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1. Drug-induced impairment of mitochondrial fatty acid oxidation and steatosis: assessment of causal relationship with 45 pharmaceuticals.

Author

Buron, Nelly, Porceddu, Mathieu, Loyant, Roxane, Martel, Cécile, Allard, Julien A, Fromenty, Bernard, and Borgne-Sanchez, Annie

Subjects
LIVER mitochondria, FATTY acid oxidation, MEMBRANE potential, REACTIVE oxygen species, DRUG side effects
Abstract

Drug-induced liver injury (DILI) represents a major issue for pharmaceutical companies, being a potential cause of black-box warnings on marketed pharmaceuticals, or drug withdrawal from the market. Lipid accumulation in the liver also referred to as steatosis, may be secondary to impaired mitochondrial fatty acid oxidation (mtFAO). However, an overall causal relationship between drug-induced mtFAO inhibition and the occurrence of steatosis in patients has not yet been established with a high number of pharmaceuticals. Hence, 32 steatogenic and 13 nonsteatogenic drugs were tested for their ability to inhibit mtFAO in isolated mouse liver mitochondria. To this end, mitochondrial respiration was measured with palmitoyl- l -carnitine, palmitoyl-CoA + l -carnitine, or octanoyl- l -carnitine. This mtFAO tri-parametric assay was able to predict the occurrence of steatosis in patients with a sensitivity and positive predictive value above 88%. To get further information regarding the mechanism of drug-induced mtFAO impairment, mitochondrial respiration was also measured with malate/glutamate or succinate. Drugs such as diclofenac, methotrexate, and troglitazone could inhibit mtFAO secondary to an impairment of the mitochondrial respiratory chain, whereas dexamethasone, olanzapine, and zidovudine appeared to impair mtFAO directly. Mitochondrial swelling, transmembrane potential, and production of reactive oxygen species were also assessed for all compounds. Only the steatogenic drugs amiodarone, ketoconazole, lovastatin, and toremifene altered all these 3 mitochondrial parameters. In conclusion, our tri-parametric mtFAO assay could be useful in predicting the occurrence of steatosis in patients. The combination of this assay with other mitochondrial parameters could also help to better understand the mechanism of drug-induced mtFAO inhibition. [ABSTRACT FROM AUTHOR]

Published
2024
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4. Supplementary Figures S1 & S2 from Chemosensitization by Knockdown of Adenine Nucleotide Translocase-2

Author

Le Bras, Morgane, primary, Borgne-Sanchez, Annie, primary, Touat, Zahia, primary, El Dein, Ossama Sharaf, primary, Deniaud, Aurélien, primary, Maillier, Evelyne, primary, Lecellier, Gael, primary, Rebouillat, Dominique, primary, Lemaire, Christophe, primary, Kroemer, Guido, primary, Jacotot, Etienne, primary, and Brenner, Catherine, primary

Published
2023
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5. Data from Chemosensitization by Knockdown of Adenine Nucleotide Translocase-2

Author

Le Bras, Morgane, primary, Borgne-Sanchez, Annie, primary, Touat, Zahia, primary, El Dein, Ossama Sharaf, primary, Deniaud, Aurélien, primary, Maillier, Evelyne, primary, Lecellier, Gael, primary, Rebouillat, Dominique, primary, Lemaire, Christophe, primary, Kroemer, Guido, primary, Jacotot, Etienne, primary, and Brenner, Catherine, primary

Published
2023
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7. Data from Chemosensitization by Knockdown of Adenine Nucleotide Translocase-2

Author

Catherine Brenner, Etienne Jacotot, Guido Kroemer, Christophe Lemaire, Dominique Rebouillat, Gael Lecellier, Evelyne Maillier, Aurélien Deniaud, Ossama Sharaf El Dein, Zahia Touat, Annie Borgne-Sanchez, and Morgane Le Bras

Abstract

Mitochondrial membrane permeabilization (MMP) is a rate-limiting step of apoptosis, including in anticancer chemotherapy. Adenine nucleotide translocase (ANT) mediates the exchange of ADP and ATP on the inner mitochondrial membrane in healthy cells. In addition, ANT can cooperate with Bax to form a lethal pore during apoptosis. Humans possess four distinct ANT isoforms, encoded by four genes, whose transcription depends on the cell type, developmental stage, cell proliferation, and hormone status. Here, we show that the ANT2 gene is up-regulated in several hormone-dependent cancers. Knockdown of ANT2 by RNA interference induced no major changes in the aspect of the mitochondrial network or cell cycle but provoked minor increase in mitochondrial transmembrane potential and reactive oxygen species level and reduced intracellular ATP concentration without affecting glycolysis. At expression and functional levels, ANT2 depletion was not compensated by other ANT isoforms. Most importantly, ANT2, but not ANT1, silencing facilitated MMP induction by lonidamine, a mitochondrion-targeted antitumor compound already used in clinical studies for breast, ovarian, glioma, and lung cancer as well as prostate adenoma. The combination of ANT2 knockdown with lonidamine induced apoptosis irrespective of the Bcl-2 status. These data identify ANT2 as an endogenous inhibitor of MMP and suggest that its selective inhibition could constitute a promising strategy of chemosensitization. (Cancer Res 2006; 66(18): 9143-52)

Published
2023

11. The Mitochondrion-lysosome Axis in Adaptive and Innate Immunity: Effect of Lupus Regulator Peptide P140 on Mitochondria Autophagy and NETosis

Author

Mykolas Bendorius, Indira Neeli, Fengjuan Wang, Srinivasa Reddy Bonam, Eszter Dombi, Nelly Buron, Annie Borgne-Sanchez, Joanna Poulton, Marko Radic, and Sylviane Muller

Subjects
NETosis, autophagy, mitochondrion, systemic lupus erythematosus, neuroinflammation, P140 peptide, Immunologic diseases. Allergy, RC581-607
Abstract

Mitochondria deserve special attention as sensors of cellular energy homeostasis and metabolic state. Moreover, mitochondria integrate intra- and extra-cellular signals to determine appropriate cellular responses that range from proliferation to cell death. In autoimmunity, as in other inflammatory chronic disorders, the metabolism of immune cells may be extensively remodeled, perturbing sensitive tolerogenic mechanisms. Here, we examine the distribution and effects of the therapeutic 21-mer peptide called P140, which shows remarkable efficacy in modulating immune responses in inflammatory settings. We measured P140 and control peptide effects on isolated mitochondria, the distribution of peptides in live cells, and their influence on the levels of key autophagy regulators. Our data indicate that while P140 targets macro- and chaperone-mediated autophagy processes, it has little effect, if any, on mitochondrial autophagy. Remarkably, however, it suppresses NET release from neutrophils exposed to immobilized NET-anti-DNA IgG complexes. Together, our results suggest that in the mitochondrion-lysosome axis, a likely driver of NETosis and inflammation, the P140 peptide does not operate by affecting mitochondria directly.

Published
2018
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12. Adipose tissue senescence is mediated by increased ATP content after a short-term high-fat diet exposure

Author

PINI, MARIA, Czibik, Gabor, Sawaki, Daigo, Mezdari, Zaineb, Braud, Laura, Delmont, Thaïs, Mercedes, Raquel, Martel, Cécile, Buron, Nelly, Marcelin, Geneviève, Borgne‐sanchez, Annie, Foresti, Roberta, Motterlini, Roberto, Henegar, Corneliu, Derumeaux, Geneviève, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Henri Mondor, Mitologics S.A.S., Hôpital Robert Debré Paris, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Nutrition et obésités: approches systémiques (UMR-S 1269) (Nutriomics), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Foresti, Roberta, and Nutrition et obésités: approches systémiques (nutriomics) (UMR-S 1269 INSERM - Sorbonne Université)

Subjects
Male, Original Paper, obesity, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, exercise, nutritional and metabolic diseases, food and beverages, Original Articles, Diet, High-Fat, bioenergetics, adipose tissue senescence, ATP, Mice, Adenosine Triphosphate, Adipose Tissue, Animals, lipids (amino acids, peptides, and proteins), Energy Metabolism, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, hormones, hormone substitutes, and hormone antagonists, xanthine oxidase
Abstract

In the context of obesity, senescent cells accumulate in white adipose tissue (WAT). The cellular underpinnings of WAT senescence leading to insulin resistance are not fully elucidated. The objective of the current study was to evaluate the presence of WAT senescence early after initiation of high‐fat diet (HFD, 1–10 weeks) in 5‐month‐old male C57BL/6J mice and the potential role of energy metabolism. We first showed that WAT senescence occurred 2 weeks after HFD as evidenced in whole WAT by increased senescence‐associated ß‐galactosidase activity and cyclin‐dependent kinase inhibitor 1A and 2A expression. WAT senescence affected various WAT cell populations, including preadipocytes, adipose tissue progenitors, and immune cells, together with adipocytes. WAT senescence was associated with higher glycolytic and mitochondrial activity leading to enhanced ATP content in HFD‐derived preadipocytes, as compared with chow diet‐derived preadipocytes. One‐month daily exercise, introduced 5 weeks after HFD, was an effective senostatic strategy, since it reversed WAT cellular senescence, while reducing glycolysis and production of ATP. Interestingly, the beneficial effect of exercise was independent of body weight and fat mass loss. We demonstrated that WAT cellular senescence is one of the earliest events occurring after HFD initiation and is intimately linked to the metabolic state of the cells. Our data uncover a critical role for HFD‐induced elevated ATP as a local danger signal inducing WAT senescence. Exercise exerts beneficial effects on adipose tissue bioenergetics in obesity, reversing cellular senescence, and metabolic abnormalities., High‐fat diet (HFD) induced senescence of various white adipose tissue (WAT) cell types as one of the earliest events preceding mitochondrial dysfunction, inflammation, and fibrosis. In WAT of HFD‐fed mice and preadipocytes derived from HFD‐fed mice, ATP levels were increased. The anti‐senescence effects of exercise were partially dependent on purine catabolism as blocking xanthine oxidase activity increased ATP levels and inhibited exercise's rescue effects in subcutaneous WAT.

Published
2021

14. A flavivirus protein M-derived peptide directly permeabilizes mitochondrial membranes, triggers cell death and reduces human tumor growth in nude mice

Author

Brabant, Magali, Baux, Ludwig, Casimir, Richard, Briand, Jean Paul, Chaloin, Olivier, Porceddu, Mathieu, Buron, Nelly, Chauvier, David, Lassalle, Myriam, Lecoeur, Hervé, Langonné, Alain, Dupont, Sylvie, Déas, Olivier, Brenner, Catherine, Rebouillat, Dominique, Muller, Sylviane, Borgne-Sanchez, Annie, and Jacotot, Etienne

Published
2009
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15. A Fast, Simple, and Affordable Technique to Measure Oxygen Consumption in Living Zebrafish Embryos

Author

Roxane Loyant, Annie Borgne-Sanchez, Nadia Soussi-Yanicostas, Julie Somkhit, Constantin Yanicostas, Mathieu Porceddu, Alexandre Brenet, Rahma Hassan-Abdi, Université de Paris, NeuroDiderot, Inserm U1141, F-75019 Paris, France, Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Mitologics S.A.S., Hôpital Robert Debré Paris, Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), ANR-16-CE18-0010,MITOXDRUGS,Toxicité mitochondriale des médicaments et stéatose hépatique. Généralisation de la relation causale pour le développement de nouveaux tests prédictifs.(2016), and Soussi-Yanicostas, Nadia

Subjects
Embryo, Nonmammalian, animal structures, [SDV]Life Sciences [q-bio], Antimycin A, chemistry.chemical_element, Biology, Oxygen, 03 medical and health sciences, 0302 clinical medicine, Rotenone, Zebrafish larvae, Animals, Animal species, Zebrafish, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Consumption (economics), 0303 health sciences, fungi, TechnoFish—Methods, Spectrofluorometer, biology.organism_classification, oxygen consumption, Cell biology, [SDV] Life Sciences [q-bio], Mitochondrial respiratory chain, chemistry, Larva, Zebrafish embryo, zebrafish larvae, Animal Science and Zoology, 030217 neurology & neurosurgery, respiration, Developmental Biology
Abstract

International audience; In all animal species, oxygen consumption is a key process that is partially impaired in a large number of pathological situations and thus provides informative details on the physiopathology of the disease. In this study, we describe a simple and affordable method to precisely measure oxygen consumption in living zebrafish larvae using a spectrofluorometer and the MitoXpress Xtra Oxygen Consumption Assay. In addition, we used zebrafish larvae treated with mitochondrial respiratory chain inhibitors, antimycin A or rotenone, to verify that our method enables precise and reliable measurements of oxygen consumption.

Published
2020

18. Use of human cancer cell lines mitochondria to explore the mechanisms of BH3 peptides and ABT-737-induced mitochondrial membrane permeabilization.

Author

Nelly Buron, Mathieu Porceddu, Magali Brabant, Diana Desgué, Cindy Racoeur, Myriam Lassalle, Christine Péchoux, Pierre Rustin, Etienne Jacotot, and Annie Borgne-Sanchez

Subjects
Medicine, Science
Abstract

Current limitations of chemotherapy include toxicity on healthy tissues and multidrug resistance of malignant cells. A number of recent anti-cancer strategies aim at targeting the mitochondrial apoptotic machinery to induce tumor cell death. In this study, we set up protocols to purify functional mitochondria from various human cell lines to analyze the effect of peptidic and xenobiotic compounds described to harbour either Bcl-2 inhibition properties or toxic effects related to mitochondria. Mitochondrial inner and outer membrane permeabilization were systematically investigated in cancer cell mitochondria versus non-cancerous mitochondria. The truncated (t-) Bid protein, synthetic BH3 peptides from Bim and Bak, and the small molecule ABT-737 induced a tumor-specific and OMP-restricted mitochondrio-toxicity, while compounds like HA-14.1, YC-137, Chelerythrine, Gossypol, TW-37 or EM20-25 did not. We found that ABT-737 can induce the Bax-dependent release of apoptotic proteins (cytochrome c, Smac/Diablo and Omi/HtrA2 but not AIF) from various but not all cancer cell mitochondria. Furthermore, ABT-737 addition to isolated cancer cell mitochondria induced oligomerization of Bax and/or Bak monomers already inserted in the mitochondrial membrane. Finally immunoprecipatations indicated that ABT-737 induces Bax, Bak and Bim desequestration from Bcl-2 and Bcl-xL but not from Mcl-1L. This study investigates for the first time the mechanism of action of ABT-737 as a single agent on isolated cancer cell mitochondria. Hence, this method based on MOMP (mitochondrial outer membrane permeabilization) is an interesting screening tool, tailored for identifying Bcl-2 antagonists with selective toxicity profile against cancer cell mitochondria but devoid of toxicity against healthy mitochondria.

Published
2010
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21. Drug-induced hepatic steatosis in absence of severe mitochondrial dysfunction in HepaRG cells: proof of multiple mechanism-based toxicity

Author

Allard, Julien, primary, Bucher, Simon, additional, Massart, Julie, additional, Ferron, Pierre-Jean, additional, Le Guillou, Dounia, additional, Loyant, Roxane, additional, Daniel, Yoann, additional, Launay, Youenn, additional, Buron, Nelly, additional, Begriche, Karima, additional, Borgne-Sanchez, Annie, additional, and Fromenty, Bernard, additional

Published
2020
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22. The mitochondrion-lysosome axis in adaptive and innate immunity: effect of lupus regulator peptide P140 on mitochondria autophagy and NETosis

Author

Bendorius, M, Neeli, I, Wang, F, Bonam, SR, Dombi, E, Buron, N, Borgne-Sanchez, A, Poulton, J, Radic, M, Muller, S, Biotechnologie et signalisation cellulaire (BSC), and Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
autophagy, P140 peptide, Microscopy, Confocal, Intravital Microscopy, Neutrophils, Immunology, Primary Cell Culture, Mitophagy, NETosis, Adaptive Immunity, Extracellular Traps, Immunity, Innate, Peptide Fragments, neuroinflammation, Mitochondria, Mice, systemic lupus erythematosus, [SDV.IMM]Life Sciences [q-bio]/Immunology, mitochondrion, Animals, Humans, Sciences du Vivant [q-bio]/Immunologie, Lysosomes, Cells, Cultured, Original Research
Abstract

Mitochondria deserve special attention as sensors of cellular energy homeostasis and metabolic state. Moreover, mitochondria integrate intra- and extra-cellular signals to determine appropriate cellular responses that range from proliferation to cell death. In autoimmunity, as in other inflammatory chronic disorders, the metabolism of immune cells may be extensively remodeled, perturbing sensitive tolerogenic mechanisms. Here, we examine the distribution and effects of the therapeutic 21-mer peptide called P140, which shows remarkable efficacy in modulating immune responses in inflammatory settings. We measured P140 and control peptide effects on isolated mitochondria, the distribution of peptides in live cells, and their influence on the levels of key autophagy regulators. Our data indicate that while P140 targets macro- and chaperone-mediated autophagy processes, it has little effect, if any, on mitochondrial autophagy. Remarkably, however, it suppresses NET release from neutrophils exposed to immobilized NET-anti-DNA IgG complexes. Together, our results suggest that in the mitochondrion-lysosome axis, a likely driver of NETosis and inflammation, the P140 peptide does not operate by affecting mitochondria directly.

Published
2018

23. Chronic and low exposure to a pharmaceutical cocktail induces mitochondrial dysfunction in liver and hyperglycemia: Differential responses between lean and obese mice

Author

Viviane Trak-Smayra, Thomas Gicquel, Nelly Buron, Karima Begriche, Annie Borgne-Sanchez, Célestin Roussel, Bernard Fromenty, and Mathieu Porceddu

Subjects
0301 basic medicine, Drug, Health, Toxicology and Mutagenesis, media_common.quotation_subject, Respiratory chain, 010501 environmental sciences, Management, Monitoring, Policy and Law, Mitochondrion, Pharmacology, Biology, Toxicology, medicine.disease_cause, 01 natural sciences, 03 medical and health sciences, medicine, Beta oxidation, 0105 earth and related environmental sciences, media_common, Fatty liver, General Medicine, medicine.disease, 3. Good health, 030104 developmental biology, 13. Climate action, Environmental toxicology, Steatosis, Oxidative stress
Abstract

Pharmaceuticals are found in the environment but the impact of this contamination on human and animal health is poorly known. The liver could be particularly targeted since a significant number of these drugs are hepatotoxic, in particular via oxidative stress and mitochondrial dysfunction. Notably, the latter events can also be observed in liver diseases linked to obesity, so that the obese liver might be more sensitive to drug toxicity. In this study, we determined the effects of a chronic exposure to low doses of pharmaceuticals in wild-type and obese mice, with a particular focus on mitochondrial function. To this end, wild-type and ob/ob mice were exposed for 4 months to a cocktail of 11 pharmaceuticals provided in drinking water containing 0.01, 0.1, or 1 mg/L of each drug. At the end of the treatment, liver mitochondria were isolated and different parameters were measured. Chronic exposure to the pharmaceuticals reduced mitochondrial respiration driven by succinate and palmitoyl-l-carnitine in wild-type mice and increased antimycin-induced ROS production in ob/ob mice. Hyperglycemia and hepatic histological abnormalities were also observed in treated ob/ob mice. Investigations were also carried out in isolated liver mitochondria incubated with the mixture, or with each individual drug. The mitochondrial effects of the mixture were different from those observed in treated mice and could not be predicted from the results obtained with each drug. Because some of the 11 drugs included in our cocktail can be found in water at relatively high concentrations, our data could be relevant in environmental toxicology. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1375-1389, 2017.

Published
2016

24. Drug-Induced Mitochondrial Toxicity

Author

Julie Massart, Annie Borgne-Sanchez, Bernard Fromenty, Karolinska University Hospital [Stockholm], Mitologics S.A.S., Hôpital Robert Debré Paris, Nutrition, Métabolismes et Cancer (NuMeCan), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Nutrition, Métabolismes et Cancer ( NuMeCan ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Drug, Steatosis, Myopathy, [SDV]Life Sciences [q-bio], media_common.quotation_subject, Respiratory chain, Oxidative phosphorylation, Mitochondrion, Pharmacology, Adverse effect, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, medicine, Beta oxidation, media_common, Cardiotoxicity, [ SDV ] Life Sciences [q-bio], Toxicity, business.industry, Heart, medicine.disease, Mitochondria, 3. Good health, Mitochondrial toxicity, 030104 developmental biology, Liver, Oxidative stress, 030220 oncology & carcinogenesis, Muscle, business
Abstract

International audience; Mitochondrial dysfunction can be a major mechanism whereby different drugs can induce adverse effects affecting different tissues such as liver, heart and skeletal muscle. In the most severe cases, drug-induced mitochondrial dysfunction can require a hospitalization, or lead to the death of the patient. Moreover, these adverse effects can lead to the withdrawal of drugs from the market, or earlier during clinical trials. Drugs can induce mitochondrial dysfunction by different mechanisms including inhibition of fatty acid oxidation, impairment of oxidative phosphorylation and respiratory chain activity as well as alteration of the integrity of the mitochondrial membranes. Some drugs also impair mitochondrial function via the production of reactive oxygen species and the generation of reactive metabolites, which can covalently bind to key mitochondrial proteins. The present chapter focuses on different drugs for which enough clinical and experimental evidence indicates the potential role of mitochondrial dysfunction in the pathogenesis of adverse effects such as liver injury, myopathy and cardiotoxicity acetaminophen, amiodarone, doxorubicin, nucleoside reverse transcriptase inhibitors (e.g. stavudine, zidovudine, didanosine), statins (e.g. atorvastatin, cerivastatin, simvastatin) and valproic acid. Notably, these drugs epitomize the diversity of the mechanisms whereby xenobiotics can induce mitochondrial dysfunction and also the variety of the targeted tissues. Other drugs affecting mitochondrial function by similar mechanisms are discussed more briefly in the present chapter. Because drug-induced mitochondrial dysfunction and related adverse events are major issues for public health and pharmaceutical companies, mitochondrial liability should be systematically investigated during preclinical safety studies. © Springer International Publishing AG, part of Springer Nature 2018.

Published
2018

25. In vitro assessment of mitochondrial toxicity to predict drug-induced liver injury

Author

Bernard Fromenty, Pierre Rustin, Nelly Buron, Annie Borgne-Sanchez, Mathieu Porceddu, Mitologics S.A.S., Hôpital Robert Debré Paris, Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition, Métabolismes et Cancer (NuMeCan), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), and Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Drug, Drug-induced liver injury, media_common.quotation_subject, [SDV]Life Sciences [q-bio], Pharmacology, 03 medical and health sciences, 0302 clinical medicine, medicine, Transmembrane potential, media_common, Liver injury, Mitochondrial toxicity, Chemistry, Hepatotoxicity, Respiratory chain, medicine.disease, In vitro, 3. Good health, Mitochondria, 030104 developmental biology, Liver, Oxidative stress, Hepatocytes, DILI, 030217 neurology & neurosurgery
Abstract

International audience; Mitochondrial liability of drugs and other xenobiotics is a major issue for patients because such toxicity can damage different tissues and organs such as liver, heart, and muscle. Drug-induced mitochondrial toxicity is also a major concern for pharmaceutical industries. Indeed, it is now acknowledged that such mechanism of toxicity can induce severe, and sometimes fatal, liver injury which can lead to the interruption of clinical trials, or drug withdrawal after marketing, such as in the case of troglitazone. Therefore, drug-induced mitochondrial dysfunction is increasingly sought after by pharmaceutical companies by using reliable in vitro assays in order to discard potential mitochondrion-toxic drugs during drug discovery stage. This chapter presents the in vitro methods used to identify potential mitochondrion-toxic drugs. To this end, different types of biological materials are used such as isolated mouse liver mitochondria and the human hepatic HepaRG® cell line, which expresses the main enzymes and transcription factors involved in drug metabolism. The in vitro method we discussed allows to investigate several key mitochondrial parameters such as oxygen consumption, transmembrane potential, respiratory chain complex activities, and mtDNA levels. These investigations are able to detect not only direct and acute mitochondrial alterations due to parent drugs but also indirect and chronic mitochondrial liability that can be induced by secondary metabolites. Hence, it could be used to detect potential drug-induced mitochondrial liability and to understand the involved mechanisms. © 2018, Springer Science+Business Media, LLC, part of Springer Nature.

Published
2018

26. Mitochondrial Dysfunction in Drug-Induced Liver Injury

Author

Annie Borgne-Sanchez, Bernard Fromenty, Mitologics S.A.S., Hôpital Robert Debré Paris, Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)

Subjects
Hepatitis, Liver injury, Drug, 0303 health sciences, Steatosis, Drug-induced liver injury, business.industry, media_common.quotation_subject, [SDV]Life Sciences [q-bio], Hepatotoxicity, Pharmacology, Mitochondrion, medicine.disease, 3. Good health, Mitochondria, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, medicine, business, 030304 developmental biology, media_common
Abstract

International audience; Mitochondrial dysfunction is a major mechanism whereby different drugs can induce liver injury such as cytolytic hepatitis, microvesicular and/or macrovacuolar steatosis, steatohepatitis, and possibly cholestasis. In the most severe cases, drug-induced mitochondrial dysfunction and liver injury can require liver transplantation or lead to the death of the patient. Moreover, these adverse effects can lead to the withdrawal of drugs from the market, or earlier during clinical trials. Drugs can induce mitochondrial dysfunction by different mechanisms including inhibition of fatty acid oxidation, impairment of oxidative phosphorylation and respiratory chain activity, and alteration of the integrity of the mitochondrial membranes. The present chapter focuses on different drugs for which enough clinical and experimental evidence indicates the potential role of mitochondrial dysfunction in the pathogenesis of liver injury acetaminophen, amiodarone, fialuridine, linezolid, nucleoside reverse transcriptase inhibitors (e.g., stavudine, zidovudine, and didanosine), tamoxifen, tetracycline, troglitazone, and valproic acid. Because drug-induced mitochondrial dysfunction and liver injury are major issues for public health and pharmaceutical companies, mitochondrial liability should be systematically investigated during preclinical safety studies. © 2018 John Wiley and Sons, Inc. All rights reserved.

Published
2018

28. Chronic and low exposure to a pharmaceutical cocktail induces mitochondrial dysfunction in liver and hyperglycemia: Differential responses between lean and obese mice

Author

Nelly, Buron, Mathieu, Porceddu, Célestin, Roussel, Karima, Begriche, Viviane, Trak-Smayra, Thomas, Gicquel, Bernard, Fromenty, Annie, Borgne-Sanchez, Mitologics S.A.S., Hôpital Robert Debré Paris, Foie, métabolismes et cancer, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Pathology Department, Saint-Joseph University, CHU Pontchaillou [Rennes], PHARMECO 09-CESA-014-01, Agence Nationale de la Recherche, Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
Blood Glucose, hepatotoxicity, respiratory chain, Mice, Obese, Mitochondria, Liver, [SDV.CAN]Life Sciences [q-bio]/Cancer, Mice, steatosis, Animals, Obesity, fatty acid oxidation, Membrane Potential, Mitochondrial, Dose-Response Relationship, Drug, water contamination, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Mitochondria, Mice, Inbred C57BL, Fatty Liver, Oxidative Stress, Liver, Hyperglycemia, Environmental Pollutants, Female, DILI, Mitochondrial Swelling, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract

International audience; Pharmaceuticals are found in the environment but the impact of this contamination on human and animal health is poorly known. The liver could be particularly targeted since a significant number of these drugs are hepatotoxic, in particular via oxidative stress and mitochondrial dysfunction. Notably, the latter events can also be observed in liver diseases linked to obesity, so that the obese liver might be more sensitive to drug toxicity. In this study, we determined the effects of a chronic exposure to low doses of pharmaceuticals in wild-type and obese mice, with a particular focus on mitochondrial function. To this end, wild-type and ob/ob mice were exposed for 4 months to a cocktail of 11 pharmaceuticals provided in drinking water containing 0.01, 0.1, or 1 mg/L of each drug. At the end of the treatment, liver mitochondria were isolated and different parameters were measured. Chronic exposure to the pharmaceuticals reduced mitochondrial respiration driven by succinate and palmitoyl-l-carnitine in wild-type mice and increased antimycin-induced ROS production in ob/ob mice. Hyperglycemia and hepatic histological abnormalities were also observed in treated ob/ob mice. Investigations were also carried out in isolated liver mitochondria incubated with the mixture, or with each individual drug. The mitochondrial effects of the mixture were different from those observed in treated mice and could not be predicted from the results obtained with each drug. Because some of the 11 drugs included in our cocktail can be found in water at relatively high concentrations, our data could be relevant in environmental toxicology. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1375-1389, 2017.

Published
2017

30. Abstract 788: Identification and optimization of pro-apoptotic molecules targeting adenine nucleotide translocator 2 (hANT2) in tumor mitochondria

Author

Nelly Buron, Claire Pertuiset, Roxane Loyant, Cécile Martel, Mathieu Porceddu, and Annie Borgne-Sanchez

Subjects
Cancer Research, Oncology
Abstract

The mitochondrial protein ANT2 is one of the four isoforms of the ADP/ATP translocase and is expressed in highly proliferating cells. ANT2 plays a crucial role in the maintenance of transmembrane potential and mitochondrial integrity in tumor cells by importing glycolytic ATP into the mitochondrial matrix. Thus, this protein is required for tumor cell survival and displays anti-apoptotic function. Recently, ANT2 upregulation was shown to be involved in drug resistance process in various cancer types. Considering ANT2 role in tumor cell metabolism, we searched for ANT2-ligand small molecules. Ligands were first identified by virtual screening of chemical library on 3D model of human ANT2 and validated as ADP/ATP translocase inhibitors using our screening platform on isolated mitochondria. Compound specificity for ANT2 isoform was validated by cellular knock-down and pull-down experiments. ANT2-ligands optimization lead to the selection of MTL105 compound that induce characteristic intrinsic apoptotic cell death, specifically in tumor cell lines at sub-µM concentrations with no effect on healthy cells, suggesting a strong safety margin. According to the NCI60 compare analysis, this compound constitutes a first-in-class product in cancer therapy with this MoA and would be particularly interesting to overcome multidrug-resistant cancers. Citation Format: Nelly Buron, Claire Pertuiset, Roxane Loyant, Cécile Martel, Mathieu Porceddu, Annie Borgne-Sanchez. Identification and optimization of pro-apoptotic molecules targeting adenine nucleotide translocator 2 (hANT2) in tumor mitochondria [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 788.

Published
2019

33. Prediction of Liver Injury Induced by Chemicals in Human With a Multiparametric Assay on Isolated Mouse Liver Mitochondria

Author

Gilles Labbe, Célestin Roussel, Nelly Buron, Bernard Fromenty, Mathieu Porceddu, Annie Borgne-Sanchez, Mitologics SAS, Hôpital Robert Debré, Sanofi-Aventis R&D, SANOFI Recherche, Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
Drug, hepatotoxicity, media_common.quotation_subject, chemicals, Mitochondria, Liver, 010501 environmental sciences, Biology, Mitochondrion, Pharmacology, Toxicology, 01 natural sciences, Article, drugs, 03 medical and health sciences, Mice, medicine, Animals, Humans, 030304 developmental biology, 0105 earth and related environmental sciences, media_common, Liver injury, Membrane Potential, Mitochondrial, 0303 health sciences, Mice, Inbred BALB C, Cytochrome c, screening, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, prediction, medicine.disease, 3. Good health, mitochondria, Mitochondrial toxicity, Mechanism of action, biology.protein, DILI, Animal studies, medicine.symptom, Chemical and Drug Induced Liver Injury, Bacterial outer membrane
Abstract

International audience; Drug-induced liver injury (DILI) in humans is difficult to predict using classical in vitro cytotoxicity screening and regulatory animal studies. This explains why numerous compounds are stopped during clinical trials or withdrawn from the market due to hepatotoxicity. Thus, it is important to improve early prediction of DILI in human. In the present study, we hypothesized that this goal could be achieved by investigating drug-induced mitochondrial dysfunction as this toxic effect is a major mechanism of DILI. To this end, we developed a high-throughput screening platform using isolated mouse liver mitochondria. Our broad spectrum multiparametric assay was designed to detect the global mitochondrial membrane permeabilization (swelling), inner membrane permeabilization (transmembrane potential), outer membrane permeabilization (cytochrome c release) and alteration of mitochondrial respiration driven by succinate or malate/glutamate. A pool of 124 chemicals (mainly drugs) was selected, including 87 with documented DILI and 37 without reported clinical hepatotoxicity. Our screening assay revealed an excellent sensitivity for clinical outcome of DILI (94 or 92% depending on cut-off) and a high positive predictive value (89 or 82%). A highly significant relationship between drug-induced mitochondrial toxicity and DILI occurrence in patients was calculated (P

Published
2012

34. Drug-induced toxicity on mitochondria and lipid metabolism: Mechanistic diversity and deleterious consequences for the liver

Author

Julie Massart, Bernard Fromenty, Annie Borgne-Sanchez, Karima Begriche, Marie-Anne Robin, Department of Metabolism and Aging, The Scripps Research Institute, Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Mitologics SAS, Hôpital Robert Debré, The Scripps Research Institute [La Jolla, San Diego], Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Brébion, Alice

Subjects
Leptin, MESH: Oxidation-Reduction, MESH: Cell Death, Steatosis, MESH: Carbohydrate Metabolism, Microvesicular Steatosis, Mitochondria, Liver, Mitochondrial Membrane Transport Proteins, Oxidative Phosphorylation, 0302 clinical medicine, Nonalcoholic fatty liver disease, MESH: Obesity, MESH: Animals, MESH: Fatty Liver, MESH: Lipid Metabolism, Liver injury, 0303 health sciences, Fatty Acids, MESH: Energy Metabolism, MESH: Genetic Predisposition to Disease, Drugs, MESH: Reactive Oxygen Species, MESH: Mitochondrial Membrane Transport Proteins, MESH: Adiponectin, Hepatitis C, Lipids, Mitochondria, MESH: Fatty Acids, 3. Good health, MESH: Insulin Resistance, Mitochondrial respiratory chain, Adipose Tissue, 030220 oncology & carcinogenesis, Carbohydrate Metabolism, Adiponectin, MESH: Genome, Mitochondrial, Chemical and Drug Induced Liver Injury, MESH: Mitochondria, Liver, Oxidation-Reduction, MESH: Adipose Tissue, MESH: Diabetes Mellitus, Type 2, Cell death, MESH: Drug-Induced Liver Injury, medicine.medical_specialty, Biology, Models, Biological, 03 medical and health sciences, MESH: Oxidative Phosphorylation, Internal medicine, medicine, Animals, Humans, Genetic Predisposition to Disease, Obesity, 030304 developmental biology, MESH: Hepatitis C, MESH: Humans, Hepatology, Mitochondrial Permeability Transition Pore, Hepatotoxicity, MESH: Models, Biological, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Lipid metabolism, MESH: Leptin, Lipid Metabolism, medicine.disease, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Fatty Liver, Endocrinology, Diabetes Mellitus, Type 2, MESH: Alcoholic Intoxication, Mitochondrial permeability transition pore, Oxidative stress, Genome, Mitochondrial, Insulin Resistance, Steatohepatitis, Energy Metabolism, Reactive Oxygen Species, Alcoholic Intoxication
Abstract

International audience; Numerous investigations have shown that mitochondrial dysfunction is a major mechanism of drug-induced liver injury, which involves the parent drug or a reactive metabolite generated through cytochromes P450. Depending of their nature and their severity, the mitochondrial alterations are able to induce mild to fulminant hepatic cytolysis and steatosis (lipid accumulation), which can have different clinical and pathological features. Microvesicular steatosis, a potentially severe liver lesion usually associated with liver failure and profound hypoglycemia, is due to a major inhibition of mitochondrial fatty acid oxidation (FAO). Macrovacuolar steatosis, a relatively benign liver lesion in the short term, can be induced not only by a moderate reduction of mitochondrial FAO but also by an increased hepatic de novo lipid synthesis and a decreased secretion of VLDL-associated triglycerides. Moreover, recent investigations suggest that some drugs could favor lipid deposition in the liver through primary alterations of white adipose tissue (WAT) homeostasis. If the treatment is not interrupted, steatosis can evolve toward steatohepatitis, which is characterized not only by lipid accumulation but also by necroinflammation and fibrosis. Although the mechanisms involved in this aggravation are not fully characterized, it appears that overproduction of reactive oxygen species by the damaged mitochondria could play a salient role. Numerous factors could favor drug-induced mitochondrial and metabolic toxicity, such as the structure of the parent molecule, genetic predispositions (in particular those involving mitochondrial enzymes), alcohol intoxication, hepatitis virus C infection, and obesity. In obese and diabetic patients, some drugs may induce acute liver injury more frequently while others may worsen the pre-existent steatosis (or steatohepatitis).

Published
2011

36. The fourth isoform of the adenine nucleotide translocator inhibits mitochondrial apoptosis in cancer cells

Author

Cécile Martel, Morgane Le Bras, Etienne Jacotot, Christophe Lemaire, Zahia Touat, Shazib Pervaiz, Zhi Xiong Chen, Annie Borgne-Sanchez, Nelly Buron, Antoinette Lemoine, Cindy Gallerne, Catherine Brenner, Eleonore Mayola, and Ossama Sharaf el dein

Subjects
Programmed cell death, Indazoles, Antineoplastic Agents, Apoptosis, Biology, Mitochondrion, Biochemistry, Oxidative Phosphorylation, Superoxides, medicine, Humans, Staurosporine, Cell Shape, Protein Kinase Inhibitors, Cell Proliferation, chemistry.chemical_classification, Reactive oxygen species, Kinase, Adenine nucleotide translocator, Hydrogen Peroxide, Cell Biology, Adenine Nucleotide Translocator 3, Caspase 9, Mitochondria, Cell biology, Isoenzymes, Cytosol, Proto-Oncogene Proteins c-bcl-2, chemistry, Cytoprotection, biology.protein, Mitochondrial ADP, ATP Translocases, HeLa Cells, medicine.drug
Abstract

The adenine nucleotide translocator (ANT) is a mitochondrial bi-functional protein, which catalyzes the exchange of ADP and ATP between cytosol and mitochondria and participates in many models of mitochondrial apoptosis. The human adenine nucleotide translocator sub-family is composed of four isoforms, namely ANT1-4, encoded by four nuclear genes, whose expression is highly regulated. Previous studies have revealed that ANTI and 3 induce mitochondrial apoptosis, whereas ANT2 is anti-apoptotic. However, the role of the recently identified isoform ANT4 in the apoptotic pathway has not yet been elucidated. Here, we investigated the effects of stable heterologous expression of the ANT4 on proliferation, mitochondrial respiration and cell death in human cancer cells, using ANT3 as a control of pro-apoptotic isoform. As expected, ANT3 enhanced mitochondria-mediated apoptosis in response to lonidamine, a mitochondriotoxic chemotherapeutic drug, and staurosporine, a protein kinase inhibitor. Our results also indicate that the pro-apoptotic effect of ANT3 was accompanied by decreased rate of cell proliferation, alteration in the mitochondrial network topology, and decreased reactive oxygen species production. Of note, we demonstrate for the first time that ANT4 enhanced cell growth without impacting mitochondria] network or respiration. Moreover, ANT4 differentially regulated the intracellular levels of hydrogen peroxide without affecting superoxide anion levels. Finally, stable ANT4 overexpression protected cancer cells from lonidamine and staurosporine apoptosis in a manner independent of Bcl-2 expression. These data highlight a hitherto undefined cytoprotective activity of ANT4, and provide a novel dichotomy in the human ANT isoform sub-family with ANT1 and 3 isoforms functioning as pro-apoptotic while ANT2 and 4 isoforms render cells resistant to death inducing stimuli. (C) 2010 Elsevier Ltd. All rights reserved.

Published
2010

37. A screening strategy to identify modulators of the mitochondrial ADP/ATP translocase (ANT) for cardioprotection

Author

Nicolas, Claire, Porceddu, Mathieu, Buron, Nelly, Wang, Zhenyu, Colas, Claire, Iorga, Bogdan, Ambroise, Yves, Vandecasteele, Gregoire, Fischmeister, Rodolphe, Borgne-Sanchez, Annie, Brenner, Catherine, Institut de Chimie des Substances Naturelles (ICSN), and Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2014

41. Aftins increase amyloid-β42, lower amyloid-β38, and do not alter amyloid-β40 extracellular production in vitro: toward a chemical model of Alzheimer's disease?

Author

Xavier Fant, Laurent Meijer, Mathieu Porceddu, Arnaud Hochard, Annie Borgne-Sanchez, Marc Flajolet, Karima Bettayeb, Nassima Oumata, Olfa Gloulou, Emilie Durieu, Nelly Buron, and Hervé Galons

Subjects
Amyloid, Cell Survival, Peptide, Mitochondrion, Article, Cell Line, Downregulation and upregulation, Alzheimer Disease, Extracellular, Humans, chemistry.chemical_classification, Amyloid beta-Peptides, biology, Dose-Response Relationship, Drug, General Neuroscience, Cytochrome c, Adenine, Autophagy, General Medicine, Peptide Fragments, Cell biology, Psychiatry and Mental health, Clinical Psychology, Biochemistry, chemistry, Models, Chemical, biology.protein, Geriatrics and Gerontology, Extracellular Space, Intracellular
Abstract

Increased production of amyloid-β (Aβ)42 peptide, derived from the amyloid-β protein precursor, and its subsequent aggregation into oligomers and plaques constitutes a hallmark of Alzheimer's disease (AD). We here report on a family of low molecular weight molecules, the Aftins (Amyloid-β Forty-Two Inducers), which, in cultured cells, dramatically affect the production of extracellular/secreted amyloid peptides. Aftins trigger β-secretase inhibitor and γ-secretase inhibitors (GSIs) sensitive, robust upregulation of Aβ42, and parallel down-regulation of Aβ38, while Aβ40 levels remain stable. In contrast, intracellular levels of these amyloids appear to remain stable. In terms of their effects on Aβ38/Aβ40/Aβ42 relative abundance, Aftins act opposite to γ-secretase modulators (GSMs). Aβ42 upregulation induced by Aftin-5 is unlikely to originate from reduced proteolytic degradation or diminished autophagy. Aftin-5 has little effects on mitochondrial functional parameters (swelling, transmembrane potential loss, cytochrome c release, oxygen consumption) but reversibly alters the ultrastructure of mitochondria. Aftins thus alter the Aβ levels in a fashion similar to that described in the brain of AD patients. Aftins therefore constitute new pharmacological tools to investigate this essential aspect of AD, in cell cultures, allowing (1) the detection of inhibitors of Aftin induced action (potential 'anti-AD compounds', including GSIs and GSMs) but also (2) the identification, in the human chemical exposome, of compounds that, like Aftins, might trigger sustained Aβ42 production and Aβ38 down-regulation (potential 'pro-AD compounds').

Published
2013

42. Drug-Induced Inhibition of Mitochondrial Fatty Acid Oxidation and Steatosis

Author

Bernard Fromenty, Nelly Buron, Mathieu Porceddu, Julie Massart, Annie Borgne-Sanchez, Karima Begriche, Department of Molecular Medicine and Surgery, Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Mitologics SAS, Hôpital Robert Debré, This work was supported by INSERM (Institut Nationale de la Santé et de la Recherche Médicale) and ANR (Agence Nationale de la Recherche, PHARMECO Project from the CES program). Julie Massart was supported by a scholarship from the Swedish Institute., and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
Cancer Research, medicine.medical_specialty, Steatosis, [SDV]Life Sciences [q-bio], Microvesicular Steatosis, Respiratory chain, Biology, Pathology and Forensic Medicine, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Fatty liver, Nonalcoholic fatty liver disease, medicine, Molecular Biology, Beta oxidation, 030304 developmental biology, 0303 health sciences, Cell Biology, medicine.disease, 3. Good health, Mitochondria, Mitochondrial respiratory chain, Endocrinology, 030220 oncology & carcinogenesis, Fatty acid oxidation, Steatohepatitis, Drug
Abstract

Mitochondrial Dysfunction and Diseases (H Jaeschke, Section Editor); International audience; Drug-induced inhibition of mitochondrial fatty acid β-oxidation (mtFAO) is a key mechanism whereby drugs can induce steatosis. The type and severity of this liver lesion is dependent on the residual mtFAO flux. Indeed, a severe inhibition of mtFAO leads to microvesicular steatosis, hypoglycemia and liver failure, which can be favored by genetic predispositions. In contrast, moderate impairment of mtFAO can cause macrovacuolar steatosis, which is by itself a benign lesion. In the long-term, however, macrovacuolar steatosis can progress with some drugs to steatohepatitis. Interestingly, drugs that are more likely to cause steatohepatitis are those impairing the mitochondrial respiratory chain (MRC) activity. Indeed, MRC impairment favors not only hepatic fat accretion but also oxidative stress and lipid peroxidation. Drugs inhibiting mtFAO could be more toxic in obese patients with preexisting nonalcoholic fatty liver disease (NAFLD) since higher mtFAO is a key metabolic adaptation to curb fat accretion during NAFLD.

Published
2013

45. Predictive toxicology: the paths of the future

Author

Detilleux, Ph, Vallier, L, Legallais, C, Leclerc, E, Prot J, M, Choucha, L, Baudoin, R, Dufresne, M, Gautier, A, Carpentier, B, Mansuy, D, Pery, Alexandre R.R., Brochot, C, Manivet, Ph, Rabilloud, Thierry, Spire, C, Coumoul, Xavier, Junot, Ch, Laprevote, O, Le Pape, A, Tourneur, E, Ben Mkaddem, S, Chassin, C, Aloulou, M, Goujon J, M, Hertif, A, Ouali, N, Vimont, S, Monteiro, R, Rondeau, E, Elbim, C, Werts, C, Vandewalle, A, Pedruzzi, E, Coant, N, Bens, M, Cluzeaud, F, Ogier-Denis, E, Pongnimitprasert, N, Babin-Chevaye, C, Fay, M, Bernard, M, Dupuy, C, Ei Benna, J, Gougerot-Pocidale M, A, Braut-Boucher, F, Pinton, Philippe, Lucioli, Joelma, Tsybulskyy, D, Joly, Baptiste, Laffitte, J, Bourges-Abella, N, Oswald, Isabelle P., Kolf-Clauw, Martine, Pierre, St, Bats A, S, Chevalier, Aline, Bui L, Ch, Ambolet-Camoit, A, Garlatti, M, Aggerbeck, M, Barouki, R, Al Khansa, I, Blanck, O, Guillouzo, A, Bars, R, Rouas, C, Bensoussan, H, Suhard, D, Tessier, C, Grandcolas, L, Pallardy, M, Gueguen, Y, Sparfel, L, Pinel-Marie M, L, Boize, M, Koscielny, S, Desmots, S, Fardel, O, Alvergnas, M, Rouleau, A, Lucchi, G, Mantion, G, Heyd, B, Richert, L, Ducoroy, P, Martin, H, Val, St, Martinon, L, Cachier, H, Yahyaoui, A, Marfaing, H, Baeza-Squiban, A, Martin-Chouly, Corinne, Bonvallet, M, Morzadec, C, Vernhet, L, Baverel, G, El Hage, M, Nazaret, R, Conjard-Duplany, A, Ferrier, B, Martin, G, Legendre, A, Lecomte, Anthony, Froment, P, Habert, R, Lemazurier, E, Robinel, F, Dupont, O, Sanfins, E, Dairou, J, Chaffotte A, F, Busi, F, Rodrigues Lima, F, Dupret J, M, Mayati, A, Le Ferrec, Eric, Levoin, N, Paris, H, Uriac, Ph, N'Diaye, M, Lagadic-Gossmann, D, Assemat, E, Boublil, L, Borot M, C, Marano, F, Martiny V, Y, Moroy, G, Badel, A, Miteva M, A, Hussain, S, Ferecatu, I, Borot, C, Andreau, K, Boland, S, Leroux, M, Zucchini-Pascal, Nathalie, Peyre, L, Rahmani, Roger, Buron, N, Porcedou, M, Fromenty, B, Borgne-Sanchez, A, Rogue, A, Claude, N, Le Guével, Rémy, Institut National de l'Environnement Industriel et des Risques (INERIS), Laboratoire pharmaceutique Biologie Servier, Biologie Servier, Pharmacologie, toxicologie et signalisation cellulaire (U747), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Faculté de Médecine Xavier Bichat, Centre de recherche biomédicale Bichat-Beaujon (CRB3), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de recherche Pharmacologie-Toxicologie (UPT), Institut National de la Recherche Agronomique (INRA), Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Cytokines, chimiokines et immunopathologie, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Fonctions et dysfonctions épithéliales - UFC (EA 4267) (FDE), Université de Franche-Comté (UFC), Plate-forme Protéomique CLIPP - Clinical and Innovation Proteomic Platform [Dijon] (CLIPP), 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)-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)-Institut de Chimie Moléculaire de l'Université de Bourgogne [Dijon] (ICMUB), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS), Laboratoire des Sciences du Climat et de l'Environnement [Gif-sur-Yvette] (LSCE), Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Centre National de la Recherche Scientifique (CNRS), Cellules Souches et Radiations (SCSR (U967 / UMR-E_008)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris-Sud - Paris 11 (UP11), Laboratoire Bioprojet, Institut des Sciences Chimiques de Rennes (ISCR), 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)-Ecole Nationale Supérieure de Chimie de Rennes-Centre National de la Recherche Scientifique (CNRS), 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), Mitologics SAS, Hôpital Robert Debré, Biomécanique et Bioingénierie (BMBI), Université de Technologie de Compiègne (UTC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de radiotoxicologie expérimentale (IRSN/DRPH/SRBE/LRTOX), Service de RadioBiologie et d'Epidémiologie (IRSN/DRPH/SRBE), Institut de Radioprotection et de Sûreté Nucléaire (IRSN)-Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), 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 Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-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 Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Institut de Chimie Moléculaire de l'Université de Bourgogne [Dijon] (ICMUB), Université de Bourgogne (UB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Bourgogne (UB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Stabilité génétique, Cellules Souches et Radiations (SCSR (U_967)), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS)-Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie Moléculaire de l'Université de Bourgogne [Dijon] (ICMUB), Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-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 Paris-Sud - Paris 11 (UP11)-Université Paris Diderot - Paris 7 (UPD7)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Institut National de l'Environnement Industriel et des Risques ( INERIS ), Physiologie Cellulaire des Regulations Hormonales, Nutritionnelles et Pharmacologiques, Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de recherche biomédicale Bichat-Beaujon ( CRB3 ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Unité de recherche Pharmacologie-Toxicologie ( UPT ), Institut National de la Recherche Agronomique ( INRA ), Toxicologie, Pharmacologie et Signalisation Cellulaire ( U1124 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de biostatistique et d'épidémiologie ( SBE ), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Institut de recherche, santé, environnement et travail ( Irset ), Université d'Angers ( UA ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -École des Hautes Études en Santé Publique [EHESP] ( EHESP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ) -Université des Antilles ( UA ), Fonctions et dysfonctions épithéliales - UFC (EA 4267) ( FDE ), Université de Franche-Comté ( UFC ), Plate-forme Protéomique CLIPP - Clinical and Innovation Proteomic Platform [Dijon] ( CLIPP ), 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 ) -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 ) -Institut de Chimie Moléculaire de l'Université de Bourgogne [Dijon] ( ICMUB ), Université de Bourgogne ( UB ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Bourgogne ( UB ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire des Sciences du Climat et de l'Environnement [Gif-sur-Yvette] ( LSCE ), Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Centre National de la Recherche Scientifique ( CNRS ), Cellules Souches et Radiations ( SCSR - U 967 ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut des Sciences Chimiques de Rennes ( ISCR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Ecole Nationale Supérieure de Chimie de Rennes-Institut National des Sciences Appliquées ( INSA ) -Centre National de la Recherche Scientifique ( CNRS ), Biologie Fonctionnelle et Adaptative ( BFA ), and Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS )

Subjects
[ SDV ] Life Sciences [q-bio], [SDV.TOX]Life Sciences [q-bio]/Toxicology, [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract

National audience

Published
2010

46. Toxicologie predictive: les voies du futur

Author

Ph Detilleux, Vallier, L., Legallais, C., Leclerc, E., M Prot J, Choucha, L., Baudoin, R., Dufresne, M., Gautier, A., Carpentier, B., Mansuy, D., Pery, Alexandre R. R., Brochot, C., Ph Manivet, Thierry Rabilloud, Spire, C., Xavier Coumoul, Ch Junot, Laprevote, O., Le Pape, A., Ronan Le Guével, Tourneur, E., Ben Mkaddem, S., Chassin, C., Aloulou, M., M Goujon J, Hertif, A., Ouali, N., Vimont, S., Monteiro, R., Rondeau, E., Elbim, C., Werts, C., Vandewalle, A., Pedruzzi, E., Coant, N., Bens, M., Cluzeaud, F., Ogier-Denis, E., Pongnimitprasert, N., Babin-Chevaye, C., Fay, M., Bernard Fromenty, Dupuy, C., Ei Benna, J., A Gougerot-Pocidale M, Braut-Boucher, F., Ph Pinton, Lucioli, J., Tsybulskyy, D., Baptiste Joly, Laffitte, J., Bourges-Abella, N., P Oswald I, Kolf-Clauw, M., St Pierre, S Bats A, Aline Chevalier, Ch Bui L, Ambolet-Camoit, A., Garlatti, M., Aggerbeck, M., Barouki, R., Al Khansa, I., Blanck, O., Guillouzo, A., Bars, R., Rouas, C., Bensoussan, H., Suhard, D., Tessier, C., Grandcolas, L., Pallardy, M., Gueguen, Y., Sparfel, L., L Pinel-Marie M, Boize, M., Koscielny, S., Desmots, S., Fardel, O., Alvergnas, M., Rouleau, A., Lucchi, G., Mantion, G., Heyd, B., Richert, L., Ducoroy, P., Martin, H., St Val, Martinon, L., Cachier, H., Yahyaoui, A., Marfaing, H., Baeza-Squiban, A., Corinne Martin-Chouly, Bonvallet, M., Morzadec, C., Vernhet, L., Baverel, G., El Hage, M., Nazaret, R., Conjard-Duplany, A., Ferrier, B., Martin, G., Legendre, A., Lecomte, A., Froment, P., Habert, R., Lemazurier, E., Robinel, F., Dupont, O., Sanfins, E., Dairou, J., F Chaffotte A, Busi, F., Rodrigues Lima, F., M Dupret J, Mayati, A., Eric Le Ferrec, Levoin, N., Paris, H., Ph Uriac, Diaye, M. N., Lagadic-Gossmann, D., Assemat, E., Boublil, L., C Borot M, Marano, F., Y Martiny V, Moroy, G., Badel, A., A Miteva M, Hussain, S., Ferecatu, I., Borot, C., Andreau, K., Boland, S., Leroux, M., Zucchini-Pascal, N., Peyre, L., Rahmani, R., Buron, N., Porcedou, M., Fromenty, B., Borgne-Sanchez, A., Rogue, A., Claude, N., and Jonchère, Laurent

Subjects
[SDV] Life Sciences [q-bio], [SDV.TOX] Life Sciences [q-bio]/Toxicology
Published
2010

47. A flavivirus protein M-derived peptide directly permeabilizes mitochondrial membranes, triggers cell death and reduces human tumor growth in nude mice

Author

Dominique Rebouillat, Olivier Chaloin, Nelly Buron, Sylviane Muller, Magali Brabant, Sylvie Dupont, Alain Langonne, Jean Paul Briand, David Chauvier, Catherine Brenner, Hervé Lecoeur, Myriam Lassalle, Mathieu Porceddu, Olivier Deas, Richard Casimir, Annie Borgne-Sanchez, Etienne Jacotot, Ludwig Baux, Theraptosis Research Laboratory, Theraptosis S.A., Immunologie et chimie thérapeutiques (ICT), Cancéropôle du Grand Est-Centre National de la Recherche Scientifique (CNRS), Department of Reproductive Biology, and Imperial College London

Subjects
Cancer Research, Programmed cell death, Amino Acid Motifs, Molecular Sequence Data, Clinical Biochemistry, Cell, Mice, Nude, Pharmaceutical Science, Peptide, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Biology, Mitochondrion, Permeability, Mice, Viral Proteins, 03 medical and health sciences, Transduction (genetics), 0302 clinical medicine, Cell Line, Tumor, medicine, Animals, Humans, Amino Acid Sequence, Cell Proliferation, 030304 developmental biology, Membrane Potential, Mitochondrial, Pharmacology, chemistry.chemical_classification, 0303 health sciences, Cell Death, Flavivirus, Biochemistry (medical), Cell Biology, Survival Analysis, Xenograft Model Antitumor Assays, Molecular biology, Mitochondria, Protein Structure, Tertiary, 3. Good health, Protein M, medicine.anatomical_structure, Ectodomain, chemistry, Apoptosis, 030220 oncology & carcinogenesis, Mitochondrial Membranes, tat Gene Products, Human Immunodeficiency Virus, Mitochondrial Swelling, Peptides
Abstract

International audience; Dengue viruses belong to the Flavivirus family and are responsible for hemorrhagic fever in Human. Dengue virus infection triggers apoptosis especially through the expression of the small membrane (M) protein. Using isolated mitochondria, we found that synthetic peptides containing the C-terminus part of the M ectodomain caused apoptosis-related mitochondrial membrane permeabilization (MMP) events. These events include matrix swelling and the dissipation of the mitochondrial transmembrane potential (DeltaPsi(m)). Protein M Flavivirus sequence alignments and helical wheel projections reveal a conserved distribution of charged residues. Moreover, when combined to the cell penetrating HIV-1 Tat peptide transduction domain (Tat-PTD), this sequence triggers a caspase-dependent cell death associated with DeltaPsi(m) loss and cytochrome c release. Mutational approaches coupled to functional screening on isolated mitochondria resulted in the selection of a protein M derived sequence containing nine residues with potent MMP-inducing properties on isolated mitochondria. A chimeric peptide composed of a Tat-PTD linked to the 9-mer entity triggers MMP and cell death. Finally, local administration of this chimeric peptide induces growth inhibition of xenograft prostate PC3 tumors in immuno-compromised mice, and significantly enhances animal survival. Together, these findings support the notion of using viral genomes as valuable sources to discover mitochondria-targeted sequences that may lead to the development of new anticancer compounds.

Published
2009

48. Pharmacological screening and enzymatic assays for apoptosis

Author

Claire Pertuiset, Cécile Martel, Annie Borgne-Sanchez, Anne-Sophie Belzacq-Casagrande, Catherine Brenner, Etienne Jacotot, Begue, Angelique, Laboratoire de génétique et biologie cellulaire (LGBC), and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)

Subjects
Cell Membrane Permeability, Voltage-dependent anion channel, Apoptosis, Mitochondria, Liver, Mitochondrion, Rhodamine 123, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Animals, Inner membrane, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, biology, Chemistry, vpr Gene Products, Human Immunodeficiency Virus, Cell biology, 030220 oncology & carcinogenesis, Mastoparan, biology.protein, Calcium, ATP–ADP translocase, Mitochondrial Swelling, Intermembrane space, Bacterial outer membrane
Abstract

Mitochondria play a central role in the intrinsic pathway of apoptosis. In response to many pro-apoptotic stimuli, mitochondria undergo an irreversible process called mitochondrial membrane permeabilization (MMP). The detection of MMP in isolated mitochondria is most often based on assays that monitor either the loss of the inner transmembrane potential (DYm; classically with Rhodamine 123), permeability transition (PT, cyclosporin A-sensitive matrix swelling), or the release of critical pro-apoptotic intermembrane space effectors. To gain complementary information on MMP mechanisms, we have systematically used three additional assays optimized for the 96-well microplate format: (1) inner membrane permeability, (2) VDAC-associated NADH reductase activity, and (3) ATP/ADP translocase activity. We report that ad hoc combinations of ANT and VDAC ligands, carbonyl cyanide m-chlorophenylhydrazone (CCCP), mastoparan and Vpr52-96 peptide and PT inhibitors, permit to explore relationships between enzymatic functions of sessile mitochondrial proteins (i.e. ANT, VDAC) and MMP. These assays should be useful tools to investigate mitochondrial apoptosis, decipher the implication of inner and outer membrane permeabilization and provide a multi-parametric approach for drug discovery.

Published
2009

49. Chemosensitization by knockdown of adenine nucleotide translocase-2

Author

Christophe Lemaire, Aurélien Deniaud, Zahia Touat, Annie Borgne-Sanchez, Morgane Le Bras, Guido Kroemer, Dominique Rebouillat, Evelyne Maillier, Ossama Sharaf el dein, Etienne Jacotot, Gaël Lecellier, and Catherine Brenner

Subjects
Cancer Research, Indazoles, Antineoplastic Agents, Apoptosis, Biology, Permeability, chemistry.chemical_compound, Adenosine Triphosphate, Adenine nucleotide, RNA interference, Cell Line, Tumor, Humans, Gene Silencing, RNA, Small Interfering, Inner mitochondrial membrane, Gene knockdown, Cell growth, Lonidamine, Adenine Nucleotide Translocator 1, Adenine Nucleotide Translocator 2, Cell cycle, Molecular biology, Cell biology, Oncology, chemistry, Proto-Oncogene Proteins c-bcl-2, Drug Resistance, Neoplasm, Mitochondrial Membranes, ATP–ADP translocase, HeLa Cells
Abstract

Mitochondrial membrane permeabilization (MMP) is a rate-limiting step of apoptosis, including in anticancer chemotherapy. Adenine nucleotide translocase (ANT) mediates the exchange of ADP and ATP on the inner mitochondrial membrane in healthy cells. In addition, ANT can cooperate with Bax to form a lethal pore during apoptosis. Humans possess four distinct ANT isoforms, encoded by four genes, whose transcription depends on the cell type, developmental stage, cell proliferation, and hormone status. Here, we show that the ANT2 gene is up-regulated in several hormone-dependent cancers. Knockdown of ANT2 by RNA interference induced no major changes in the aspect of the mitochondrial network or cell cycle but provoked minor increase in mitochondrial transmembrane potential and reactive oxygen species level and reduced intracellular ATP concentration without affecting glycolysis. At expression and functional levels, ANT2 depletion was not compensated by other ANT isoforms. Most importantly, ANT2, but not ANT1, silencing facilitated MMP induction by lonidamine, a mitochondrion-targeted antitumor compound already used in clinical studies for breast, ovarian, glioma, and lung cancer as well as prostate adenoma. The combination of ANT2 knockdown with lonidamine induced apoptosis irrespective of the Bcl-2 status. These data identify ANT2 as an endogenous inhibitor of MMP and suggest that its selective inhibition could constitute a promising strategy of chemosensitization. (Cancer Res 2006; 66(18): 9143-52)

Published
2006

50. Targeted Vpr-derived Peptides Reach Mitochondria to Induce Apoptosis of aVb3-Expressing Endothelial Cells

Author

Pierre Rustin, Etienne Jacotot, Dominique Rebouillat, J. Brière, Hervé Lecoeur, Déas O, Deniaud A, Myriam Lassalle, Johan Hoebeke, Lena Edelman, Christine Péchoux, D. Chauvier, Magali Brabant, Roux P, Brenner C, Dupont S, Baux L, Alain Langonne, J. P. Briand, A. Borgne-Sanchez, Laboratoire de génétique et biologie cellulaire (LGBC), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Theraptosis Research Laboratory, Theraptosis S.A., Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie Dynamique (Plate-Forme) (PFID), Institut Pasteur [Paris], Unité de recherche génomique et physiologie de la lactation (GPL), Institut National de la Recherche Agronomique (INRA), Immunologie et chimie thérapeutiques (ICT), Cancéropôle du Grand Est-Centre National de la Recherche Scientifique (CNRS), Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie, conséquences fonctionnelles et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-IFR2-Institut National de la Santé et de la Recherche Médicale (INSERM), Génomique et Physiologie de la Lactation (GPL), Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institut Pasteur [Paris] (IP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-École Pratique des Hautes Études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)

Subjects
[SDV]Life Sciences [q-bio], Apoptosis, MESH: Amino Acid Sequence, Mitochondrion, APOPTOSE, Mitochondrial apoptosis-induced channel, MESH: Dose-Response Relationship, Drug, Mice, 0302 clinical medicine, MESH: Mitochondrial Membranes, ENDOTHELIAL CELLS, BIOLOGIE CELLULAIRE, MESH: Animals, MESH: Endothelial Cells, Peptide sequence, Inbred BALB C, 0303 health sciences, Mice, Inbred BALB C, biology, MESH: Peptides, Cytochrome c, Adenine nucleotide translocator, PEPTIDES, Cell biology, Mitochondria, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], MESH: Integrin alphaVbeta3, MESH: Cell Survival, 030220 oncology & carcinogenesis, MESH: Permeability, Mitochondrial Membranes, Mitochondrial fission, Drug, CELLULAR TRAFFICKING APOPTOSIS, Voltage-dependent anion channel, MESH: Gene Products, vpr, MESH: Mitochondria, Cell Survival, Integrin, Molecular Sequence Data, MESH: Mice, Inbred BALB C, PTP, Permeability, Dose-Response Relationship, 03 medical and health sciences, Gene Products, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [INFO]Computer Science [cs], Amino Acid Sequence, Molecular Biology, MESH: Mice, 030304 developmental biology, MESH: Molecular Sequence Data, MESH: Humans, Dose-Response Relationship, Drug, MESH: Apoptosis, Gene Products, vpr, vpr, Cell Biology, Integrin alphaVbeta3, biology.protein, Lysosomes, MESH: Lysosomes
Abstract

International audience; The HIV-1 encoded apoptogenic protein Vpr induces mitochondrial membrane permeabilization (MMP) via interactions with the voltage-dependent anion channel (VDAC) and the adenine nucleotide translocator (ANT). We have designed a peptide, TEAM-VP, composed of two functional domains, one a tumor blood vessel RGD-like 'homing' motif and the other an MMP-inducing sequence derived from Vpr. When added to isolated mitochondria, TEAM-VP interacts with ANT and VDAC, reduces oxygen consumption and overcomes Bcl-2 protection to cause inner and outer MMP. TEAM-VP specifically recognizes cell-surface expressed alpha(V)beta(3) integrins, internalizes, temporarily localizes to lysosomes and progressively co-distributes with the mitochondrial compartment with no sign of lysosomal membrane permeabilization. Finally TEAM-VP reaches mitochondria of angiogenic endothelial cells to induce mitochondrial fission, dissipation of the mitochondrial transmembrane potential (DeltaPsi(m)), cytochrome c release and apoptosis hallmarks. Hence, this chimeric peptide constitutes the first example of a virus-derived mitochondriotoxic compound as a candidate to kill selectively tumor neo-endothelia.

Published
2006

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