, reactive oxygen species, Stress, Physiological, PUFA, polyunsaturated fatty acid, Autophagy, Animals, Humans, Kelch-like ECH-associated protein 1 (Keap1), PG, prostaglandin, Molecular Biology, PPARγ, peroxisome-proliferator-activated receptor γ, 030304 developmental biology, HSF, heat-shock factor, RLS, reactive lipid species, Lipid metabolism, Cell Biology, Glutathione, Lipid Metabolism, reactive lipid species (RLS), chemistry, 030217 neurology & neurosurgery, CysLT, cysteinyl leukotriene receptor, Cysteine
Abstract

The process of lipid peroxidation is widespread in biology and is mediated through both enzymatic and non-enzymatic pathways. A significant proportion of the oxidized lipid products are electrophilic in nature, the RLS (reactive lipid species), and react with cellular nucleophiles such as the amino acids cysteine, lysine and histidine. Cell signalling by electrophiles appears to be limited to the modification of cysteine residues in proteins, whereas non-specific toxic effects involve modification of other nucleophiles. RLS have been found to participate in several physiological pathways including resolution of inflammation, cell death and induction of cellular antioxidants through the modification of specific signalling proteins. The covalent modification of proteins endows some unique features to this signalling mechanism which we have termed the ‘covalent advantage’. For example, covalent modification of signalling proteins allows for the accumulation of a signal over time. The activation of cell signalling pathways by electrophiles is hierarchical and depends on a complex interaction of factors such as the intrinsic chemical reactivity of the electrophile, the intracellular domain to which it is exposed and steric factors. This introduces the concept of electrophilic signalling domains in which the production of the lipid electrophile is in close proximity to the thiol-containing signalling protein. In addition, we propose that the role of glutathione and associated enzymes is to insulate the signalling domain from uncontrolled electrophilic stress. The persistence of the signal is in turn regulated by the proteasomal pathway which may itself be subject to redox regulation by RLS. Cell death mediated by RLS is associated with bioenergetic dysfunction, and the damaged proteins are probably removed by the lysosome-autophagy pathway.

Published
2012
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133. Measuring reactive oxygen and nitrogen species with fluorescent probes: challenges and limitations

Author

Henry Jay Forman, Victor M. Darley-Usmar, Matthew B. Grisham, Giovanni E. Mann, Balaraman Kalyanaraman, Kevin P. Moore, Kelvin J.A. Davies, Harry Ischiropoulos, L. Jackson Roberts, and Phyllis A. Dennery

Subjects
Staining and Labeling, Inorganic chemistry, chemistry.chemical_element, Oxidation reduction, Hydrogen Peroxide, Reactive Nitrogen Species, Biochemistry, Nitrogen, Oxygen, Fluorescence, Article, chemistry.chemical_compound, Spectrometry, Fluorescence, chemistry, Superoxides, Peroxynitrous Acid, Physiology (medical), Biochemical engineering, Reactive Oxygen Species, Oxidation-Reduction, Reactive nitrogen species, Fluorescent Dyes
Abstract

The purpose of this position paper is to present a critical analysis of the challenges and limitations of the most widely used fluorescent probes for detecting and measuring reactive oxygen and nitrogen species. Where feasible, we have made recommendations for the use of alternate probes and appropriate analytical techniques that measure the specific products formed from the reactions between fluorescent probes and reactive oxygen and nitrogen species. We have proposed guidelines that will help present and future researchers with regard to the optimal use of selected fluorescent probes and interpretation of results.

Published
2012
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134. The role of GABARAPL1/GEC1 in Autophagic Flux and Mitochondrial Quality Control in MDA-MB-436 Breast Cancer Cells

Author

Victor M. Darley-Usmar, Michaël Boyer-Guittaut, Jianhua Zhang, and Sooryanarayana Varambally

Subjects
0301 basic medicine, Programmed cell death, Tumor suppressor gene, LAMP1, Autophagy, Mitochondrion, Biology, medicine.disease_cause, Biochemistry, Cell biology, 03 medical and health sciences, 030104 developmental biology, Downregulation and upregulation, Physiology (medical), Mitophagy, medicine, Carcinogenesis
Abstract

The clearance of cellular damaged molecules and organelles are dependent on a fundamental process called autophagy which is now emerging as an important pathway in cancer biology. Since the discovery of the phenomena and the genetic program in the 1960 and 1990s, autophagy has been found to play an important role in a broad range of pathologies including breast cancer. One key feature of macroautophagy is the formation of the double membraned vesicles which contain lipidated microtubule associated protein 1A/1B light chain 3 (LC3-II). LC3 has 7 homologs in humans, one of the understudied LC3 homolog is GABARAPL1/GEC1 which was first discovered as an early estrogen-regulated gene, and later found to be an autophagy effector gene. High expression of GABARAPL1 mRNA is associated with a better outcome for patients with lymph node-positive breast cancer (1). Overexpression of GABARAPL1 protein decreased MCF7 proliferation and tumor growth in xenografts (1;2). We have shown that downregulation of GABARAPL1 in MDA-MB-436 cells promotes cell growth, colony formation and invasion through mechanisms involving decreased autophagic flux, decreased lysosomal number, increased mitochondrial number, mtDNA damage, oxidative protein damage, as well as glutathione, and resistance to oxidative stress-induced cell death (3). These results demonstrate that GABARAPL1 is important in integrating cellular metabolism with proliferation and resistance to cell death. Recent bioinformatics studies have found that GABARAPL1 transcripts are downregulated in all breast cancers independent of stage, race, age, menopause status, or BRCA. Furthermore, while prior studies have shown that GABARAPL1 gene is epigenetically regulated, and bioinformatics studies have found that its expression is mutually exclusive with EZH2. Thus understanding how GABARAPL1 is regulated in breast cancer cells and the exact mechanisms of how GABARAPL1 plays a role in suppressing lysosomal biogenesis, and enhancing mitochondrial number, bioenergetics, and reductive potential will be important for us to better understand tumorigenesis and therapeutic strategies against cancers with loss of tumor suppressor gene GABARAPL1 and is thus our current focus.

Published
2017
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135. Autophagy and the redox connection: Virtual collection Vol 2

Author

Jianhua Zhang and Victor M. Darley-Usmar

Subjects
lcsh:R5-920, Organic Chemistry, Clinical Biochemistry, Autophagy, Oxidation reduction, Biology, Biochemistry, Redox, Connection (mathematics), Cell biology, Disease susceptibility, Editorial, lcsh:Biology (General), Animals, Humans, Disease Susceptibility, lcsh:Medicine (General), Oxidation-Reduction, lcsh:QH301-705.5, Signal Transduction
Published
2017
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136. Nitric oxide and hypoxia exacerbate alcohol-induced mitochondrial dysfunction in hepatocytes

Author

Blake R. Zelickson, Victor M. Darley-Usmar, Michelle S. Johnson, Balu K. Chacko, Shannon M. Bailey, Angela M. Betancourt, Aparna Venkatraman, Aimee Landar, and Gloria A. Benavides

Subjects
Male, medicine.medical_specialty, Bioenergetics, Cellular respiration, Bioenergetic, Cell Respiration, Biophysics, Nitric Oxide Synthase Type II, Mitochondria, Liver, Biology, Nitric Oxide, Biochemistry, Article, Nitric oxide, Rats, Sprague-Dawley, Mice, chemistry.chemical_compound, Internal medicine, medicine, Animals, Cytochrome c oxidase, Hypoxia, Inducible nitric oxide synthase, Reactive nitrogen species, Mice, Knockout, chemistry.chemical_classification, Reactive oxygen species, Ethanol, Cell Biology, Hypoxia (medical), Diet, Rats, Mice, Inbred C57BL, Nitric oxide synthase, Reserve capacity, Endocrinology, Liver, chemistry, Hepatocytes, biology.protein, medicine.symptom, Energy Metabolism
Abstract

Chronic alcohol consumption results in hepatotoxicity, steatosis, hypoxia, increased expression of inducible nitric oxide synthase (iNOS) and decreased activities of mitochondrial respiratory enzymes. The impact of these changes on cellular respiration and their interaction in a cellular setting is not well understood. In the present study we tested the hypothesis that nitric oxide ( NO)-dependent modulation of cellular respiration and the sensitivity to hypoxic stress is increased following chronic alcohol consumption. This is important since NO has been shown to regulate mitochondrial function through its interaction with cytochrome c oxidase, although at higher concentrations, and in combination with reactive oxygen species, can result in mitochondrial dysfunction. We found that hepatocytes isolated from alcohol-fed rats had decreased mitochondrial bioenergetic reserve capacity and were more sensitive to NO-dependent inhibition of respiration under room air and hypoxic conditions. We reasoned that this would result in greater hypoxic stress in vivo, and to test this, wild-type and iNOS−/− mice were administered alcohol-containing diets. Chronic alcohol consumption resulted in liver hypoxia in the wild-type mice and increased levels of hypoxia-inducible factor 1α in the peri-venular region of the liver lobule. These effects were attenuated in the alcohol-fed iNOS−/− mice suggesting that increased mitochondrial sensitivity to NO and reactive nitrogen species in hepatocytes and iNOS plays a critical role in determining the response to hypoxic stress in vivo. These data support the concept that the combined effects of NO and ethanol contribute to an increased susceptibility to hypoxia and the deleterious effects of alcohol consumption on liver.

Published
2011
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137. Assessing bioenergetic function in response to oxidative stress by metabolic profiling

Author

Luyun Zou, Bradford G. Hill, Victor M. Darley-Usmar, Blake R. Zelickson, Gloria A. Benavides, Anne R. Diers, Brian P. Dranka, Colin Reily, John C. Chatham, Jianhua Zhang, Aimee Landar, and Samantha Giordano

Subjects
Cell type, Bioenergetics, Mitochondrion, medicine.disease_cause, Biochemistry, Article, Nitric oxide, 4-Hydroxynonenal, chemistry.chemical_compound, Physiology (medical), medicine, Extracellular, Animals, Humans, Cells, Cultured, Neurodegeneration, Hydrogen-Ion Concentration, medicine.disease, Mitochondria, Cell biology, Oxygen, Oxidative Stress, chemistry, Energy Metabolism, Oxidative stress
Abstract

It is now clear that mitochondria are an important target for oxidative stress in a broad range of pathologies including cardiovascular disease, diabetes, neurodegeneration, and cancer. Methods for assessing the impact of reactive species on isolated mitochondria are well established but constrained by the need for large amounts of material to prepare intact mitochondria for polarographic measurements. With the availability of high resolution polarography and fluorescence techniques for the measurement of oxygen concentration in solution, measurements of mitochondrial function in intact cells can be made. Recently, the development of extracellular flux methods to monitor changes in oxygen concentration and pH in cultures of adherent cells in multiple sample wells simultaneously has greatly enhanced the ability to meaure bioenergetic function in response to oxidative stress. Here we describe these methods in detail using representative cell types from the renal, cardiovascular, nervous, and tumorigenic model systems while illustrating the application of three protocols to analyze the bioenergetic response of cells to oxidative stress.

Published
2011
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138. Oxidases and peroxidases in cardiovascular and lung disease: New concepts in reactive oxygen species signaling

Author

Victor M. Darley-Usmar, Patrick J. Pagano, Phillip M. Bauer, Nicholas K.H. Khoo, Mark T. Gladwin, Victor J. Thannickal, Bruce A. Freeman, Ulla G. Knaus, Imad Al Ghouleh, Eugenia Cifuentes-Pagano, Sruti Shiva, Rhian M. Touyz, William M. Nauseef, Aaron Barchowsky, Eric E. Kelley, and Kathy K. Griendling

Subjects
Lung Diseases, Cell signaling, Mitochondrion, Biochemistry, Article, Protein Structure, Secondary, Mice, Physiology (medical), Animals, Humans, Lung, Cellular localization, S1PR1, chemistry.chemical_classification, Reactive oxygen species, Oxidase test, NADPH oxidase, biology, Chemistry, Fatty Acids, NADPH Oxidases, Nitro Compounds, Mitochondria, Protein Structure, Tertiary, Rats, Peroxidases, Cardiovascular Diseases, Organ Specificity, biology.protein, Signal transduction, Energy Metabolism, Reactive Oxygen Species, Oxidation-Reduction, Signal Transduction
Abstract

Reactive oxygen species (ROS) are involved in numerous physiological and pathophysiological responses. Increasing evidence implicates ROS as signaling molecules involved in the propagation of cellular pathways. The NADPH oxidase (Nox) family of enzymes is a major source of ROS in the cell and has been related to the progression of many diseases and even in environmental toxicity. The complexity of this family’s effects on cellular processes stems from the fact that there are 7 members, each with unique tissue distribution, cellular localization and expression. Nox proteins also differ in activation mechanisms and the major ROS detected as their product. To add to this complexity, mounting evidence suggests that other cellular oxidases or their products may be involved in Nox regulation. The overall redox and metabolic status of the cell, specifically the mitochondria, also has implications on ROS signaling. Signaling of such molecules as electrophillic fatty acids has impact on many redox sensitive pathologies, and thus, as anti-inflammatory molecules, contributes to the complexity of ROS regulation. The following review is based on the proceedings of a recent international Oxidase Signaling Symposium at the University of Pittsburgh’s Vascular Medicine Institute and Department of Pharmacology and Chemical Biology, and encompasses further interaction and discussion among the presenters.

Published
2011
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139. PYK2 signaling is required for PDGF-dependent vascular smooth muscle cell proliferation

Author

Pamela A. Lucchesi, Petra Rocic, Mary J. Cismowski, David S. Weber, Rebeccca A Torres, Victor M. Darley-Usmar, and Jessica Perez

Subjects
MAPK/ERK pathway, Physiology, Myocytes, Smooth Muscle, Biology, Mitogen-activated protein kinase kinase, Retinoblastoma Protein, p38 Mitogen-Activated Protein Kinases, Muscle, Smooth, Vascular, Phosphatidylinositol 3-Kinases, Vascular Biology, Animals, Cyclin D1, Phosphorylation, RNA, Small Interfering, Extracellular Signal-Regulated MAP Kinases, Protein kinase A, Protein kinase B, Cell Proliferation, Mitogen-Activated Protein Kinase Kinases, Platelet-Derived Growth Factor, Cyclin-dependent kinase 1, Akt/PKB signaling pathway, Cell Cycle, Cyclin-dependent kinase 2, DNA, Cell Biology, Cyclin-Dependent Kinases, Rats, Cell biology, Focal Adhesion Kinase 2, Protein Biosynthesis, biology.protein, Cancer research, RNA Interference, Proto-Oncogene Proteins c-akt, Cyclin-Dependent Kinase Inhibitor p27, Platelet-derived growth factor receptor, Signal Transduction
Abstract

Aberrant vascular smooth muscle cell (VSMC) growth is associated with many vascular diseases including atherosclerosis, hypertension, and restenosis. Platelet-derived growth factor-BB (PDGF) induces VSMC proliferation through control of cell cycle progression and protein and DNA synthesis. Multiple signaling cascades control VSMC growth, including members of the mitogen-activated protein kinase (MAPK) family as well as phosphatidylinositol 3-kinase (PI3K) and its downstream effector AKT/protein kinase B (PKB). Little is known about how these signals are integrated by mitogens and whether there are common receptor-proximal signaling control points that synchronize the execution of physiological growth functions. The nonreceptor proline-rich tyrosine kinase 2 (PYK2) is activated by a variety of growth factors and G protein receptor agonists in VSMC and lies upstream of both PI3K and MAPK cascades. The present study investigated the role of PYK2 in PDGF signaling in cultured rat aortic VSMC. PYK2 downregulation attenuated PDGF-dependent protein and DNA synthesis, which correlated with inhibition of AKT and extracellular signal-regulated kinases 1 and 2 (ERK1/2) but not p38 MAPK activation. Inhibition of PDGF-dependent protein kinase B (AKT) and ERK1/2 signaling by inhibitors of upstream kinases PI3K and MEK, respectively, as well as downregulation of PYK2 resulted in modulation of the G1/S phase of the cell cycle through inhibition of retinoblastoma protein (Rb) phosphorylation and cyclin D1expression, as well as p27Kipupregulation. Cell division kinase 2 (cdc2) phosphorylation at G2/M was also contingent on PDGF-dependent PI3K-AKT and ERK1/2 signaling. These data suggest that PYK2 is an important upstream mediator in PDGF-dependent signaling cascades that regulate VSMC proliferation.

Published
2011
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140. Mitochondria-targeted ubiquinone (MitoQ) decreases ethanol-dependent micro and macro hepatosteatosis

Author

Balaraman Kalyanaraman, Anup Srivastava, Michael P. Murphy, Mi Jung Chang, Nirag Jhala, Michelle S. Johnson, Victor M. Darley-Usmar, Balu K. Chacko, Gloria A. Benavides, and Yaozu Ye

Subjects
Male, medicine.medical_specialty, Alcoholic liver disease, Ubiquinone, Mitochondria, Liver, Oxidative phosphorylation, AMP-Activated Protein Kinases, Biology, Mitochondrion, Article, Antioxidants, Electron Transport, Rats, Sprague-Dawley, chemistry.chemical_compound, Organophosphorus Compounds, Internal medicine, medicine, Animals, Reactive nitrogen species, chemistry.chemical_classification, Reactive oxygen species, MitoQ, Dose-Response Relationship, Drug, Ethanol, Hepatology, Cytochrome P-450 CYP2E1, Hypoxia-Inducible Factor 1, alpha Subunit, Lipid Metabolism, medicine.disease, Rats, Fatty Liver, Disease Models, Animal, Endocrinology, Mitochondrial respiratory chain, Liver, chemistry, Steatosis, Reactive Oxygen Species
Abstract

Chronic alcohol-induced liver disease results in inflammation, steatosis, and increased oxidative and nitrosative damage to the mitochondrion. We hypothesized that targeting an antioxidant to the mitochondria would prevent oxidative damage and attenuate the steatosis associated with alcoholic liver disease. To test this we investigated the effects of mitochondria-targeted ubiquinone (MitoQ) (5 and 25 mg/kg/day for 4 weeks) in male Sprague-Dawley rats consuming ethanol using the Lieber-DeCarli diet with pair-fed controls. Hepatic steatosis, 3-nitrotyrosine (3-NT), 4-hydroxynonenal (4-HNE), hypoxia inducible factor α (HIF1α), and the activity of the mitochondrial respiratory chain complexes were assessed. As reported previously, ethanol consumption resulted in hepatocyte ballooning, increased lipid accumulation in the form of micro and macrovesicular steatosis, and induction of cytochrome P450 2E1 (CYP2E1). MitoQ had a minor effect on the ethanol-dependent decrease in mitochondrial respiratory chain proteins and their activities; however, it did decrease hepatic steatosis in ethanol-consuming animals and prevented the ethanol-induced formation of 3-NT and 4-HNE. Interestingly, MitoQ completely blocked the increase in HIF1α in all ethanol-fed groups, which has previously been demonstrated in cell culture models and shown to be essential in ethanol-dependent hepatosteatosis. Conclusion: These results demonstrate the antioxidant capacity of MitoQ in alleviating alcohol-associated mitochondrial reactive oxygen species (ROS) and several downstream effects of ROS/RNS (reactive nitrogen species) production such as inhibiting protein nitration and protein aldehyde formation and specifically ROS-dependent HIF1α stabilization. (HEPATOLOGY 2011;)

Published
2011
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141. Loss of interstitial collagen causes structural and functional alterations of cardiomyocyte subsarcolemmal mitochondria in acute volume overload

Author

Betty Pat, Junying Zheng, Wayne E. Bradley, Victor M. Darley-Usmar, Elena Ulasova, Scott W. Ballinger, Louis J. Dell'Italia, James D. Gladden, Blake R. Zelickson, Yuanwen Chen, Pamela C. Powell, and Jaroslaw W. Zmijewski

Subjects
medicine.medical_specialty, Blotting, Western, Volume overload, Inflammation, Oxidative phosphorylation, Mitochondrion, medicine.disease_cause, digestive system, Mitochondria, Heart, Ventricular Function, Left, Article, Rats, Sprague-Dawley, chemistry.chemical_compound, Microscopy, Electron, Transmission, Internal medicine, Respiration, medicine, Animals, Myocytes, Cardiac, Molecular Biology, Microscopy, Confocal, Superoxide, Anatomy, medicine.disease, Echoencephalography, Immunohistochemistry, Rats, Oxidative Stress, Endocrinology, chemistry, Heart failure, Collagen, medicine.symptom, Cardiology and Cardiovascular Medicine, Oxidative stress
Abstract

Volume overload (VO) caused by aortocaval fistula (ACF) is associated with oxidative/inflammatory stress. The resulting inflammation, matrix metalloproteinase (MMP) activation, and collagen degradation is thought to play a pivotal role in left ventricular (LV) dilatation and failure. Since mitochondria are also targets for inflammation and oxidative stress, we hypothesized that there would be bioenergetic dysfunction with acute VO. In Sprague-Dawley rats subjected to 24 hrs of ACF, there was a two-fold increase in LV pressure-volume area in vivo, consistent with increased LV myocardial oxygen usage and increased bioenergetic demand in cardiomyocytes. Isolated cardiomyocytes from ACF LVs demonstrated increased hydrogen peroxide and superoxide formation and increased MMP activity. Subsarcolemmal mitochondria (SSM) showed a 40% decrease in state 3 respiration and proteomic analysis of SSM demonstrated decreased levels of complexes I-V in ACF. Immunohistochemical analysis revealed disruption of the subsarcolemmal location of the SSM network in ACF. To test for a potential link between SSM dysfunction and loss of interstitial collagen, rats were treated with the MMP-inhibitor PD166793 prior to ACF. MMP-inhibitor preserved interstitial collagen, integrin-α5 and the SSM structural arrangement. In addition, the decrease in state 3 mitochondrial respiration with ACF was prevented by PD166793. These studies established an important interaction between degradation of interstitial collagen in acute VO and the disruption of SSM structure and function which could contribute to progression to heart failure.

Published
2011
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142. SIRT1 Mediates Enhanced Mitochondrial Oxidative Phosphorylation in Chronic Myelogenous Leukemia Stem Cells

Author

Balu K. Chacko, Hui Li, Shaowei Qiu, Andrew J. Paterson, Victor M. Darley-Usmar, Ravi Bhatia, Mansi Shah, Robert S. Welner, Jianbo He, Puneet Agarwal, and Ajay Abraham

Subjects
0301 basic medicine, Immunology, Cell Biology, Hematology, Mitochondrion, Biology, medicine.disease, Biochemistry, Transplantation, 03 medical and health sciences, Haematopoiesis, 030104 developmental biology, Mitochondrial biogenesis, hemic and lymphatic diseases, Cancer cell, Cancer research, medicine, Stem cell, Progenitor cell, Chronic myelogenous leukemia
Abstract

Despite the success of BCR-ABL tyrosine kinase inhibitors (TKIs) in inducing remission and prolonging survival of CML patients, cures remain elusive because of persistence of primitive leukemia stem cells (LSC). We have reported that SIRT1, a NAD+ dependent deacetylase, is overexpressed in CML LSC and contributes to their maintenance and TKI resistance, related at least in part to increased p53 acetylation and transcriptional activity (Li et.al; Cancer Cell 2012). However, these studies using RNAi and pharmacological inhibitors were limited by possible off-target effects and limited duration of exposure. Therefore, to definitively delineate the role of SIRT1 in CML development, we developed a conditional SIRT1 knockout mouse model by crossing SIRT1 floxed mice (SIRT1fl/fl) with the Mx1-Cre strain to delete SIRT1 in hematopoietic stem cells (HSC), and crossed with transgenic BCR-ABL mice (BA Mx1-Cre SIRT1fl/fl). SIRT1 deletion in normal HSC did not inhibit normal hematopoiesis. In contrast, SIRT1 deletion in LSC profoundly inhibited the development of CML, and SIRT1-deleted CML mice did not develop evidence of morbidity and demonstrated significantly lower leukocytosis, neutrophilia and splenomegaly, and markedly improved survival, compared to controls (Fig-1). CML development in the SCL-tTA/BCR-ABL mouse model is associated with reduction in BM stem cells, and increase in stem/progenitor cell populations in the spleen. Splenic stem and progenitor populations were significantly decreased in SIRT1-deleted mice, whereas BM LTHSC were increased, indicating reversal of alterations associated with CML. SIRT1 deletion was associated with a significant decrease in LTHSC in G0 phase and increase in LTHSC in G1 phase of cell cycle. SIRT1-deleted LTHSCs generated significantly lower WBC counts, donor cell and donor LTHSC engraftment following transplantation into wild-type recipients compared to controls, indicating reduced in vivo repopulating ability. Treatment with the BCR-ABL TKI Nilotinib (50mg/kg/day) or vehicle for 4 weeks resulted in additional suppression of CML hematopoiesis in SIRT1-deleted mice. Gene expression analysis identified significant inhibition of mitochondria and oxidative phosphorylation related genes in SIRT1-deleted CML stem cells compared to controls. We performed extracellular flux analysis of oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) using the Seahorse XF analyzer to evaluate mitochondrial respiration and glycolysis in c-Kit+ stem/progenitor cells from SIRT1-deleted and control CML and normal mice. CML LSC demonstrated significantly increased ATP-linked respiration, maximal mitochondrial respiration and mitochondrial reserve capacity compared to normal HSC. SIRT1-deletion resulted in significant reduction in basal and maximal mitochondrial respiration, and in mitochondrial reserve capacity, in CML LSC (Fig-2). In contrast, SIRT1-deletion did not result in significant change in mitochondrial respiration in normal HSC, suggesting that effects of SIRT1 deletion on mitochondrial respiration were specific to CML cells. The SIRT1 substrate PGC-1α is a master regulator of mitochondrial biogenesis and activity. Treatment of CML mice with the PGC-1α inhibitor SR-18292 significantly reduced basal, ATP-linked and maximal mitochondrial respiration. Consistent with results obtained with murine LSC, SIRT1 inhibition with TV39OH resulted in significant reduction in mitochondrial respiration in CML CD34+ cells compared to vehicle controls. Treatment of CML mice with Nilotinib did not significantly alter mitochondrial respiration in LSC. Similarly TKI treatment did not affect mitochondrial respiration in CML CD34+ cells compared to vehicle controls. In conclusion, our studies definitively demonstrate that SIRT1 is required for leukemia development, and reveal its critical role in increased mitochondrial respiration in CML LSC. Increased mitochondrial metabolism is kinase-independent, and is mediated by PGC-1a. SIRT1 inhibition results in enhanced inhibition of TKI-treated LSC. Our studies demonstrate an essential role for SIRT1 in altered mitochondrial metabolism in CML LSC, and support further exploration of SIRT1 pathway inhibition for LSC targeting. Disclosures No relevant conflicts of interest to declare.

Published
2018
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143. Acquisition of Temozolomide Chemoresistance in Gliomas Leads to Remodeling of Mitochondrial Electron Transport Chain

Author

G. Yancey Gillespie, Shannon M. Bailey, Jann N. Sarkaria, Victor M. Darley-Usmar, Anne R. Diers, Claudia R. Oliva, Susan Nozell, Samuel G. McClugage, Aimee Landar, James M. Markert, and Corinne E. Griguer

Subjects
Programmed cell death, DNA damage, Transplantation, Heterologous, Apoptosis, Bioenergetics, Mitochondrion, Biology, DNA, Mitochondrial, Biochemistry, Mice, Oxygen Consumption, Cell Line, Tumor, Glioma, Temozolomide, medicine, Animals, Humans, Cytochrome c oxidase, Respiratory function, Antineoplastic Agents, Alkylating, Molecular Biology, Cell Biology, medicine.disease, Molecular biology, Mitochondria, Neoplasm Proteins, Dacarbazine, Electron Transport Chain Complex Proteins, Drug Resistance, Neoplasm, Cancer research, biology.protein, Neoplasm Transplantation, DNA Damage, medicine.drug
Abstract

Temozolomide (TMZ) is an oral alkylating agent used for the treatment of high-grade gliomas. Acquired chemoresistance is a severe limitation to this therapy with more than 90% of recurrent gliomas showing no response to a second cycle of chemotherapy. Efforts to better understand the underlying mechanisms of acquired chemoresistance to TMZ and potential strategies to overcome chemoresistance are, therefore, critically needed. TMZ methylates nuclear DNA and induces cell death; however, the impact on mitochondria DNA (mtDNA) and mitochondrial bioenergetics is not known. Herein, we tested the hypothesis that TMZ-mediated alterations in mtDNA and respiratory function contribute to TMZ-dependent acquired chemoresistance. Using an in vitro model of TMZ-mediated acquired chemoresistance, we report 1) a decrease in mtDNA copy number and the presence of large heteroplasmic mtDNA deletions in TMZ-resistant glioma cells, 2) remodeling of the entire electron transport chain with significant decreases of complexes I and V and increases of complexes II/III and IV, and 3) pharmacologic and genetic manipulation of cytochrome c oxidase, which restores sensitivity to TMZ-dependent apoptosis in resistant glioma cells. Importantly, human primary and recurrent pairs of glioblastoma multiforme (GBM) biopsies as well as primary and TMZ-resistant GBM xenograft lines exhibit similar remodeling of the ETC. Overall these results suggest that TMZ-dependent acquired chemoresistance may be due to a mitochondrial adaptive response to TMZ genotoxic stress with a major contribution from cytochrome c oxidase. Thus, abrogation of this adaptive response may reverse chemoresistance and restore sensitivity to TMZ, providing a strategy for improved therapeutic outcomes in GBM patients.

Published
2010
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144. Metabolome-wide association study in human platelets for identification of metabolic signatures related to precision medicine

Author

Gloria A. Benavides, Young-Mi Go, Matthew R. Smith, Dean P. Jones, Balu K. Chacko, Michelle S. Johnson, Victor M. Darley-Usmar, and Karan Uppal

Subjects
Exposome, Bioenergetics, Mechanism (biology), Biology, Mitochondrion, medicine.disease_cause, Biochemistry, Cell biology, Metabolomics, Physiology (medical), Metabolome, medicine, Flux (metabolism), Oxidative stress
Abstract

Background Mitochondria play a critical role in the integration of cellular bioenergetic homeostasis. Bioenergetic diversity exists between individuals due to influence of factors such as age, genetics, or through differences in the exposome. The mechanism for this bioenergetic diversity has not been fully elucidated. Metabolism, which is regulated through the redox interface, has been suggested to govern bioenergetics homeostasis. Hence, it is crucial to understand the impact of bioenergetic and metabolic signatures to further develop a personalized approach for clinical management. Recent research has suggested circulating platelets act as surrogate markers of bioenergetic health. Objective Therefore, the goal of this study was to determine distinct correlations between metabolic profiles and bioenergetic signatures in human platelets from multiple individuals with or without doxorubicin, a chemotherapeutic agent. Methods 300 million platelets from 14 donors were treated for 2h using 25 µM doxorubicin or vehicle control and monitored for perturbations associated with doxorubicin using extracellular flux analysis and untargeted high-resolution metabolomics (HRM). Results Flux analyses showed decreased mitochondrial oxygen consumption after treatment with doxorubicin treatment amongst the 14 donors. HRM analysis showed separation of the doxorubicin and vehicle control group using both hierarchal clustering and principal component analysis. Differences in TCA, fatty acid, and CoA metabolism, consistent with mitochondrial energetic disruption were observed. 3 metabolic clusters of individuals were identified within the treatment group. These clusters were identified to have altered amino acid, nucleotide, and lipid pathways, indicating associations between doxorubicin metabolism and metabolic adaptation. Conclusions Metabolic and bioenergetic variations of cellular bioenergetics observed in human platelets are consistent with metabolic adaption, repair, and increases in oxidative stress by doxorubicin. This pilot study suggests distinct correlations between bioenergetic activity and metabolic signatures during normal and under acute stress. This study also expands the knowledge between the interplay of the exposome and bioenergetic diversity.

Published
2018
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145. Effects of nitric oxide and sulfide donors on stored platelet bioenergetics

Author

Gloria A. Benavides, Dianna Xing, and Victor M. Darley-Usmar

Subjects
biology, Chemistry, Diallyl disulfide, 0208 environmental biotechnology, 02 engineering and technology, Oxidative phosphorylation, 010501 environmental sciences, 01 natural sciences, Biochemistry, 020801 environmental engineering, Cell biology, Nitric oxide, chemistry.chemical_compound, Physiology (medical), biology.protein, Cytochrome c oxidase, Platelet, Platelet activation, Peroxynitrite, Oxygen binding, 0105 earth and related environmental sciences
Abstract

Platelet adhesion and aggregation are involved in hemostatic maintenance of vascular tone, regulating blood flow turbidity, and inducing inflammatory immune responses to injury. Platelets have been found to secrete redox gasotransmitters, nitric oxide (NO) and hydrogen sulfide (H2S), to regulate their thrombolytic functions. High concentrations of NO can competitively inhibit oxygen binding to cytochrome c oxidase, suppressing oxidative phosphorylation. Nitric oxide can react with superoxide radicals (O2•–) to form peroxynitrite (ONOO•–), a potent oxidant that can damage mitochondrial electron transport proteins. Conversely, H2S can antagonize the deleterious effects of NO through inhibiting O2•– formation and scavenging ONOO•–. Previous work from our lab has found that platelet activation is primarily dependent on glycolysis, but oxidative phosphorylation plays a secondary role for normal functions. Therefore, we propose the presence of a gasotransmitter-mediated mechanism protecting against spontaneous platelet activation during the induction of ROS/RNS. In this study, DetaNONOate (an NO donor) in conjunction with diallyl disulfide (DADS), a H2S donor, was used to evaluate the potential roles of redox transmitters in platelet metabolism using the Seahorse Extracellular Flux Analyser. Our findings corroborated previous understandings of the mitochondrially toxic effects of NO, as elevated DetaNONOate inhibited oxygen consumption rate (OCR) in a dose-dependent manner, suggesting that electron transport machinery was being suppressed or damaged; this dose-dependence was also found with DADS pre-treatment. Damage was reversed when platelets were pre-treated with DADS prior to DetaNONoate exposure; DADS resulted in increased glycolytic flux, leading to recovery of mitochondrial function. These data demonstrate the platelets’ abilities to compensate for acute damage to oxidative phosphorylation machinery using H2S.

Published
2018
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146. Abstract B16: Evaluation of LDH inhibition as a treatment strategy in Ewing sarcoma

Author

Choh Yeung, Michelle S. Johnson, Lillian Culp, Guiseppe L. Squadrito, Christine M. Heske, Len Neckers, Victor M. Darley-Usmar, Sameer H. Issaq, Josh Baumgart, Arnulfo Mendoza, and Anna E. Gibson

Subjects
Cancer Research, Oncology, business.industry, Cancer research, Medicine, Treatment strategy, Sarcoma, business, medicine.disease
Abstract

Long-term outcomes for patients with relapsed, recurrent, or metastatic Ewing sarcoma (ES) remain poor despite advances in multimodal chemotherapy and local tumor control. The discovery of new targets and novel therapies is therefore critical to improving care for these patients. Recent insights into the metabolic landscape of ES have revealed that the EWS/FLI1 fusion oncoprotein regulates metabolic pathways in this disease, including shifting glucose consumption away from oxidative metabolism and towards glycolysis, a pathway that relies on LDH. Targeting this increased dependence on glycolysis presents an opportunity to inhibit the growth of ES cells through a novel therapeutic approach, while potentially limiting the toxicity delivered to normal cells. We therefore sought to evaluate the activity of NCGC-737 and NCGC-006, two novel LDHA/B inhibitors identified and validated as part of the Experimental Therapeutics Program of the National Cancer Institute (NCI-NExT), in ES. For in vitro studies, proliferation of ES cells lines was assessed after inhibition of LDHA/B by each agent using IncuCyte and MTS assays. Protein expression of phospho- and total LDH was evaluated by Western blot. LDH activity was assessed using the pyruvate-dependent oxidation of NADH. NAD/NADH levels were determined using NAD/NADH-Glo. Analysis of glycolytic profiles was performed using the Agilent Extracellular Flux Analyzer. For in vivo studies, female SCID mice underwent orthotopic injection of ES cells from established cell lines. When tumors reached a desired size, mice were randomized and then treated on a variety of dosing schedules. Toxicity assessments included evaluation of overall appearance, weekly weights, blood sampling, and full necropsies on selected mice. Tumors were measured twice per week for assessment of efficacy. Tumors were harvested at midpoints and at study endpoint for assessments of drug level, target inhibition, and biology. ES cell lines displayed varying sensitivity to NCGC-737 and NCGC-006, with IC-50 values ranging from 50 nM to 500 nM. While protein expression of phospho-LDH, total LDH-A, and total LDH-B were not correlated with sensitivity to either agent, glycolytic profiles were predictive of sensitivity. Cell lines that underwent a greater reduction in glycolytic capacity (the change in ECAR measured before and after oligomycin treatment) after LDHA/B inhibition experienced a greater antiproliferative effect, while cell lines that were able to maintain glycolytic capacity despite LDHA/B inhibition exhibited less of an effect on growth. In vivo studies to describe the toxicity of these agents demonstrated that hemolysis was the primary dose-limiting toxicity, and was dose dependent. Additional toxicity studies of specific tissues are ongoing and will be reported. Preliminary in vivo studies to optimize dosing regimen established that compared to oral dosing, intravenous dosing resulted in higher and more consistent tumor drug levels and improved target inhibition, with up to 93% of intratumoral LDH activity inhibited. Efficacy studies are ongoing and will be reported. Preclinical data suggest that inhibition of LDHA/B may represent a potentially novel therapeutic strategy in the treatment of ES. Citation Format: Christine M. Heske, Anna E. Gibson, Josh T. Baumgart, Choh Yeung, Sameer H. Issaq, A Mendoza, Michelle S. Johnson, Guiseppe L. Squadrito, Lillian Culp, Victor M. Darley-Usmar, Len M. Neckers. Evaluation of LDH inhibition as a treatment strategy in Ewing sarcoma [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr B16.

Published
2018
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147. Prevention of diabetic nephropathy in Ins2+/−AkitaJ mice by the mitochondria-targeted therapy MitoQ

Author

Anupam Agarwal, Balu K. Chacko, Kurt R. Zinn, Anup Srivastava, Balaraman Kalyanaraman, Yaozu Ye, Michelle S. Johnson, Elena Ulasova, Michael P. Murphy, Colin Reily, and Victor M. Darley-Usmar

Subjects
Blood Glucose, Male, Mitochondrial ROS, Ubiquinone, medicine.medical_treatment, ROI, region of interest, Smad2 Protein, Mitochondrion, Kidney, MitoQ, Biochemistry, Diabetic nephropathy, Mice, Ins2+/−AkitaJ mice (Akita mice), AUC, area under the curve, chemistry.chemical_compound, 0302 clinical medicine, Fibrosis, TGFβ, transforming growth factor β, Insulin, Diabetic Nephropathies, Phosphorylation, beta Catenin, 0303 health sciences, diabetes, 99mTc, technetium-99m, Immunohistochemistry, Glomerular Mesangium, Mitochondria, MitoQ, mitoubiquinone, 3. Good health, Kidney Tubules, medicine.anatomical_structure, 030220 oncology & carcinogenesis, RCR, respiratory control ratio, GBM, glomerular basement membrane, Research Article, PASR, Picric Acid Sirius Red, medicine.medical_specialty, MAG3, mercaptoacetyltriglycine, Biology, STZ, streptozotocin, CoQ, coenzyme Q, 03 medical and health sciences, ROS, reactive oxygen species, mitochondrial function, SOD, superoxide dismutase, Internal medicine, Diabetes mellitus, medicine, Animals, Smad3 Protein, DTPA, diethylenetriaminepenta-acetic acid, Molecular Biology, 030304 developmental biology, Cell Nucleus, renal clearance, Cell Biology, interstitial fibrosis, medicine.disease, Mice, Mutant Strains, Mice, Inbred C57BL, Microscopy, Electron, Diabetes Mellitus, Type 1, Endocrinology, chemistry, EMT, epithelial-to-mesenchymal transition
Abstract

Mitochondrial production of ROS (reactive oxygen species) is thought to be associated with the cellular damage resulting from chronic exposure to high glucose in long-term diabetic patients. We hypothesized that a mitochondria-targeted antioxidant would prevent kidney damage in the Ins2+/−AkitaJ mouse model (Akita mice) of Type 1 diabetes. To test this we orally administered a mitochondria-targeted ubiquinone (MitoQ) over a 12-week period and assessed tubular and glomerular function. Fibrosis and pro-fibrotic signalling pathways were determined by immunohistochemical analysis, and mitochondria were isolated from the kidney for functional assessment. MitoQ treatment improved tubular and glomerular function in the Ins2+/−AkitaJ mice. MitoQ did not have a significant effect on plasma creatinine levels, but decreased urinary albumin levels to the same level as non-diabetic controls. Consistent with previous studies, renal mitochondrial function showed no significant change between any of the diabetic or wild-type groups. Importantly, interstitial fibrosis and glomerular damage were significantly reduced in the treated animals. The pro-fibrotic transcription factors phospho-Smad2/3 and β-catenin showed a nuclear accumulation in the Ins2+/−AkitaJ mice, which was prevented by MitoQ treatment. These results support the hypothesis that mitochondrially targeted therapies may be beneficial in the treatment of diabetic nephropathy. They also highlight a relatively unexplored aspect of mitochondrial ROS signalling in the control of fibrosis.

Published
2010
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148. Abstract 4104: Evaluation of a novel LDH inhibitor efficacy in vivo in a glycolytic cancer model using hyperpolarized 13C magnetic resonance imaging

Author

Nobu Oshima, Ganesha Rai, Matthew Hall, Anastasia L. Sowers, Leonard M. Neckers, Daniel J. Urban, Shun Kishimoto, Kazutoshi Yamamoto, Giuseppe L. Squadrito, Jeffry R. Brender, Victor M. Darley-Usmar, Kristin Beebe, James Mitchell, Murali Krishna, Michael A. Moses, Goria Benavides, and Dan Crooks

Subjects
In vivo magnetic resonance spectroscopy, Cancer Research, education.field_of_study, medicine.diagnostic_test, Cell growth, business.industry, Lactate dehydrogenase A, Magnetic resonance imaging, In vitro, Oncology, In vivo, medicine, Cancer research, Glycolysis, business, education, Ex vivo
Abstract

Increased conversion of pyruvate to lactate by Lactate Dehydrogenase A (LDHA) is a feature of many neoplasms. Therefore, LDHA inhibition is considered a promising approach toward developing a new therapeutic strategy against cancers expressing the Warburg phenotype. To develop this strategy for clinical use, a feasible and sensitive noninvasive imaging approach that can dynamically evaluate LDHA activity in vivo would be highly beneficial since in vitro metabolic profiling dose not always predict in vivo cancer metabolism. Hyperpolarized (HP) 13C Magnetic Resonance Imaging (MRI) can be used to perform dynamic 13C metabolic flux analysis in vivo. In particular, use of [1-13C]pyruvate (13C-pyr) with 13C MRI permits real-time monitoring of intratumoral LDHA activity through dynamic observation of conversion of 13C-pyr to [1-13C]lactate (13C-lac). This study aimed to apply 13C MRI technology in support of a therapeutic strategy to explore efficacy of a newly developed and highly potent LDH inhibitor (LDHi) in a glycolytic tumor model using MiaPaCa2 xenografts in mice. In vitro analysis showed that the LDHi dose-dependently inhibited human LDH activity and suppressed in vitro cell growth in MiaPaCa2 cells. By ex vivo assay, LDH activity in MiaPaCa2 xenografts was significantly suppressed (82.2 ± 5.6 % decrease compared to vehicle controls) following a single intravenous(IV) injection of 50 mg/kg LDHi. Next, 13C MRI imaging of HP 13C-pyr metabolism was performed before and after a single LDHi IV injection to assess inhibitor impact on intratumoral metabolic flux in vivo. 13C MR spectroscopy confirmed that LDHi suppressed intratumor LDHA activity dose- and time-dependently. The maximum effective dose was 50 mg/kg and inhibitor impact in the tumor persisted for 10-12 hrs after a single injection. In addition, lactate production in the tumor was suppressed 30 minutes after IV administration of LDHi, as was the 13C-lac to 13C-pyr ratio decreased by 83.3 ± 4.4 % compared to vehicle controls. Importantly, the close correlation of these data with the results of the ex vivo LDH activity assay, suggests that 13C MRI can reliably monitor in vivo on target effects of LDHi without need for tissue sampling. Based on the data using 13C MRI, we developed a therapeutic strategy for using LDHi in an efficacy study of MiaPaCa2 xenografts. Intermittent IV administration of LDHi significantly suppressed tumor growth in this glycolytic model. In conclusion, intratumoral inhibition of LDHA in vivo upon IV administration of a novel LDHi was readily visualized by HP 13C MRI, confirming the utility of this noninvasive method. This methodology can be of great value in developing new therapeutic strategies using LDHi and perhaps other metabolic inhibitors to treat cancers characterized by the Warburg phenotype. Further, HP 13C MRI should allow for selection of those patients likely to respond to such treatments. Citation Format: Nobu Oshima, Shun Kishimoto, Kristin Beebe, Dan Crooks, Michael Moses, Kazutoshi Yamamoto, Jeffry R. Brender, Anastasia Sowers, Ganesha Rai, Daniel Urban, Goria Benavides, Giuseppe Squadrito, Victor Darley-Usmar, Matthew Hall, James B. Mitchell, Murali C. Krishna, Leonard M. Neckers. Evaluation of a novel LDH inhibitor efficacy in vivo in a glycolytic cancer model using hyperpolarized 13C magnetic resonance imaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4104.

Published
2018
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149. What Part of NO Don't You Understand? Some Answers to the Cardinal Questions in Nitric Oxide Biology

Author

Shannon M. Bailey, Victor M. Darley-Usmar, Brian P. Dranka, Jack R. Lancaster, and Bradford G. Hill

Subjects
Free Radicals, Hemoglobin Myoglobin, Iron, Context (language use), Computational biology, Nitric Oxide, Cardiovascular System, Biochemistry, Nitric oxide, Hemoglobins, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Signaling proteins, Animals, Humans, Molecular Biology, 030304 developmental biology, 0303 health sciences, Oxygen Radicals, Chemistry, Minireviews, Cell Biology, Mitochondria, Oxidative Stress, Protein Processing, Post-Translational, 030217 neurology & neurosurgery, Protein Binding, Signal Transduction
Abstract

Nitric oxide (NO) regulates biological processes through signaling mechanisms that exploit its unique biochemical properties as a free radical. For the last several decades, the key aspects of the chemical properties of NO relevant to biological systems have been defined, but it has been a challenge to assign these to specific cellular processes. Nevertheless, it is now clear that the high affinity of NO for transition metal centers, particularly iron, and the rapid reaction of NO with oxygen-derived free radicals can explain many of its biological and pathological properties. Emerging studies also highlight a growing importance of the secondary metabolites of NO-dependent reactions in the post-translational modification of key metabolic and signaling proteins. In this minireview, we emphasize the current understanding of the biochemistry of NO and place it in a biological context.

Published
2010
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150. Role of cellular bioenergetics in smooth muscle cell proliferation induced by platelet-derived growth factor

Author

Gloria A. Benavides, Victor M. Darley-Usmar, Brian P. Dranka, Jessica Perez, and Bradford G. Hill

Subjects
medicine.medical_specialty, Platelet-derived growth factor, Vascular smooth muscle, Morpholines, medicine.medical_treatment, Blotting, Western, Myocytes, Smooth Muscle, Citrate (si)-Synthase, Deoxyglucose, Mitochondrion, Biology, Biochemistry, Article, Muscle, Smooth, Vascular, chemistry.chemical_compound, Internal medicine, medicine, Animals, Myocyte, Enzyme Inhibitors, Molecular Biology, Cells, Cultured, Chromatography, High Pressure Liquid, PI3K/AKT/mTOR pathway, Cell Proliferation, Phosphoinositide-3 Kinase Inhibitors, Membrane Potential, Mitochondrial, Platelet-Derived Growth Factor, Adenine Nucleotides, Cell growth, Growth factor, Cell Biology, Mitochondria, Rats, Glucose, Endocrinology, chemistry, Chromones, biology.protein, Energy Metabolism, Glycolysis, Platelet-derived growth factor receptor, Signal Transduction
Abstract

Abnormal smooth muscle cell proliferation is a hallmark of vascular disease. Although growth factors are known to contribute to cell hyperplasia, the changes in metabolism associated with this response, particularly mitochondrial respiration, remain unclear. Given the increased energy requirements for proliferation, we hypothesized that PDGF (platelet-derived growth factor) would stimulate glycolysis and mitochondrial respiration and that this elevated bioenergetic capacity is required for smooth muscle cell hyperplasia. To test this hypothesis, cell proliferation, glycolytic flux and mitochondrial oxygen consumption were measured after treatment of primary rat aortic VSMCs (vascular smooth muscle cells) with PDGF. PDGF increased basal and maximal rates of glycolytic flux and mitochondrial oxygen consumption; enhancement of these bioenergetic pathways led to a substantial increase in the mitochondrial reserve capacity. Interventions with the PI3K (phosphoinositide 3-kinase) inhibitor LY-294002 or the glycolysis inhibitor 2-deoxy-D-glucose abrogated PDGF-stimulated proliferation and prevented augmentation of glycolysis and mitochondrial reserve capacity. Similarly, when L-glucose was substituted for D-glucose, PDGF-dependent proliferation was abolished, as were changes in glycolysis and mitochondrial respiration. Interestingly, LDH (lactate dehydrogenase) protein levels and activity were significantly increased after PDGF treatment. Moreover, substitution of L-lactate for D-glucose was sufficient to increase mitochondrial reserve capacity and cell proliferation after treatment with PDGF; these effects were inhibited by the LDH inhibitor oxamate. These results suggest that glycolysis, by providing substrates that enhance the mitochondrial reserve capacity, plays an essential role in PDGF-induced cell proliferation, underscoring the integrated metabolic response required for proliferation of VSMCs in the diseased vasculature.

Published
2010
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