444 results on '"Antonio Zorzano"'
Search Results
2. MAP kinase ERK5 modulates cancer cell sensitivity to extrinsic apoptosis induced by death-receptor agonists
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Sergio Espinosa-Gil, Saska Ivanova, Elisenda Alari-Pahissa, Melek Denizli, Beatriz Villafranca-Magdalena, Maria Viñas-Casas, Idoia Bolinaga-Ayala, Andrés Gámez-García, Claudia Faundez-Vidiella, Eva Colas, Miguel Lopez-Botet, Antonio Zorzano, and José Miguel Lizcano
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Cytology ,QH573-671 - Abstract
Abstract Death receptor ligand TRAIL is a promising cancer therapy due to its ability to selectively trigger extrinsic apoptosis in cancer cells. However, TRAIL–based therapies in humans have shown limitations, mainly due inherent or acquired resistance of tumor cells. To address this issue, current efforts are focussed on dissecting the intracellular signaling pathways involved in resistance to TRAIL, to identify strategies that sensitize cancer cells to TRAIL-induced cytotoxicity. In this work, we describe the oncogenic MEK5-ERK5 pathway as a critical regulator of cancer cell resistance to the apoptosis induced by death receptor ligands. Using 2D and 3D cell cultures and transcriptomic analyses, we show that ERK5 controls the proteostasis of TP53INP2, a protein necessary for full activation of caspase-8 in response to TNFα, FasL or TRAIL. Mechanistically, ERK5 phosphorylates and induces ubiquitylation and proteasomal degradation of TP53INP2, resulting in cancer cell resistance to TRAIL. Concordantly, ERK5 inhibition or genetic deletion, by stabilizing TP53INP2, sensitizes cancer cells to the apoptosis induced by recombinant TRAIL and TRAIL/FasL expressed by Natural Killer cells. The MEK5-ERK5 pathway regulates cancer cell proliferation and survival, and ERK5 inhibitors have shown anticancer activity in preclinical models of solid tumors. Using endometrial cancer patient-derived xenograft organoids, we propose ERK5 inhibition as an effective strategy to sensitize cancer cells to TRAIL-based therapies.
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- 2023
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3. Disruption of mitochondrial dynamics triggers muscle inflammation through interorganellar contacts and mitochondrial DNA mislocation
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Andrea Irazoki, Isabel Gordaliza-Alaguero, Emma Frank, Nikolaos Nikiforos Giakoumakis, Jordi Seco, Manuel Palacín, Anna Gumà, Lykke Sylow, David Sebastián, and Antonio Zorzano
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Science - Abstract
Some forms of mitochondrial dysfunction can cause sterile inflammation, but the way in which it might affect muscle fitness is not well understood. Here, the authors show that altered mitochondrial dynamics can cause the production of mitochondrial DNA-driven inflammatory signals mediated by endosome-mitochondria contacts, leading to muscle inflammation, atrophy, reduced physical performance and enhanced exercise-induced inflammatory responses.
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- 2023
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4. THE BNIP3 TRIAD: MITOCHONDRIA, LYSOSOMES AND INFLAMMATION IN HEALTHY MUSCLE AGING
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Andrea Irazoki, Antonio Zorzano, and David Sebastian
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aging ,inflammation ,lysosome ,mitochondria ,mitophagy ,muscle ,sarcopenia ,Cytology ,QH573-671 - Abstract
During aging, skeletal muscle undergoes a loss of mass, strength and function, encompassed in the biological process termed sarcopenia. Given demographic aging, it is essential to comprehend the molecular determinants resulting in age-related sarcopenia. Here we studied the role of the mitophagy adaptor BNIP3 in mitochondrial homeostasis and muscle during aging. Our findings reveal that BNIP3 orchestrates mitochondrial and lysosomal function to mitigate muscle inflammation and atrophy during aging.
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- 2022
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5. Mitofusin-2 in nucleus accumbens D2-MSNs regulates social dominance and neuronal function
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Sriparna Ghosal, Elias Gebara, Eva Ramos-Fernández, Alessandro Chioino, Jocelyn Grosse, Isabelle Guillot de Suduiraut, Olivia Zanoletti, Bernard Schneider, Antonio Zorzano, Simone Astori, and Carmen Sandi
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CP: Neuroscience ,Biology (General) ,QH301-705.5 - Abstract
Summary: The nucleus accumbens (NAc) is a brain hub regulating motivated behaviors, including social competitiveness. Mitochondrial function in the NAc links anxiety with social competitiveness, and the mitochondrial fusion protein mitofusin 2 (Mfn2) in NAc neurons regulates anxiety-related behaviors. However, it remains unexplored whether accumbal Mfn2 levels also affect social behavior and whether Mfn2 actions in the emotional and social domain are driven by distinct cell types. Here, we found that subordinate-prone highly anxious rats show decreased accumbal Mfn2 levels and that Mfn2 overexpression promotes dominant behavior. In mice, selective Mfn2 downregulation in NAc dopamine D2 receptor-expressing medium spiny neurons (D2-MSNs) induced social subordination, accompanied by decreased accumbal mitochondrial functions and decreased excitability in D2-MSNs. Instead, D1-MSN-targeted Mfn2 downregulation affected competitive ability only transiently and likely because of an increase in anxiety-like behaviors. Our results assign dissociable cell-type specific roles to Mfn2 in the NAc in modulating social dominance and anxiety.
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- 2023
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6. Decreased expression of mitochondrial aminoacyl-tRNA synthetases causes downregulation of OXPHOS subunits in type 2 diabetic muscle
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Iliana López-Soldado, Adrian Gabriel Torres, Raúl Ventura, Inma Martínez-Ruiz, Angels Díaz-Ramos, Evarist Planet, Diane Cooper, Agnieszka Pazderska, Krzysztof Wanic, Declan O'Hanlon, Donal J. O'Gorman, Teresa Carbonell, Lluís Ribas de Pouplana, John J. Nolan, Antonio Zorzano, and María Isabel Hernández-Alvarez
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Type 2 diabetes ,Mitochondrial aminoacyl tRNA synthetases ,Nitrosative stress ,OXPHOS ,Skeletal muscle ,Nitric oxide ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Type 2 diabetes mellitus (T2D) affects millions of people worldwide and is one of the leading causes of morbidity and mortality. The skeletal muscle (SKM) is one of the most important tissues involved in maintaining glucose homeostasis and substrate oxidation, and it undergoes insulin resistance in T2D. In this study, we identify the existence of alterations in the expression of mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs) in skeletal muscle from two different forms of T2D: early-onset type 2 diabetes (YT2) (onset of the disease before 30 years of age) and the classical form of the disease (OT2). GSEA analysis from microarray studies revealed the repression of mitochondrial mt-aaRSs independently of age, which was validated by real-time PCR assays. In agreement with this, a reduced expression of several encoding mt-aaRSs was also detected in skeletal muscle from diabetic (db/db) mice but not in obese ob/ob mice. In addition, the expression of the mt-aaRSs proteins most relevant in the synthesis of mitochondrial proteins, threonyl-tRNA, and leucyl-tRNA synthetases (TARS2 and LARS2) were also repressed in muscle from db/db mice. It is likely that these alterations participate in the reduced expression of proteins synthesized in the mitochondria detected in db/db mice. We also document an increased iNOS abundance in mitochondrial-enriched muscle fractions from diabetic mice that may inhibit aminoacylation of TARS2 and LARS2 by nitrosative stress.Our results indicate a reduced expression of mt-aaRSs in skeletal muscle from T2D patients, which may participate in the reduced expression of proteins synthesized in mitochondria. An enhanced mitochondrial iNOS could play a regulatory role in diabetes.
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- 2023
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7. Cannabidiol alters mitochondrial bioenergetics via VDAC1 and triggers cell death in hormone-refractory prostate cancer
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Ali Mokhtar Mahmoud, Magdalena Kostrzewa, Viviana Marolda, Marianna Cerasuolo, Federica Maccarinelli, Daniela Coltrini, Sara Rezzola, Arianna Giacomini, Maria Pina Mollica, Andrea Motta, Debora Paris, Antonio Zorzano, Vincenzo Di Marzo, Roberto Ronca, and Alessia Ligresti
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Mitochondrial bioenergetics ,CBD ,VDAC1 ,Hormone refractory prostate cancer ,Phytocannabinoids ,Therapeutics. Pharmacology ,RM1-950 - Abstract
In spite of the huge advancements in both diagnosis and interventions, hormone refractory prostate cancer (HRPC) remains a major hurdle in prostate cancer (PCa). Metabolic reprogramming plays a key role in PCa oncogenesis and resistance. However, the dynamics between metabolism and oncogenesis are not fully understood. Here, we demonstrate that two multi-target natural products, cannabidiol (CBD) and cannabigerol (CBG), suppress HRPC development in the TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model by reprogramming metabolic and oncogenic signaling. Mechanistically, CBD increases glycolytic capacity and inhibits oxidative phosphorylation in enzalutamide-resistant HRPC cells. This action of CBD originates from its effect on metabolic plasticity via modulation of VDAC1 and hexokinase II (HKII) coupling on the outer mitochondrial membrane, which leads to strong shifts of mitochondrial functions and oncogenic signaling pathways. The effect of CBG on enzalutamide-resistant HRPC cells was less pronounced than CBD and only partially attributable to its action on mitochondria. However, when optimally combined, these two cannabinoids exhibited strong anti-tumor effects in TRAMP mice, even when these had become refractory to enzalutamide, thus pointing to their therapeutical potential against PCa.
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- 2023
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8. Hypoxia-induced HIF1α activation regulates small extracellular vesicle release in human embryonic kidney cells
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Ana Muñiz-García, Montserrat Romero, Juan Manuel Falcόn-Perez, Patricia Murray, Antonio Zorzano, and Silvia Mora
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Medicine ,Science - Abstract
Abstract Extracellular vesicles (EVs) are membrane enclosures released by eukaryotic cells that carry bioactive molecules and serve to modulate biological responses in recipient cells. Both increased EV release and altered EV composition are associated with the development and progression of many pathologies including cancer. Hypoxia, a feature of rapidly growing solid tumours, increases the release of EVs. However, the molecular mechanisms remain unknown. The hypoxia inducible factors (HIFs) are transcription factors that act as major regulators of the cellular adaptations to hypoxia. Here, we investigated the requirement of HIF pathway activation for EV release in Human Embryonic Kidney Cells (HEK293). Time course experiments showed that EV release increased concomitantly with sustained HIF1α and HIF2α activation following the onset of hypoxia. shRNA mediated knock-down of HIF1α but not HIF2α abrogated the effect of hypoxia on EV release, suggesting HIF1α is involved in this process. However, stabilization of HIF proteins in normoxic conditions through: (i) heterologous expression of oxygen insensitive HIF1α or HIF2α mutants in normoxic cells or (ii) chemical inhibition of the prolyl hydroxylase 2 (PHD2) repressor protein, did not increase EV release, suggesting HIF activation alone is not sufficient for this process. Our findings suggest HIF1α plays an important role in the regulation of EV release during hypoxia in HEK293 cells, however other hypoxia triggered mechanisms likely contribute as stabilization of HIF1α alone in normoxia is not sufficient for EV release.
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- 2022
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9. Mechanisms of Modulation of Mitochondrial Architecture
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Juan Pablo Muñoz, Fernanda Luisa Basei, María Laura Rojas, David Galvis, and Antonio Zorzano
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mitochondria ,metabolism ,mitochondrial dynamics ,pharmacology ,lipids ,metabolic disease ,Microbiology ,QR1-502 - Abstract
Mitochondrial network architecture plays a critical role in cellular physiology. Indeed, alterations in the shape of mitochondria upon exposure to cellular stress can cause the dysfunction of these organelles. In this scenario, mitochondrial dynamics proteins and the phospholipid composition of the mitochondrial membrane are key for fine-tuning the modulation of mitochondrial architecture. In addition, several factors including post-translational modifications such as the phosphorylation, acetylation, SUMOylation, and o-GlcNAcylation of mitochondrial dynamics proteins contribute to shaping the plasticity of this architecture. In this regard, several studies have evidenced that, upon metabolic stress, mitochondrial dynamics proteins are post-translationally modified, leading to the alteration of mitochondrial architecture. Interestingly, several proteins that sustain the mitochondrial lipid composition also modulate mitochondrial morphology and organelle communication. In this context, pharmacological studies have revealed that the modulation of mitochondrial shape and function emerges as a potential therapeutic strategy for metabolic diseases. Here, we review the factors that modulate mitochondrial architecture.
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- 2023
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10. Diabetes alters the protein secretome of human adipose‐derived stem cells and promotes tumorigenesis in hepatic cancer cells
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Miriam Ejarque, Joan Sabadell‐Basallote, Ester Benaiges, Catalina Núñez‐Roa, Eduardo Sabido, Eva Borras, Erik Llacer, Antonio Zorzano, Joan Vendrell, and Sonia Fernández‐Veledo
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Medicine (General) ,R5-920 - Published
- 2022
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11. FTY720-P, a Biased S1PR Ligand, Increases Mitochondrial Function through STAT3 Activation in Cardiac Cells
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Juan Pablo Muñoz, Paula Sànchez-Fernàndez-de-Landa, Elena María Goretti Diarte-Añazco, Antonio Zorzano, Francisco Blanco-Vaca, and Josep Julve
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FTY720-P ,mitochondria ,TFAM ,STAT3 ,DRP1 S616 ,cardiomyocytes ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
FTY720 is an FDA-approved sphingosine derivative drug for the treatment of multiple sclerosis. This compound blocks lymphocyte egress from lymphoid organs and autoimmunity through sphingosine 1-phosphate (S1P) receptor blockage. Drug repurposing of FTY720 has revealed improvements in glucose metabolism and metabolic diseases. Studies also demonstrate that preconditioning with this compound preserves the ATP levels during cardiac ischemia in rats. The molecular mechanisms by which FTY720 promotes metabolism are not well understood. Here, we demonstrate that nanomolar concentrations of the phosphorylated form of FTY720 (FTY720-P), the active ligand of S1P receptor (S1PR), activates mitochondrial respiration and the mitochondrial ATP production rate in AC16 human cardiomyocyte cells. Additionally, FTY720-P increases the number of mitochondrial nucleoids, promotes mitochondrial morphology alterations, and induces activation of STAT3, a transcription factor that promotes mitochondrial function. Notably, the effect of FTY720-P on mitochondrial function was suppressed in the presence of a STAT3 inhibitor. In summary, our results suggest that FTY720 promotes the activation of mitochondrial function, in part, through a STAT3 action.
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- 2023
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12. CBL/CAP Is Essential for Mitochondria Respiration Complex I Assembly and Bioenergetics Efficiency in Muscle Cells
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Cho-Cho Aye, Dean E. Hammond, Sergio Rodriguez-Cuenca, Mary K. Doherty, Phillip D. Whitfield, Marie M. Phelan, Chenjing Yang, Rafael Perez-Perez, Xiaoxin Li, Angels Diaz-Ramos, Gopal Peddinti, Matej Oresic, Antonio Vidal-Puig, Antonio Zorzano, Cristina Ugalde, and Silvia Mora
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CBL ,SORBS1 ,mitochondria ,insulin signalling ,insulin resistance ,glucose transport ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
CBL is rapidly phosphorylated upon insulin receptor activation. Mice whole body CBL depletion improved insulin sensitivity and glucose clearance; however, the precise mechanisms remain unknown. We depleted either CBL or its associated protein SORBS1/CAP independently in myocytes and assessed mitochondrial function and metabolism compared to control cells. CBL- and CAP-depleted cells showed increased mitochondrial mass with greater proton leak. Mitochondrial respiratory complex I activity and assembly into respirasomes were reduced. Proteome profiling revealed alterations in proteins involved in glycolysis and fatty acid degradation. Our findings demonstrate CBL/CAP pathway couples insulin signaling to efficient mitochondrial respiratory function and metabolism in muscle.
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- 2023
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13. Metabolite Changes After Metabolic Surgery – Associations to Parameters Reflecting Glucose Homeostasis and Lipid Levels
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Sofie Ahlin, Consuelo Cefalo, Isabel Bondia-Pons, Kajetan Trošt, Esmeralda Capristo, Luca Marini, Montserrat Romero, Antonio Zorzano, Amalia Gastaldelli, Geltrude Mingrone, and John J. Nolan
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metabolic surgery ,metabolomics ,branched chain amino acids (BCAA) ,adipose tissue ,metabolic pathway ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
AimsTo test the hypothesis that adipose tissue gene expression patterns would be affected by metabolic surgery and we aimed to identify genes and metabolic pathways as well as metabolites correlating with metabolic changes following metabolic surgery.Materials and MethodsThis observational study was conducted at the Obesity Unit at the Catholic University Hospital of the Sacred Heart in Rome, Italy. Fifteen patients, of which six patients underwent Roux-en-Y gastric bypass and nine patients underwent biliopancreatic diversion, were included. The participants underwent an oral glucose tolerance test and a hyperinsulinemic euglycemic clamp. Small polar metabolites were analyzed with a two-dimensional gas chromatography coupled to time-of-flight mass spectrometry (GC×GC-TOFMS). Gene expression analysis of genes related to metabolism of amino acids and fatty acids were analyzed in subcutaneous adipose tissue. All procedures were performed at study start and at follow-up (after 185.3 ± 72.9 days).ResultsTwelve metabolites were significantly changed after metabolic surgery. Six metabolites were identified as 3-indoleacetic acid, 2-hydroxybutyric acid, valine, glutamic acid, 4-hydroxybenzeneacetic acid and alpha-tocopherol. The branched chain amino acids displayed a significant decrease together with a decrease in BCAT1 adipose tissue mRNA levels. Changes in the identified metabolites were associated to changes in lipid, insulin and glucose levels.ConclusionsOur study has identified metabolites and metabolic pathways that are altered by metabolic surgery and may be used as biomarkers for metabolic improvement.
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- 2021
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14. Increased glycolysis is an early consequence of palmitate lipotoxicity mediated by redox signaling
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Pamela A. Kakimoto, Julian David C. Serna, Vitor de Miranda Ramos, Antonio Zorzano, and Alicia J. Kowaltowski
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Palmitic acid ,Mitochondria ,Glycolysis ,Oxidative stress ,Reactive oxygen species ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Exposure to toxic levels of fatty acids (lipotoxicity) leads to cell damage and death and is involved in the pathogenesis of the metabolic syndrome. Since the metabolic consequences of lipotoxicity are still poorly understood, we studied the bioenergetic effects of the saturated fatty acid palmitate, quantifying changes in mitochondrial morphology, real-time oxygen consumption, ATP production sources, and extracellular acidification in hepatoma cells. Surprisingly, glycolysis was enhanced by the presence of palmitate as soon as 1 h after stimulus, while oxygen consumption and oxidative phosphorylation were unchanged, despite overt mitochondrial fragmentation. Palmitate only induced mitochondrial fragmentation if glucose and glutamine were available, while glycolytic enhancement did not require glutamine, showing it is independent of mitochondrial morphological changes. Redox state was altered by palmitate, as indicated by NAD(P)H quantification. Furthermore, the mitochondrial antioxidant mitoquinone, or a selective inhibitor of complex I electron leakage (S1QEL) further enhanced palmitate-induced glycolysis. Our results demonstrate that palmitate overload and lipotoxicity involves an unexpected and early increase in glycolytic flux, while, surprisingly, no changes in oxidative phosphorylation are observed. Interestingly, enhanced glycolysis involves signaling by mitochondrially-generated oxidants, uncovering a novel regulatory mechanism for this pathway.
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- 2021
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15. The sensing of mitochondrial DAMPs by non-immune cells
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Aida Rodríguez-Nuevo and Antonio Zorzano
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mitochondria ,DAMP ,immunity ,mitochondrial DNA ,TLR9 ,cGAS ,Medicine ,Biology (General) ,QH301-705.5 - Abstract
Mitochondria are the source of damage-associated molecular patterns (DAMPs), which are molecules that play a key modulatory role in immune cells. These molecules include proteins and peptides, such as N-formyl peptides and TFAM, as well as lipids, and metabolites such as cardiolipin, succinate and ATP, and also mitochondrial DNA (mtDNA). Recent data indicate that somatic cells sense mitochondrial DAMPs and trigger protective mechanisms in response to these signals. In this review we focus on the well-described effects of mitochondrial DAMPs on immune cells and also how these molecules induce immunogenic responses in non-immune cells. Special attention will be paid to the response to mtDNA.
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- 2019
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16. L amino acid transporter structure and molecular bases for the asymmetry of substrate interaction
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Ekaitz Errasti-Murugarren, Joana Fort, Paola Bartoccioni, Lucía Díaz, Els Pardon, Xavier Carpena, Meritxell Espino-Guarch, Antonio Zorzano, Christine Ziegler, Jan Steyaert, Juan Fernández-Recio, Ignacio Fita, and Manuel Palacín
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Science - Abstract
L-Amino acid Transporters (LATs) are asymmetric amino acid exchangers. Here the authors determine the crystal structure of a prokaryotic LAT, the alanine-serine-cysteine exchanger (BasC) and identify key residues for asymmetric substrate interaction in both BasC and the homologous human transporter Asc-1 through functional studies.
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- 2019
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17. Patient-Specific iPSC-Derived Astrocytes Contribute to Non-Cell-Autonomous Neurodegeneration in Parkinson's Disease
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Angelique di Domenico, Giulia Carola, Carles Calatayud, Meritxell Pons-Espinal, Juan Pablo Muñoz, Yvonne Richaud-Patin, Irene Fernandez-Carasa, Marta Gut, Armida Faella, Janani Parameswaran, Jordi Soriano, Isidro Ferrer, Eduardo Tolosa, Antonio Zorzano, Ana Maria Cuervo, Angel Raya, and Antonella Consiglio
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Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Summary: Parkinson's disease (PD) is associated with the degeneration of ventral midbrain dopaminergic neurons (vmDAns) and the accumulation of toxic α-synuclein. A non-cell-autonomous contribution, in particular of astrocytes, during PD pathogenesis has been suggested by observational studies, but remains to be experimentally tested. Here, we generated induced pluripotent stem cell-derived astrocytes and neurons from familial mutant LRRK2 G2019S PD patients and healthy individuals. Upon co-culture on top of PD astrocytes, control vmDAns displayed morphological signs of neurodegeneration and abnormal, astrocyte-derived α-synuclein accumulation. Conversely, control astrocytes partially prevented the appearance of disease-related phenotypes in PD vmDAns. We additionally identified dysfunctional chaperone-mediated autophagy (CMA), impaired macroautophagy, and progressive α-synuclein accumulation in PD astrocytes. Finally, chemical enhancement of CMA protected PD astrocytes and vmDAns via the clearance of α-synuclein accumulation. Our findings unveil a crucial non-cell-autonomous contribution of astrocytes during PD pathogenesis, and open the path to exploring novel therapeutic strategies aimed at blocking the pathogenic cross talk between neurons and glial cells. : In this article, Consiglio and colleagues show that PD iPSC-derived astrocytes contribute to dopaminergic neurodegeneration, indicating an important role for astrocytes in the pathogenesis of Parkinson's disease. PD astrocytes display dysfunctional chaperone-mediated autophagy (CMA), impaired macroautophagy, and progressive α-synuclein accumulation. In co-culture, PD astrocytes transfer α-synuclein to vmDAns and trigger dopaminergic neuronal cell death that can be rescued by treatment with a chemical enhancement of CMA. Keywords: iPSC, Parkinson's disease, non-cell-autonomous, astrocytes, α-synuclein, LRRK2, CRISPR/Cas9, disease modeling, autophagy, neurodegeneration
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- 2019
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18. Altered Mitochondrial Opa1-Related Fusion in Mouse Promotes Endothelial Cell Dysfunction and Atherosclerosis
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Ahmad Chehaitly, Anne-Laure Guihot, Coralyne Proux, Linda Grimaud, Jade Aurrière, Benoit Legouriellec, Jordan Rivron, Emilie Vessieres, Clément Tétaud, Antonio Zorzano, Vincent Procaccio, Françoise Joubaud, Pascal Reynier, Guy Lenaers, Laurent Loufrani, and Daniel Henrion
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mitochondrial fusion ,blood flow ,shear stress ,arteries ,endothelial cell ,atherosclerosis ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Flow (shear stress)-mediated dilation (FMD) of resistance arteries is a rapid endothelial response involved in tissue perfusion. FMD is reduced early in cardiovascular diseases, generating a major risk factor for atherosclerosis. As alteration of mitochondrial fusion reduces endothelial cells’ (ECs) sprouting and angiogenesis, we investigated its role in ECs responses to flow. Opa1 silencing reduced ECs (HUVECs) migration and flow-mediated elongation. In isolated perfused resistance arteries, FMD was reduced in Opa1+/− mice, a model of the human disease due to Opa1 haplo-insufficiency, and in mice with an EC specific Opa1 knock-out (EC-Opa1). Reducing mitochondrial oxidative stress restored FMD in EC-Opa1 mice. In isolated perfused kidneys from EC-Opa1 mice, flow induced a greater pressure, less ATP, and more H2O2 production, compared to control mice. Opa1 expression and mitochondrial length were reduced in ECs submitted in vitro to disturbed flow and in vivo in the atheroprone zone of the mouse aortic cross. Aortic lipid deposition was greater in Ldlr−/--Opa1+/- and in Ldlr−/--EC-Opa1 mice than in control mice fed with a high-fat diet. In conclusion, we found that reduction in mitochondrial fusion in mouse ECs altered the dilator response to shear stress due to excessive superoxide production and induced greater atherosclerosis development.
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- 2022
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19. Involvement of the mitochondrial nuclease EndoG in the regulation of cell proliferation through the control of reactive oxygen species
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Natividad Blasco, Aida Beà, Gisel Barés, Cristina Girón, Raúl Navaridas, Andrea Irazoki, Guillermo López-Lluch, Antonio Zorzano, Xavier Dolcet, Marta Llovera, and Daniel Sanchis
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EndoG ,Cell proliferation ,Mitochondria ,Reactive oxygen species ,Cell signaling ,Humanin ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
The apoptotic nuclease EndoG is involved in mitochondrial DNA replication. Previous results suggested that, in addition to regulate cardiomyocyte hypertrophy, EndoG could be involved in cell proliferation. Here, by using in vivo and cell culture models, we investigated the role of EndoG in cell proliferation. Genetic deletion of Endog both in vivo and in cultured cells or Endog silencing in vitro induced a defect in rodent and human cell proliferation with a tendency of cells to accumulate in the G1 phase of cell cycle and increased reactive oxygen species (ROS) production. The defect in cell proliferation occurred with a decrease in the activity of the AKT/PKB-GSK-3β-Cyclin D axis and was reversed by addition of ROS scavengers. EndoG deficiency did not affect the expression of ROS detoxifying enzymes, nor the expression of the electron transport chain complexes and oxygen consumption rate. Addition of the micropeptide Humanin to EndoG-deficient cells restored AKT phosphorylation and proliferation without lowering ROS levels. Thus, our results show that EndoG is important for cell proliferation through the control of ROS and that Humanin can restore cell division in EndoG-deficient cells and counteracts the effects of ROS on AKT phosphorylation.
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- 2020
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20. Mitofusin 2 in Macrophages Links Mitochondrial ROS Production, Cytokine Release, Phagocytosis, Autophagy, and Bactericidal Activity
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Juan Tur, Selma Pereira-Lopes, Tania Vico, Eros A. Marín, Juan P. Muñoz, Maribel Hernández-Alvarez, Pere-Joan Cardona, Antonio Zorzano, Jorge Lloberas, and Antonio Celada
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macrophages ,reactive oxygen species (ROS) ,mitochondria ,mitofusin ,lipopolysaccharide (LPS) ,phagocytosis ,Biology (General) ,QH301-705.5 - Abstract
Summary: Mitofusin 2 (Mfn2) plays a major role in mitochondrial fusion and in the maintenance of mitochondria-endoplasmic reticulum contact sites. Given that macrophages play a major role in inflammation, we studied the contribution of Mfn2 to the activity of these cells. Pro-inflammatory stimuli such as lipopolysaccharide (LPS) induced Mfn2 expression. The use of the Mfn2 and Mfn1 myeloid-conditional knockout (KO) mouse models reveals that Mfn2 but not Mfn1 is required for the adaptation of mitochondrial respiration to stress conditions and for the production of reactive oxygen species (ROS) upon pro-inflammatory activation. Mfn2 deficiency specifically impairs the production of pro-inflammatory cytokines and nitric oxide. In addition, the lack of Mfn2 but not Mfn1 is associated with dysfunctional autophagy, apoptosis, phagocytosis, and antigen processing. Mfn2floxed;CreLysM mice fail to be protected from Listeria, Mycobacterium tuberculosis, or LPS endotoxemia. These results reveal an unexpected contribution of Mfn2 to ROS production and inflammation in macrophages.
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- 2020
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21. Neuregulin, an Effector on Mitochondria Metabolism That Preserves Insulin Sensitivity
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Anna Gumà, Francisco Díaz-Sáez, Marta Camps, and Antonio Zorzano
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mitochondria ,neuregulin ,ErbB receptors ,obesity ,diabetes ,insulin resistance ,Physiology ,QP1-981 - Abstract
Various external factors modulate the metabolic efficiency of mitochondria. This review focuses on the impact of the growth factor neuregulin and its ErbB receptors on mitochondria and their relationship with several physiopathological alterations. Neuregulin is involved in the differentiation of heart, skeletal muscle, and the neuronal system, among others; and its deficiency is deleterious for the health. Information gathered over the last two decades suggests that neuregulin plays a key role in regulating the mitochondrial oxidative machinery, which sustains cell survival and insulin sensitivity.
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- 2020
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22. Re-analysis of public genetic data reveals a rare X-chromosomal variant associated with type 2 diabetes
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Sílvia Bonàs-Guarch, Marta Guindo-Martínez, Irene Miguel-Escalada, Niels Grarup, David Sebastian, Elias Rodriguez-Fos, Friman Sánchez, Mercè Planas-Fèlix, Paula Cortes-Sánchez, Santi González, Pascal Timshel, Tune H. Pers, Claire C. Morgan, Ignasi Moran, Goutham Atla, Juan R. González, Montserrat Puiggros, Jonathan Martí, Ehm A. Andersson, Carlos Díaz, Rosa M. Badia, Miriam Udler, Aaron Leong, Varindepal Kaur, Jason Flannick, Torben Jørgensen, Allan Linneberg, Marit E. Jørgensen, Daniel R. Witte, Cramer Christensen, Ivan Brandslund, Emil V. Appel, Robert A. Scott, Jian’an Luan, Claudia Langenberg, Nicholas J. Wareham, Oluf Pedersen, Antonio Zorzano, Jose C Florez, Torben Hansen, Jorge Ferrer, Josep Maria Mercader, and David Torrents
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Science - Abstract
Genome-wide association studies have uncovered several loci associated with diabetes risk. Here, the authors reanalyse public type 2 diabetes GWAS data to fine map 50 known loci and identify seven new ones, including one near ATGR2 on the X-chromosome that doubles the risk of diabetes in men.
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- 2018
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23. The mitochondrial negative regulator MCJ is a therapeutic target for acetaminophen-induced liver injury
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Lucía Barbier-Torres, Paula Iruzubieta, David Fernández-Ramos, Teresa C. Delgado, Daniel Taibo, Virginia Guitiérrez-de-Juan, Marta Varela-Rey, Mikel Azkargorta, Nicolas Navasa, Pablo Fernández-Tussy, Imanol Zubiete-Franco, Jorge Simon, Fernando Lopitz-Otsoa, Sofia Lachiondo-Ortega, Javier Crespo, Steven Masson, Misti Vanette McCain, Erica Villa, Helen Reeves, Felix Elortza, Maria Isabel Lucena, Maria Isabel Hernández-Alvarez, Antonio Zorzano, Raúl J. Andrade, Shelly C. Lu, José M. Mato, Juan Anguita, Mercedes Rincón, and María Luz Martínez-Chantar
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Science - Abstract
Acetaminophen-induced liver injury is one of the most common causes of liver failure and has to be treated within hours of the overdose. Here Barbier-Torres et al. show that targeting MCJ, a mitochondrial negative regulator, even 24 h after the overdose protects liver from acetaminophen-induced damage.
- Published
- 2017
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24. Neuregulin 4 Downregulation Induces Insulin Resistance in 3T3-L1 Adipocytes through Inflammation and Autophagic Degradation of GLUT4 Vesicles
- Author
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Francisco Díaz-Sáez, Carla Blanco-Sinfreu, Adrià Archilla-Ortega, David Sebastian, Montserrat Romero, Maria Isabel Hernández-Alvarez, Sílvia Mora, Xavier Testar, Wifredo Ricart, José Manuel Fernández-Real, José María Moreno-Navarrete, Julián Aragonés, Marta Camps, Antonio Zorzano, and Anna Gumà
- Subjects
insulin resistance ,neuregulin 4 ,adipocytes ,autophagy ,inflammation ,insulin receptor ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
The adipokine Neuregulin 4 (Nrg4) protects against obesity-induced insulin resistance. Here, we analyze how the downregulation of Nrg4 influences insulin action and the underlying mechanisms in adipocytes. Validated shRNA lentiviral vectors were used to generate scramble (Scr) and Nrg4 knockdown (KD) 3T3-L1 adipocytes. Adipogenesis was unaffected in Nrg4 KD adipocytes, but there was a complete impairment of the insulin-induced 2-deoxyglucose uptake, which was likely the result of reduced insulin receptor and Glut4 protein. Downregulation of Nrg4 enhanced the expression of proinflammatory cytokines. Anti-inflammatory agents recovered the insulin receptor, but not Glut4, content. Proteins enriched in Glut4 storage vesicles such as the insulin-responsive aminopeptidase (IRAP) and Syntaxin-6 as well as TBC1D4, a protein involved in the intracellular retention of Glut4 vesicles, also decreased by Nrg4 KD. Insulin failed to reduce autophagy in Nrg4 KD adipocytes, observed by a minor effect on mTOR phosphorylation, at the time that proteins involved in autophagy such as LC3-II, Rab11, and Clathrin were markedly upregulated. The lysosomal activity inhibitor bafilomycin A1 restored Glut4, IRAP, Syntaxin-6, and TBC1D4 content to those found in control adipocytes. Our study reveals that Nrg4 preserves the insulin responsiveness by preventing inflammation and, in turn, benefits the insulin regulation of autophagy.
- Published
- 2021
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25. Crohn's Disease Disturbs the Immune Properties of Human Adipose-Derived Stem Cells Related to Inflammasome Activation
- Author
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Carolina Serena, Noelia Keiran, Ana Madeira, Elsa Maymó-Masip, Miriam Ejarque, Margarida Terrón-Puig, Eloy Espin, Marc Martí, Natalia Borruel, Francisco Guarner, Margarida Menacho, Antonio Zorzano, Monica Millan, Sonia Fernández-Veledo, and Joan Vendrell
- Subjects
creeping fat ,cell therapy ,interleukin 1B ,immunity ,invasion ,migration ,phagocytosis ,lymphocytes ,regulatory T cell ,mesenchymal stem cells ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Crohn's disease (CD) is characterized by the expansion of mesenteric fat, also known as “creeping fat.” We explored the plasticity and immune properties of adipose-derived stem cells (ASCs) in the context of CD as potential key players in the development of creeping fat. Mesenteric CD-derived ASCs presented a more proliferative, inflammatory, invasive, and phagocytic phenotype than equivalent cells from healthy donors, irrespective of the clinical stage. Remarkably, ASCs from the subcutaneous depot of patients with CD also showed an activated immune response that was associated with a reduction in their immunosuppressive properties. The invasive phenotype of mesenteric CD ASCs was governed by an inflammasome-mediated inflammatory state since blocking inflammasome signaling, mainly the secretion of interleukin-1β, reversed this characteristic. Thus, CD alters the biological functions of ASCs as adipocyte precursors, but also their immune properties. Selection of ASCs with the best immunomodulatory properties is advocated for the success of cell-based therapies.
- Published
- 2017
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26. Neurons and neuronal activity control gene expression in astrocytes to regulate their development and metabolism
- Author
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Philip Hasel, Owen Dando, Zoeb Jiwaji, Paul Baxter, Alison C. Todd, Samuel Heron, Nóra M. Márkus, Jamie McQueen, David W. Hampton, Megan Torvell, Sachin S. Tiwari, Sean McKay, Abel Eraso-Pichot, Antonio Zorzano, Roser Masgrau, Elena Galea, Siddharthan Chandran, David J. A. Wyllie, T. Ian Simpson, and Giles E. Hardingham
- Subjects
Science - Abstract
How neurons and neuronal activity regulate astrocyte functions is poorly understood. Haselet al. identify two large groups of astrocytic genes that are regulated by neuronal contact and synaptic activity respectively, with distinct roles in astrocytic function; interestingly, many of these genes are dysregulated in neurodegeneration.
- Published
- 2017
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27. TP53INP2 at the crossroad of apoptosis and autophagy in death receptor signaling
- Author
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Saška Ivanova and Antonio Zorzano
- Subjects
tp53inp2 ,death receptor signaling ,apoptosis ,autophagy ,trail ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
The binding of ligands to death receptors elicits distinct outcomes, such as apoptosis, inflammation and necroptosis, depending on the cellular context. We have recently described that the autophagic protein TP53INP2 favors apoptosis upon death receptor signaling and is a potential biomarker of responsiveness to TRAIL treatment.
- Published
- 2019
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28. Epithelial–Mesenchymal Transition (EMT) Induced by TGF-β in Hepatocellular Carcinoma Cells Reprograms Lipid Metabolism
- Author
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Jitka Soukupova, Andrea Malfettone, Esther Bertran, María Isabel Hernández-Alvarez, Irene Peñuelas-Haro, Francesco Dituri, Gianluigi Giannelli, Antonio Zorzano, and Isabel Fabregat
- Subjects
liver ,HCC ,EMT ,TGF-beta ,lipid metabolism ,oxidative metabolism ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
(1) Background: The transforming growth factor (TGF)-β plays a dual role in liver carcinogenesis. At early stages, it inhibits cell growth and induces apoptosis. However, TGF-β expression is high in advanced stages of hepatocellular carcinoma (HCC) and cells become resistant to TGF-β induced suppressor effects, responding to this cytokine undergoing epithelial–mesenchymal transition (EMT), which contributes to cell migration and invasion. Metabolic reprogramming has been established as a key hallmark of cancer. However, to consider metabolism as a therapeutic target in HCC, it is necessary to obtain a better understanding of how reprogramming occurs, which are the factors that regulate it, and how to identify the situation in a patient. Accordingly, in this work we aimed to analyze whether a process of full EMT induced by TGF-β in HCC cells induces metabolic reprogramming. (2) Methods: In vitro analysis in HCC cell lines, metabolomics and transcriptomics. (3) Results: Our findings indicate a differential metabolic switch in response to TGF-β when the HCC cells undergo a full EMT, which would favor lipolysis, increased transport and utilization of free fatty acids (FFA), decreased aerobic glycolysis and an increase in mitochondrial oxidative metabolism. (4) Conclusions: EMT induced by TGF-β in HCC cells reprograms lipid metabolism to facilitate the utilization of FFA and the entry of acetyl-CoA into the TCA cycle, to sustain the elevated requirements of energy linked to this process.
- Published
- 2021
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29. Role of Mitochondrial Complex IV in Age-Dependent Obesity
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Ines Soro-Arnaiz, Qilong Oscar Yang Li, Mar Torres-Capelli, Florinda Meléndez-Rodríguez, Sónia Veiga, Koen Veys, David Sebastian, Ainara Elorza, Daniel Tello, Pablo Hernansanz-Agustín, Sara Cogliati, Jose Maria Moreno-Navarrete, Eduardo Balsa, Esther Fuertes, Eduardo Romanos, Antonio Martínez-Ruiz, Jose Antonio Enriquez, Jose Manuel Fernandez-Real, Antonio Zorzano, Katrien De Bock, and Julián Aragonés
- Subjects
mitochondrial complex IV ,mitochondrial dysfunction ,COX5B ,aging ,white adipocytes ,obesity ,HIF-1 ,human adipose tissue ,Biology (General) ,QH301-705.5 - Abstract
Aging is associated with progressive white adipose tissue (WAT) enlargement initiated early in life, but the molecular mechanisms involved remain unknown. Here we show that mitochondrial complex IV (CIV) activity and assembly are already repressed in white adipocytes of middle-aged mice and involve a HIF1A-dependent decline of essential CIV components such as COX5B. At the molecular level, HIF1A binds to the Cox5b proximal promoter and represses its expression. Silencing of Cox5b decreased fatty acid oxidation and promoted intracellular lipid accumulation. Moreover, local in vivo Cox5b silencing in WAT of young mice increased the size of adipocytes, whereas restoration of COX5B expression in aging mice counteracted adipocyte enlargement. An age-dependent reduction in COX5B gene expression was also found in human visceral adipose tissue. Collectively, our findings establish a pivotal role for CIV dysfunction in progressive white adipocyte enlargement during aging, which can be restored to alleviate age-dependent WAT expansion.
- Published
- 2016
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30. Mitoquinone (MitoQ) Inhibits Platelet Activation Steps by Reducing ROS Levels
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Diego Méndez, Diego Arauna, Francisco Fuentes, Ramiro Araya-Maturana, Iván Palomo, Marcelo Alarcón, David Sebastián, Antonio Zorzano, and Eduardo Fuentes
- Subjects
mitoquinone ,mitochondria ,platelets ,ROS ,MitoQ ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Platelet activation plays a key role in cardiovascular diseases. The generation of mitochondrial reactive oxygen species (ROS) has been described as a critical step required for platelet activation. For this reason, it is necessary to find new molecules with antiplatelet activity and identify their mechanisms of action. Mitoquinone (MitoQ) is a mitochondria-targeted antioxidant that reduces mitochondrial overproduction of ROS. In this work, the antiplatelet effect of MitoQ through platelet adhesion and spreading, secretion, and aggregation was evaluated. Thus MitoQ, in a non-toxic effect, decreased platelet adhesion and spreading on collagen surface, and expression of P-selectin and CD63, and inhibited platelet aggregation induced by collagen, convulxin, thrombin receptor activator peptide-6 (TRAP-6), and phorbol 12-myristate 13-acetate (PMA). As an antiplatelet mechanism, we showed that MitoQ produced mitochondrial depolarization and decreased ATP secretion. Additionally, in platelets stimulated with antimycin A and collagen MitoQ significantly decreased ROS production. Our findings showed, for the first time, an antiplatelet effect of MitoQ that is probably associated with its mitochondrial antioxidant effect.
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- 2020
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31. Mutations in L-type amino acid transporter-2 support SLC7A8 as a novel gene involved in age-related hearing loss
- Author
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Meritxell Espino Guarch, Mariona Font-Llitjós, Silvia Murillo-Cuesta, Ekaitz Errasti- Murugarren, Adelaida M Celaya, Giorgia Girotto, Dragana Vuckovic, Massimo Mezzavilla, Clara Vilches, Susanna Bodoy, Ignasi Sahún, Laura González, Esther Prat, Antonio Zorzano, Mara Dierssen, Isabel Varela-Nieto, Paolo Gasparini, Manuel Palacín, and Virginia Nunes
- Subjects
LAT2 ,Slc7a8 ,hearing loss ,age-related hearing loss ,knock-out mouse model ,auditory brainstem response ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Age-related hearing loss (ARHL) is the most common sensory deficit in the elderly. The disease has a multifactorial etiology with both environmental and genetic factors involved being largely unknown. SLC7A8/SLC3A2 heterodimer is a neutral amino acid exchanger. Here, we demonstrated that SLC7A8 is expressed in the mouse inner ear and that its ablation resulted in ARHL, due to the damage of different cochlear structures. These findings make SLC7A8 transporter a strong candidate for ARHL in humans. Thus, a screening of a cohort of ARHL patients and controls was carried out revealing several variants in SLC7A8, whose role was further investigated by in vitro functional studies. Significant decreases in SLC7A8 transport activity was detected for patient’s variants (p.Val302Ile, p.Arg418His, p.Thr402Met and p.Val460Glu) further supporting a causative role for SLC7A8 in ARHL. Moreover, our preliminary data suggest that a relevant proportion of ARHL cases could be explained by SLC7A8 mutations.
- Published
- 2018
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32. Reduced α-MSH Underlies Hypothalamic ER-Stress-Induced Hepatic Gluconeogenesis
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Marc Schneeberger, Alicia G. Gómez-Valadés, Jordi Altirriba, David Sebastián, Sara Ramírez, Ainhoa Garcia, Yaiza Esteban, Anne Drougard, Albert Ferrés-Coy, Analía Bortolozzi, Pablo M. Garcia-Roves, John G. Jones, Bruno Manadas, Antonio Zorzano, Ramon Gomis, and Marc Claret
- Subjects
Biology (General) ,QH301-705.5 - Abstract
Alterations in ER homeostasis have been implicated in the pathophysiology of obesity and type-2 diabetes (T2D). Acute ER stress induction in the hypothalamus produces glucose metabolism perturbations. However, the neurobiological basis linking hypothalamic ER stress with abnormal glucose metabolism remains unknown. Here, we report that genetic and induced models of hypothalamic ER stress are associated with alterations in systemic glucose homeostasis due to increased gluconeogenesis (GNG) independent of body weight changes. Defective alpha melanocyte-stimulating hormone (α-MSH) production underlies this metabolic phenotype, as pharmacological strategies aimed at rescuing hypothalamic α-MSH content reversed this phenotype at metabolic and molecular level. Collectively, our results posit defective α-MSH processing as a fundamental mediator of enhanced GNG in the context of hypothalamic ER stress and establish α-MSH deficiency in proopiomelanocortin (POMC) neurons as a potential contributor to the pathophysiology of T2D.
- Published
- 2015
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33. Publisher Correction: Re-analysis of public genetic data reveals a rare X-chromosomal variant associated with type 2 diabetes
- Author
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Sílvia Bonàs-Guarch, Marta Guindo-Martínez, Irene Miguel-Escalada, Niels Grarup, David Sebastian, Elias Rodriguez-Fos, Friman Sánchez, Mercè Planas-Fèlix, Paula Cortes-Sánchez, Santi González, Pascal Timshel, Tune H. Pers, Claire C. Morgan, Ignasi Moran, Goutham Atla, Juan R. González, Montserrat Puiggros, Jonathan Martí, Ehm A. Andersson, Carlos Díaz, Rosa M. Badia, Miriam Udler, Aaron Leong, Varindepal Kaur, Jason Flannick, Torben Jørgensen, Allan Linneberg, Marit E. Jørgensen, Daniel R. Witte, Cramer Christensen, Ivan Brandslund, Emil V. Appel, Robert A. Scott, Jian’an Luan, Claudia Langenberg, Nicholas J. Wareham, Oluf Pedersen, Antonio Zorzano, Jose C Florez, Torben Hansen, Jorge Ferrer, Josep Maria Mercader, and David Torrents
- Subjects
Science - Abstract
In the originally published version of this Article, the affiliation details for Santi González, Jian’an Luan and Claudia Langenberg were inadvertently omitted. Santi González should have been affiliated with 'Barcelona Supercomputing Center (BSC), Joint BSC-CRG-IRB Research Program in Computational Biology, 08034 Barcelona, Spain’, and Jian’an Luan and Claudia Langenberg should have been affiliated with ‘MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK’. Furthermore, the abstract contained an error in the SNP ID for the rare variant in chromosome Xq23, which was incorrectly given as rs146662057 and should have been rs146662075. These errors have now been corrected in both the PDF and HTML versions of the Article.
- Published
- 2018
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34. Inducible Slc7a7 Knockout Mouse Model Recapitulates Lysinuric Protein Intolerance Disease
- Author
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Susanna Bodoy, Fernando Sotillo, Meritxell Espino-Guarch, Maria Pia Sperandeo, Aida Ormazabal, Antonio Zorzano, Gianfranco Sebastio, Rafael Artuch, and Manuel Palacín
- Subjects
lpi ,rare disease ,amino acid transporter ,y+lat1 ,hypoargininemia ,hyperammonemia ,pulmonary alveolar proteinosis ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Lysinuric protein intolerance (LPI) is a rare autosomal disease caused by defective cationic amino acid (CAA) transport due to mutations in SLC7A7, which encodes for the y+LAT1 transporter. LPI patients suffer from a wide variety of symptoms, which range from failure to thrive, hyperammonemia, and nephropathy to pulmonar alveolar proteinosis (PAP), a potentially life-threatening complication. Hyperammonemia is currently prevented by citrulline supplementation. However, the full impact of this treatment is not completely understood. In contrast, there is no defined therapy for the multiple reported complications of LPI, including PAP, for which bronchoalveolar lavages do not prevent progression of the disease. The lack of a viable LPI model prompted us to generate a tamoxifen-inducible Slc7a7 knockout mouse (Slc7a7−/−). The Slc7a7−/− model resembles the human LPI phenotype, including malabsorption and impaired reabsorption of CAA, hypoargininemia and hyperammonemia. Interestingly, the Slc7a7−/− mice also develops PAP and neurological impairment. We observed that citrulline treatment improves the metabolic derangement and survival. On the basis of our findings, the Slc7a7−/− model emerges as a promising tool to further study the complexity of LPI, including its immune-like complications, and to design evidence-based therapies to halt its progression.
- Published
- 2019
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35. GRP94 Is Involved in the Lipid Phenotype of Brain Metastatic Cells
- Author
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Naiara Santana-Codina, Anna Marcé-Grau, Laia Muixí, Claudia Nieva, Mónica Marro, David Sebastián, Juan Pablo Muñoz, Antonio Zorzano, and Angels Sierra
- Subjects
GRP94 ,brain metastasis ,endoplasmic reticulum stress ,fatty acids ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Metabolic adaptation may happen in response to the pressure exerted by the microenvironment and is a key step in survival of metastatic cells. Brain metastasis occurs as a consequence of the systemic dissemination of tumor cells, a fact that correlates with poor prognosis and high morbidity due to the difficulty in identifying biomarkers that allow a more targeted therapy. Previously, we performed transcriptomic analysis of human breast cancer patient samples and evaluated the differential expression of genes in brain metastasis (BrM) compared to lung, bone and liver metastasis. Our network approach identified upregulation of glucose-regulated protein 94 (GRP94) as well as proteins related to synthesis of fatty acids (FA) in BrM. Here we report that BrM cells show an increase in FA content and decreased saturation with regard to parental cells measured by Raman spectroscopy that differentiate BrM from other metastases. Moreover, BrM cells exerted a high ability to oxidize FA and compensate hypoglycemic stress due to an overexpression of proteins involved in FA synthesis and degradation (SREBP-1, LXRα, ACOT7). GRP94 ablation restored glucose dependence, down-regulated ACOT7 and SREBP-1 and decreased tumorigenicity in vivo. In conclusion, GRP94 is required for the metabolic stress survival of BrM cells, and it might act as a modulator of lipid metabolism to favor BrM progression.
- Published
- 2019
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36. Carnitine Palmitoyltransferase 1 Increases Lipolysis, UCP1 Protein Expression and Mitochondrial Activity in Brown Adipocytes.
- Author
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María Calderon-Dominguez, David Sebastián, Raquel Fucho, Minéia Weber, Joan F Mir, Ester García-Casarrubios, María Jesús Obregón, Antonio Zorzano, Ángela M Valverde, Dolors Serra, and Laura Herrero
- Subjects
Medicine ,Science - Abstract
The discovery of active brown adipose tissue (BAT) in adult humans and the fact that it is reduced in obese and diabetic patients have put a spotlight on this tissue as a key player in obesity-induced metabolic disorders. BAT regulates energy expenditure through thermogenesis; therefore, harnessing its thermogenic fat-burning power is an attractive therapeutic approach. We aimed to enhance BAT thermogenesis by increasing its fatty acid oxidation (FAO) rate. Thus, we expressed carnitine palmitoyltransferase 1AM (CPT1AM), a permanently active mutant form of CPT1A (the rate-limiting enzyme in FAO), in a rat brown adipocyte (rBA) cell line through adenoviral infection. We found that CPT1AM-expressing rBA have increased FAO, lipolysis, UCP1 protein levels and mitochondrial activity. Additionally, enhanced FAO reduced the palmitate-induced increase in triglyceride content and the expression of obese and inflammatory markers. Thus, CPT1AM-expressing rBA had enhanced fat-burning capacity and improved lipid-induced derangements. This indicates that CPT1AM-mediated increase in brown adipocytes FAO may be a new approach to the treatment of obesity-induced disorders.
- Published
- 2016
- Full Text
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37. Correction: Author Correction: Neurons and neuronal activity control gene expression in astrocytes to regulate their development and metabolism
- Author
-
Philip Hasel, Owen Dando, Zoeb Jiwaji, Paul Baxter, Alison C. Todd, Samuel Heron, Nóra M. Márkus, Jamie McQueen, David W. Hampton, Megan Torvell, Sachin S. Tiwari, Sean McKay, Abel Eraso-Pichot, Antonio Zorzano, Roser Masgrau, Elena Galea, Siddharthan Chandran, David J. A. Wyllie, T. Ian Simpson, and Giles E. Hardingham
- Subjects
Science - Abstract
Nature Communications 8: Article number: 15132 (2017); Published: 2 May 2017; Updated: 6 February 2018 Michel Goedert, who developed the Thy1-P301S transgenic mouse, was inadvertently omitted from the Acknowledgments section of this Article. The Acknowledgements should have included the following: ‘We thank Michel Goedert for providing the Thy1-P301S transgenic mouse that was used in this study.
- Published
- 2018
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38. Expression patterns of MLC1 protein in the central and peripheral nervous systems
- Author
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Oscar Teijido, Ricardo Casaroli-Marano, Tatjana Kharkovets, Fernando Aguado, Antonio Zorzano, Manuel Palacín, Eduardo Soriano, Albert Martínez, and Raúl Estévez
- Subjects
Myelin ,Leukodystrophy ,MLC ,Neuron ,Astrocyte ,Development ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Mutations in MLC1 cause megalencephalic leukoencephalopathy with subcortical cysts (MLC), a disorder characterized clinically by macrocephaly, deterioration of motor functions, epilepsy and mental decline. Recent studies have detected MLC1 mRNA and protein in astroglial processes. In addition, our group previously reported MLC1 expression in some neurons in the adult mouse brain. Here we performed an exhaustive study of the expression pattern of MLC1 in the developing mouse brain by means of optic and electron microscopy. In the central nervous system, MLC1 was detected mainly in axonal tracts early in development. In addition, MLC1 was also observed in the peripheral nervous system and in several sensory epithelia, as retina or saccula maculae. Post-embedding immunogold experiments indicated that MLC1 is localized in astrocyte–astrocyte junctions, but not in the perivascular membrane, indicating that MLC1 is not a component of the dystrophin–glycoprotein complex. In neurons, MLC1 is located at the plasma membrane and vesicular structures. Our data provide a mouse MLC1 expression map that could be useful to understand the phenotype of MLC patients, and suggested that MLC disease is caused by an astrocytic and a neuronal dysfunction.
- Published
- 2007
- Full Text
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39. PPP2R5C Couples Hepatic Glucose and Lipid Homeostasis.
- Author
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Yong-Sheng Cheng, Oksana Seibert, Nora Klöting, Arne Dietrich, Katrin Straßburger, Sonia Fernández-Veledo, Joan J Vendrell, Antonio Zorzano, Matthias Blüher, Stephan Herzig, Mauricio Berriel Diaz, and Aurelio A Teleman
- Subjects
Genetics ,QH426-470 - Abstract
In mammals, the liver plays a central role in maintaining carbohydrate and lipid homeostasis by acting both as a major source and a major sink of glucose and lipids. In particular, when dietary carbohydrates are in excess, the liver converts them to lipids via de novo lipogenesis. The molecular checkpoints regulating the balance between carbohydrate and lipid homeostasis, however, are not fully understood. Here we identify PPP2R5C, a regulatory subunit of PP2A, as a novel modulator of liver metabolism in postprandial physiology. Inactivation of PPP2R5C in isolated hepatocytes leads to increased glucose uptake and increased de novo lipogenesis. These phenotypes are reiterated in vivo, where hepatocyte specific PPP2R5C knockdown yields mice with improved systemic glucose tolerance and insulin sensitivity, but elevated circulating triglyceride levels. We show that modulation of PPP2R5C levels leads to alterations in AMPK and SREBP-1 activity. We find that hepatic levels of PPP2R5C are elevated in human diabetic patients, and correlate with obesity and insulin resistance in these subjects. In sum, our data suggest that hepatic PPP2R5C represents an important factor in the functional wiring of energy metabolism and the maintenance of a metabolically healthy state.
- Published
- 2015
- Full Text
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40. Fatty acid transport protein 1 (FATP1) localizes in mitochondria in mouse skeletal muscle and regulates lipid and ketone body disposal.
- Author
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Maria Guitart, Oscar Osorio-Conles, Thais Pentinat, Judith Cebrià, Judit García-Villoria, David Sala, David Sebastián, Antonio Zorzano, Antonia Ribes, Josep C Jiménez-Chillarón, Celia García-Martínez, and Anna M Gómez-Foix
- Subjects
Medicine ,Science - Abstract
FATP1 mediates skeletal muscle cell fatty acid import, yet its intracellular localization and metabolic control role are not completely defined. Here, we examine FATP1 localization and metabolic effects of its overexpression in mouse skeletal muscle. The FATP1 protein was detected in mitochondrial and plasma membrane fractions, obtained by differential centrifugation, of mouse gastrocnemius muscle. FATP1 was most abundant in purified mitochondria, and in the outer membrane and soluble intermembrane, but not in the inner membrane plus matrix, enriched subfractions of purified mitochondria. Immunogold electron microscopy localized FATP1-GFP in mitochondria of transfected C2C12 myotubes. FATP1 was overexpressed in gastrocnemius mouse muscle, by adenovirus-mediated delivery of the gene into hindlimb muscles of newborn mice, fed after weaning a chow or high-fat diet. Compared to GFP delivery, FATP1 did not alter body weight, serum fed glucose, insulin and triglyceride levels, and whole-body glucose tolerance, in either diet. However, fatty acid levels were lower and β-hydroxybutyrate levels were higher in FATP1- than GFP-mice, irrespective of diet. Moreover, intramuscular triglyceride content was lower in FATP1- versus GFP-mice regardless of diet, and β-hydroxybutyrate content was unchanged in high-fat-fed mice. Electroporation-mediated FATP1 overexpression enhanced palmitate oxidation to CO2, but not to acid-soluble intermediate metabolites, while CO2 production from β-hydroxybutyrate was inhibited and that from glucose unchanged, in isolated mouse gastrocnemius strips. In summary, FATP1 was localized in mitochondria, in the outer membrane and intermembrane parts, of mouse skeletal muscle, what may be crucial for its metabolic effects. Overexpressed FATP1 enhanced disposal of both systemic fatty acids and intramuscular triglycerides. Consistently, it did not contribute to the high-fat diet-induced metabolic dysregulation. However, FATP1 lead to hyperketonemia, likely secondary to the sparing of ketone body oxidation by the enhanced oxidation of fatty acids.
- Published
- 2014
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41. High-lard and high-fish-oil diets differ in their effects on function and dynamic behaviour of rat hepatic mitochondria.
- Author
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Lillà Lionetti, Maria Pina Mollica, Immacolata Donizzetti, Giorgio Gifuni, Raffaella Sica, Angelica Pignalosa, Gina Cavaliere, Marcello Gaita, Chiara De Filippo, Antonio Zorzano, and Rosalba Putti
- Subjects
Medicine ,Science - Abstract
Mitochondria are dynamic organelles that frequently undergo fission and fusion processes, and imbalances in these processes may be involved in obesity and insulin resistance.The present work had the following aims: (a) to evaluate whether the mitochondrial dysfunction present in the hepatic steatosis induced by a high-fat diet is associated with changes in mitochondrial dynamics and morphology; (b) to evaluate whether effects on the above parameters differ between high-lard and high-fish-oil diets, as it has been suggested that fish oil may have anti-obesity and anti-steatotic effects by stimulating fatty acids utilisation.The development of hepatic steatosis and insulin resistance was monitored in rats fed a high-lard or high-fish-oil diet. Immunohistochemical and electronic microscopic observations were performed on liver sections. In isolated liver mitochondria, assessments of fatty acids oxidation rate, proton conductance and oxidative stress (by measuring H2O2 release and aconitase activity) were performed. Western blot and immunohistochemical analyses were performed to evaluate the presence of proteins involved in mitochondrial dynamics (i.e., fusion and fission processes). To investigate the fusion process, mitofusin 2 and autosomal dominant optic atrophy-1 (OPA1) were analysed. To investigate the fission process, the presence of dynamin-related protein 1 (Drp1) and fission 1 protein (Fis1) was assessed.High-lard feeding elicited greater hepatic lipid accumulation, insulin resistance with associated mitochondrial dysfunction, greater oxidative stress and a shift towards mitochondrial fission processes (versus high-fish-oil feeding, which had an anti-steatotic effect associated with increased mitochondrial fusion processes).Different types of high-fat diets differ in their effect on mitochondrial function and dynamic behaviour, leading to different cellular adaptations to over-feeding.
- Published
- 2014
- Full Text
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42. The p38α MAPK function in osteoprecursors is required for bone formation and bone homeostasis in adult mice.
- Author
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Edgardo Rodríguez-Carballo, Beatriz Gámez, Lara Sedó-Cabezón, Manuela Sánchez-Feutrie, Antonio Zorzano, Cristina Manzanares-Céspedes, José Luis Rosa, and Francesc Ventura
- Subjects
Medicine ,Science - Abstract
p38 MAPK activity plays an important role in several steps of the osteoblast lineage progression through activation of osteoblast-specific transcription factors and it is also essential for the acquisition of the osteoblast phenotype in early development. Although reports indicate p38 signalling plays a role in early skeletal development, its specific contributions to adult bone remodelling are still to be clarified.We evaluated osteoblast-specific deletion of p38α to determine its significance in early skeletogenesis, as well as for bone homeostasis in adult skeleton. Early p38α deletion resulted in defective intramembranous and endochondral ossification in both calvaria and long bones. Mutant mice showed reduction of trabecular bone volume in distal femurs, associated with low trabecular thickness. In addition, knockout mice also displayed decreased femoral cortical bone volume and thickness. Deletion of p38α did not affect osteoclast function. Yet it impaired osteoblastogenesis and osteoblast maturation and activity through decreased expression of osteoblast-specific transcription factors and their targets. Furthermore, the inducible Cre system allowed us to control the onset of p38α disruption after birth by removal of doxycycline. Deletion of p38α at three or eight weeks postnatally led to significantly lower trabecular and cortical bone volume after 6 or 12 months.Our data demonstrates that, in addition to early skeletogenesis, p38α is essential for osteoblasts to maintain their function in mineralized adult bone, as bone anabolism should be sustained throughout life. Moreover, our data also emphasizes that clinical development of p38 inhibitors should take into account their potential bone effects.
- Published
- 2014
- Full Text
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43. Biophysical assessment of human aquaporin-7 as a water and glycerol channel in 3T3-L1 adipocytes.
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Ana Madeira, Marta Camps, Antonio Zorzano, Teresa F Moura, and Graça Soveral
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Medicine ,Science - Abstract
The plasma membrane aquaporin-7 (AQP7) has been shown to be expressed in adipose tissue and its role in glycerol release/uptake in adipocytes has been postulated and correlated with obesity onset. However, some studies have contradicted this view. Based on this situation, we have re-assessed the precise localization of AQP7 in adipose tissue and analyzed its function as a water and/or glycerol channel in adipose cells. Fractionation of mice adipose tissue revealed that AQP7 is located in both adipose and stromal vascular fractions. Moreover, AQP7 was the only aquaglyceroporin expressed in adipose tissue and in 3T3-L1 adipocytes. By overexpressing the human AQP7 in 3T3-L1 adipocytes it was possible to ascertain its role as a water and glycerol channel in a gain-of-function scenario. AQP7 expression had no effect in equilibrium cell volume but AQP7 loss of function correlated with higher triglyceride content. Furthermore it is also reported for the first time a negative correlation between water permeability and the cell non-osmotic volume supporting the observation that AQP7 depleted cells are more prone to lipid accumulation. Additionally, the strong positive correlation between the rates of water and glycerol transport highlights the role of AQP7 as both a water and a glycerol channel and reflects its expression levels in cells. In all, our results clearly document a direct involvement of AQP7 in water and glycerol transport, as well as in triglyceride content in adipocytes.
- Published
- 2013
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44. DOR/Tp53inp2 and Tp53inp1 constitute a metazoan gene family encoding dual regulators of autophagy and transcription.
- Author
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Ana Sancho, Jordi Duran, Antonio García-España, Caroline Mauvezin, Endalkachew A Alemu, Trond Lamark, Maria J Macias, Rob DeSalle, Miriam Royo, David Sala, Javier U Chicote, Manuel Palacín, Terje Johansen, and Antonio Zorzano
- Subjects
Medicine ,Science - Abstract
Human DOR/TP53INP2 displays a unique bifunctional role as a modulator of autophagy and gene transcription. However, the domains or regions of DOR that participate in those functions have not been identified. Here we have performed structure/function analyses of DOR guided by identification of conserved regions in the DOR gene family by phylogenetic reconstructions. We show that DOR is present in metazoan species. Invertebrates harbor only one gene, DOR/Tp53inp2, and in the common ancestor of vertebrates Tp53inp1 may have arisen by gene duplication. In keeping with these data, we show that human TP53INP1 regulates autophagy and that different DOR/TP53INP2 and TP53INP1 proteins display transcriptional activity. The use of molecular evolutionary information has been instrumental to determine the regions that participate in DOR functions. DOR and TP53INP1 proteins share two highly conserved regions (region 1, aa residues 28-42; region 2, 66-112 in human DOR). Mutation of conserved hydrophobic residues in region 1 of DOR (that are part of a nuclear export signal, NES) reduces transcriptional activity, and blocks nuclear exit and autophagic activity under autophagy-activated conditions. We also identify a functional and conserved LC3-interacting motif (LIR) in region 1 of DOR and TP53INP1 proteins. Mutation of conserved acidic residues in region 2 of DOR reduces transcriptional activity, impairs nuclear exit in response to autophagy activation, and disrupts autophagy. Taken together, our data reveal DOR and TP53INP1 as dual regulators of transcription and autophagy, and identify two conserved regions in the DOR family that concentrate multiple functions crucial for autophagy and transcription.
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- 2012
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45. Cholesterol depletion in adipocytes causes caveolae collapse concomitant with proteosomal degradation of cavin-2 in a switch-like fashion.
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Michael R Breen, Marta Camps, Francisco Carvalho-Simoes, Antonio Zorzano, and Paul F Pilch
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Medicine ,Science - Abstract
Caveolae, little caves of cell surfaces, are enriched in cholesterol, a certain level of which is required for their structural integrity. Here we show in adipocytes that cavin-2, a peripheral membrane protein and one of 3 cavin isoforms present in caveolae from non-muscle tissue, is degraded upon cholesterol depletion in a rapid fashion resulting in collapse of caveolae. We exposed 3T3-L1 adipocytes to the cholesterol depleting agent methyl-β-cyclodextrin, which results in a sudden and extensive degradation of cavin-2 by the proteasome and a concomitant movement of cavin-1 from the plasma membrane to the cytosol along with loss of caveolae. The recovery of cavin-2 at the plasma membrane is cholesterol-dependent and is required for the return of cavin-1 from the cytosol to the cell surface and caveolae restoration. Expression of shRNA directed against cavin-2 also results in a cytosolic distribution of cavin-1 and loss of caveolae. Taken together, these data demonstrate that cavin-2 functions as a cholesterol responsive component of caveolae that is required for cavin-1 localization to the plasma membrane, and caveolae structural integrity.
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- 2012
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46. Identification of novel type 2 diabetes candidate genes involved in the crosstalk between the mitochondrial and the insulin signaling systems.
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Josep M Mercader, Montserrat Puiggros, Ayellet V Segrè, Evarist Planet, Eleonora Sorianello, David Sebastian, Sergio Rodriguez-Cuenca, Vicent Ribas, Sílvia Bonàs-Guarch, Sorin Draghici, Chenjing Yang, Sílvia Mora, Antoni Vidal-Puig, Josée Dupuis, DIAGRAM Consortium, Jose C Florez, MITIN Consortium, Antonio Zorzano, and David Torrents
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Genetics ,QH426-470 - Abstract
Type 2 Diabetes (T2D) is a highly prevalent chronic metabolic disease with strong co-morbidity with obesity and cardiovascular diseases. There is growing evidence supporting the notion that a crosstalk between mitochondria and the insulin signaling cascade could be involved in the etiology of T2D and insulin resistance. In this study we investigated the molecular basis of this crosstalk by using systems biology approaches. We combined, filtered, and interrogated different types of functional interaction data, such as direct protein-protein interactions, co-expression analyses, and metabolic and signaling dependencies. As a result, we constructed the mitochondria-insulin (MITIN) network, which highlights 286 genes as candidate functional linkers between these two systems. The results of internal gene expression analysis of three independent experimental models of mitochondria and insulin signaling perturbations further support the connecting roles of these genes. In addition, we further assessed whether these genes are involved in the etiology of T2D using the genome-wide association study meta-analysis from the DIAGRAM consortium, involving 8,130 T2D cases and 38,987 controls. We found modest enrichment of genes associated with T2D amongst our linker genes (p = 0.0549), including three already validated T2D SNPs and 15 additional SNPs, which, when combined, were collectively associated to increased fasting glucose levels according to MAGIC genome wide meta-analysis (p = 8.12×10(-5)). This study highlights the potential of combining systems biology, experimental, and genome-wide association data mining for identifying novel genes and related variants that increase vulnerability to complex diseases.
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- 2012
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47. Correction: and Constitute a Metazoan Gene Family Encoding Dual Regulators of Autophagy and Transcription.
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Ana Sancho, Jordi Duran, Antonio García-España, Caroline Mauvezin, Endalkachew A. Alemu, Trond Lamark, Maria J. Macias, Rob DeSalle, Miriam Royo, David Sala, Javier U. Chicote, Manuel Palacín, Terje Johansen, and Antonio Zorzano
- Subjects
Medicine ,Science - Published
- 2012
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48. Mitochondrial fusion is increased by the nuclear coactivator PGC-1beta.
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Marc Liesa, Bárbara Borda-d'Agua, Gema Medina-Gómez, Christopher J Lelliott, José Carlos Paz, Manuel Rojo, Manuel Palacín, Antonio Vidal-Puig, and Antonio Zorzano
- Subjects
Medicine ,Science - Abstract
There is no evidence to date on whether transcriptional regulators are able to shift the balance between mitochondrial fusion and fission events through selective control of gene expression.Here, we demonstrate that reduced mitochondrial size observed in knock-out mice for the transcriptional regulator PGC-1beta is associated with a selective reduction in Mitofusin 2 (Mfn2) expression, a mitochondrial fusion protein. This decrease in Mfn2 is specific since expression of the remaining components of mitochondrial fusion and fission machinery were not affected. Furthermore, PGC-1beta increases mitochondrial fusion and elongates mitochondrial tubules. This PGC-1beta-induced elongation specifically requires Mfn2 as this process is absent in Mfn2-ablated cells. Finally, we show that PGC-1beta increases Mfn2 promoter activity and transcription by coactivating the nuclear receptor Estrogen Related Receptor alpha (ERRalpha).Taken together, our data reveal a novel mechanism by which mammalian cells control mitochondrial fusion. In addition, we describe a novel role of PGC-1beta in mitochondrial physiology, namely the control of mitochondrial fusion mainly through Mfn2.
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- 2008
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49. Identification of a novel modulator of thyroid hormone receptor-mediated action.
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Bernhard G Baumgartner, Meritxell Orpinell, Jordi Duran, Vicent Ribas, Hans E Burghardt, Daniel Bach, Ana Victoria Villar, José C Paz, Meritxell González, Marta Camps, Josep Oriola, Francisca Rivera, Manuel Palacín, and Antonio Zorzano
- Subjects
Medicine ,Science - Abstract
BackgroundDiabetes is characterized by reduced thyroid function and altered myogenesis after muscle injury. Here we identify a novel component of thyroid hormone action that is repressed in diabetic rat muscle.Methodology/principal findingsWe have identified a gene, named DOR, abundantly expressed in insulin-sensitive tissues such as skeletal muscle and heart, whose expression is highly repressed in muscle from obese diabetic rats. DOR expression is up-regulated during muscle differentiation and its loss-of-function has a negative impact on gene expression programmes linked to myogenesis or driven by thyroid hormones. In agreement with this, DOR enhances the transcriptional activity of the thyroid hormone receptor TR(alpha1). This function is driven by the N-terminal part of the protein. Moreover, DOR physically interacts with TR( alpha1) and to T(3)-responsive promoters, as shown by ChIP assays. T(3) stimulation also promotes the mobilization of DOR from its localization in nuclear PML bodies, thereby indicating that its nuclear localization and cellular function may be related.Conclusions/significanceOur data indicate that DOR modulates thyroid hormone function and controls myogenesis. DOR expression is down-regulated in skeletal muscle in diabetes. This finding may be of relevance for the alterations in muscle function associated with this disease.
- Published
- 2007
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50. Role of myotonic dystrophy protein kinase (DMPK) in glucose homeostasis and muscle insulin action.
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Esther Llagostera, Daniele Catalucci, Luc Marti, Marc Liesa, Marta Camps, Theodore P Ciaraldi, Richard Kondo, Sita Reddy, Wolfgang H Dillmann, Manuel Palacin, Antonio Zorzano, Pilar Ruiz-Lozano, Ramon Gomis, and Perla Kaliman
- Subjects
Medicine ,Science - Abstract
Myotonic dystrophy 1 (DM1) is caused by a CTG expansion in the 3'-unstranslated region of the DMPK gene, which encodes a serine/threonine protein kinase. One of the common clinical features of DM1 patients is insulin resistance, which has been associated with a pathogenic effect of the repeat expansions. Here we show that DMPK itself is a positive modulator of insulin action. DMPK-deficient (dmpk-/-) mice exhibit impaired insulin signaling in muscle tissues but not in adipocytes and liver, tissues in which DMPK is not expressed. Dmpk-/- mice display metabolic derangements such as abnormal glucose tolerance, reduced glucose uptake and impaired insulin-dependent GLUT4 trafficking in muscle. Using DMPK mutants, we show that DMPK is required for a correct intracellular trafficking of insulin and IGF-1 receptors, providing a mechanism to explain the molecular and metabolic phenotype of dmpk-/- mice. Taken together, these findings indicate that reduced DMPK expression may directly influence the onset of insulin-resistance in DM1 patients and point to dmpk as a new candidate gene for susceptibility to type 2-diabetes.
- Published
- 2007
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