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1. Physiological and pathological roles of FATP-mediated lipid droplets in Drosophila and mice retina.

Author

Daan M Van Den Brink, Aurélie Cubizolle, Gilles Chatelain, Nathalie Davoust, Victor Girard, Simone Johansen, Francesco Napoletano, Pierre Dourlen, Laurent Guillou, Claire Angebault-Prouteau, Nathalie Bernoud-Hubac, Michel Guichardant, Philippe Brabet, and Bertrand Mollereau

Subjects
Genetics, QH426-470
Abstract

Increasing evidence suggests that dysregulation of lipid metabolism is associated with neurodegeneration in retinal diseases such as age-related macular degeneration and in brain disorders such as Alzheimer's and Parkinson's diseases. Lipid storage organelles (lipid droplets, LDs), accumulate in many cell types in response to stress, and it is now clear that LDs function not only as lipid stores but also as dynamic regulators of the stress response. However, whether these LDs are always protective or can also be deleterious to the cell is unknown. Here, we investigated the consequences of LD accumulation on retinal cell homeostasis under physiological and stress conditions in Drosophila and in mice. In wild-type Drosophila, we show that dFatp is required and sufficient for expansion of LD size in retinal pigment cells (RPCs) and that LDs in RPCs are required for photoreceptor survival during aging. Similarly, in mice, LD accumulation induced by RPC-specific expression of human FATP1 was non-toxic and promoted mitochondrial energy metabolism in RPCs and non-autonomously in photoreceptor cells. In contrast, the inhibition of LD accumulation by dFatp knockdown suppressed neurodegeneration in Aats-metFB Drosophila mutants, which carry elevated levels of reactive oxygen species (ROS). This suggests that abnormal turnover of LD may be toxic for photoreceptors cells of the retina under oxidative stress. Collectively, these findings indicate that FATP-mediated LD formation in RPCs promotes RPC and neuronal homeostasis under physiological conditions but could be deleterious for the photoreceptors under pathological conditions.

Published
2018
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2. Isopropyl‐phloroglucinol‐DHA protects outer retinal cells against lethal dose of all‐ trans ‐retinal

Author

Philippe Brabet, Mélissa Rosell, Céline Crauste, Joseph Vercauteren, Claire Angebault-Prouteau, David Cia, Guy Lenaers, Isabelle Meunier, Espérance Moine, Thierry Durand, Laurent Guillou, Aurélie Cubizolle, Nathalie Jacquemot, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Crauste, Céline, Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), and Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM)

Subjects
0301 basic medicine, Opsin, genetic structures, [SDV]Life Sciences [q-bio], Phloroglucinol, Retinal Pigment Epithelium, medicine.disease_cause, Antioxidants, chemistry.chemical_compound, Mice, 0302 clinical medicine, bisretinoid A2E, oxidative stress, ComputingMilieux_MISCELLANEOUS, Neurons, Pigmentation, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Catalase, 3. Good health, Cell biology, Mitochondria, carbonyl stress, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Retinaldehyde, Molecular Medicine, Original Article, Cell Survival, Protective Agents, isopropyl‐phloroglucinol‐DHA conjugate, outer retina cells, Lipofuscin, Cell Line, 03 medical and health sciences, Retinoids, Structure-Activity Relationship, Oxygen Consumption, medicine, Animals, Humans, Phosphatidylethanolamine, Retinal pigment epithelium, Phenol, Lethal dose, Retinal, Cell Biology, Dehydroepiandrosterone, Original Articles, [CHIM.ORGA] Chemical Sciences/Organic chemistry, eye diseases, Rats, Oxygen, 030104 developmental biology, chemistry, all‐trans‐retinal, sense organs, Reactive Oxygen Species, Oxidative stress
Abstract

All‐trans‐retinal (atRAL) is a highly reactive carbonyl specie, known for its reactivity on cellular phosphatidylethanolamine in photoreceptor. It is generated by photoisomerization of 11‐cis‐retinal chromophore linked to opsin by the Schiff's base reaction. In ABCA4‐associated autosomal recessive Stargardt macular dystrophy, atRAL results in carbonyl and oxidative stress, which leads to bisretinoid A2E, accumulation in the retinal pigment epithelium (RPE). This A2E‐accumulation presents as lipofuscin fluorescent pigment, and its photooxidation causes subsequent damage. Here we describe protection against a lethal dose of atRAL in both photoreceptors and RPE in primary cultures by a lipidic polyphenol derivative, an isopropyl‐phloroglucinol linked to DHA, referred to as IP‐DHA. Next, we addressed the cellular and molecular defence mechanisms in commonly used human ARPE‐19 cells. We determined that both polyunsaturated fatty acid and isopropyl substituents bond to phloroglucinol are essential to confer the highest protection. IP‐DHA responds rapidly against the toxicity of atRAL and its protective effect persists. This healthy effect of IP‐DHA applies to the mitochondrial respiration. IP‐DHA also rescues RPE cells subjected to the toxic effects of A2E after blue light exposure. Together, our findings suggest that the beneficial role of IP‐DHA in retinal cells involves both anti‐carbonyl and anti‐oxidative capacities.

Published
2020

3. Mitochondrial MDM2 regulates respiratory complex i activity independently of p53

Author

Kevin Nay, Romain Riscal, Christelle Bertrand-Gaday, Craig E. Cameron, Christelle Koechlin-Ramonatxo, Madi Y. Cissé, Laurent Le Cam, Béatrice Chabi, Béatrice Orsetti, Laetitia K. Linares, Kerren Murray, Charles Vincent, Hervé Dubouchaud, Laurie Gayte, Markus Kastner, Samuel Pyrdziak, Florence Bernex, Giuseppe Arena, Miria Ricchetti, François Casas, Laurent Chatre, Claire Angebault-Prouteau, Maryse Fuentes, Sandrine Etienne-Manneville, Anne Lombès, Jamie J. Arnold, Jean-Christophe Marine, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Cellules Souches et Développement / Stem Cells and Development, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Pennsylvania State University (Penn State), Penn State System, Dynamique Musculaire et Métabolisme (DMEM), Institut National de la Recherche Agronomique (INRA)-Université de Montpellier (UM), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Polarité cellulaire, Migration et Cancer - Cell Polarity, Migration and Cancer, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), VIB [Belgium], BioCampus Montpellier (BCM), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratory of Fundamental and Applied Bioenergetics = Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), This research was supported by grants from the Ligue contre le Cancer (Equipe labelisée 2016), the French National Health Institute for Biomedical Research (INSERM), the French National Cancer Institute (INCa), the General Direction for Care Provision (grant INCa-DGOS-Inserm 6045), and The Laboratory of Excellence EpiGenMed, ANR-10-LABX-0012,EpiGenMed,From Genome and Epigenome to Molecular Medicine: turning new paradigms in biology into the therapeutic strategies of tomorrow(2010), Cellules Souches et Développement, Université de Montpellier (UM)-Institut National de la Recherche Agronomique (INRA), Polarité cellulaire, Migration et Cancer / Cell Polarity, Migration and Cancer, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), This research was supported by grants from the Ligue contre le Cancer (Equipe labelisée 2016), the French National Health Institute for Biomedical Research (INSERM), the French National Cancer Institute (INCa), the General Direction for Care Provision (grant INCa-DGOS-Inserm 6045), and The Laboratory of Excellence EpiGenMed (grant ANR-10-LABX-12-01), ANR-10-LABX-0012/10-LABX-0012,EpiGenMed,From Genome and Epigenome to Molecular Medicine: turning new paradigms in biology into the therapeutic strategies of tomorrow(2010), ProdInra, Archive Ouverte, Laboratoires d'excellence - From Genome and Epigenome to Molecular Medicine: turning new paradigms in biology into the therapeutic strategies of tomorrow - - EpiGenMed2010 - ANR-10-LABX-0012 - LABX - VALID, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), BioCampus (BCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Radiothérapie moléculaire (UMR 1030), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Perelman School of Medicine, University of Pennsylvania [Philadelphia], Laboratoire Mouvement Sport Santé (M2S), École normale supérieure - Cachan (ENS Cachan)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université de Brest (UBO)-Université de Rennes 2 (UR2), Université de Rennes (UNIV-RENNES)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Perception et Mémoire, Institut national de la recherche agronomique [Montpellier] (INRA Montpellier), Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre de Génétique Humaine, Université Catholique de Louvain (UCL), Génétique Moléculaire et Cellulaire (UGMC), École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA), Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF), Génétique Moléculaire des Levures, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 1 (UM1), Institut de Génétique Moléculaire de Montpellier (IGMM), and Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Mitochondrial ROS, Lung Neoplasms, Transcription, Genetic, [SDV]Life Sciences [q-bio], translocation, Biochemistry, biophysics & molecular biology [F05] [Life sciences], Mitochondrion, dna, migration, medicine.disease_cause, Adenocarcinoma/genetics/metabolism/pathology, Mice, Cell Movement, Carcinoma, Non-Small-Cell Lung, Tumor Cells, Cultured, Carcinoma, Non-Small-Cell Lung/genetics/metabolism/pathology, Biochimie, biophysique & biologie moléculaire [F05] [Sciences du vivant], ComputingMilieux_MISCELLANEOUS, Mice, Knockout, biology, Proto-Oncogene Proteins c-mdm2/genetics/metabolism, apoptosis, Proto-Oncogene Proteins c-mdm2, Cell biology, Mitochondria, Electron Transport Complex I/genetics/metabolism, mitochondria, [SDV] Life Sciences [q-bio], Gene Expression Regulation, Neoplastic, medicine.anatomical_structure, Cell Transformation, Neoplastic, Mdm2, MT-ND6, transcription, Signal Transduction, respiratory complex I, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Adenocarcinoma, Cell Transformation, Neoplastic/genetics/metabolism/pathology, Article, Mitochondria/genetics/metabolism/pathology, 03 medical and health sciences, MDM2, medicine, Animals, Humans, metastasis, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Neoplasm Invasiveness, skeletal muscle, Molecular Biology, Lung Neoplasms/genetics/metabolism/pathology, Electron Transport Complex I, hypoxia, Skeletal muscle, Cell Biology, Xenograft Model Antitumor Assays, initiation, Mice, Inbred C57BL, Oxidative Stress, 030104 developmental biology, Apoptosis, Tumor progression, Tumor Suppressor Protein p53/genetics/metabolism, Genome, Mitochondrial, biology.protein, activation, Tumor Suppressor Protein p53, protein import, Carcinogenesis
Abstract

International audience; Accumulating evidence indicates that the MDM2 oncoprotein promotes tumorigenesis beyond its canonical negative effects on the p53 tumor suppressor, but these p53-independent functions remain poorly understood. Here, we show that a fraction of endogenous MDM2 is actively imported in mitochondria to control respiration and mitochondrial dynamics independently of p53. Mitochondrial MDM2 represses the transcription of NADH-dehydrogenase 6 (MT-ND6) in vitro and in vivo, impinging on respiratory complex I activity and enhancing mitochondrial ROS production. Recruitment of MDM2 to mitochondria increases during oxidative stress and hypoxia. Accordingly, mice lacking MDM2 in skeletal muscles exhibit higher MT-ND6 levels, enhanced complex I activity, and increased muscular endurance in mild hypoxic conditions. Furthermore, increased mitochondrial MDM2 levels enhance the migratory and invasive properties of cancer cells. Collectively, these data uncover a previously unsuspected function of the MDM2 oncoprotein in mitochondria that play critical roles in skeletal muscle physiology and may contribute to tumor progression.

Published
2018

4. Physiological and pathological roles of FATP-mediated lipid droplets in Drosophila and mice retina

Author

Michel Guichardant, Laurent Guillou, Victor Girard, Bertrand Mollereau, Nathalie Bernoud-Hubac, Aurélie Cubizolle, Daan M. Van Den Brink, Claire Angebault-Prouteau, Pierre Dourlen, Gilles Chatelain, Philippe Brabet, Francesco Napoletano, Simone Johansen, Nathalie Davoust, Laboratoire de biologie et modélisation de la cellule (LBMC UMR 5239), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), BioSciences Lyon-Gerland (BLG), École normale supérieure - Lyon (ENS Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Department of Life Sciences, Trieste, University of Trieste, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), French National Research Agency ANR-12-BSV1-0019-02, Association Francaise contre les Myopathies, a European Union's Seventh Framework Programme/AIRC (Associazione Italiana per la Ricerca sul cancro) Reintegration Grant, Bloomington Drosophila Stock Center NIH P40OD018537, CarMeN, laboratoire, Institut des Neurosciences de Montpellier (INM), Università degli studi di Trieste = University of Trieste, Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Van Den Brink, Daan M., Cubizolle, Aurélie, Chatelain, Gille, Davoust, Nathalie, Girard, Victor, Johansen, Simone, Napoletano, Francesco, Dourlen, Pierre, Guillou, Laurent, Angebault-Prouteau, Claire, Bernoud-Hubac, Nathalie, Guichardant, Michel, Brabet, Philippe, Mollereau, Bertrand, École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), École normale supérieure de Lyon (ENS de Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL)

Subjects
Pigments, Aging, Sensory Receptors, Ecology, Evolution, Behavior and Systematics, Molecular Biology, Genetics, Genetics (clinical), Cancer Research, Social Sciences, Biochemistry, Mice, 0302 clinical medicine, Animal Cells, acyltransferase, Psychology, Energy-Producing Organelles, Neurons, Genetics & Heredity, Drosophila Melanogaster, Neurodegeneration, Eukaryota, Fatty Acid Transport Proteins, Lipids, Cell biology, drosophile, [SDV] Life Sciences [q-bio], Physical Sciences, gouttelette lipidique, Cellular Types, Cellular Structures and Organelles, photoreceptor differentiation, Visual phototransduction, Evolution, Ocular Anatomy, Materials Science, Retina, 03 medical and health sciences, Genetic, Vesicles, Materials by Attribute, Organisms, Biology and Life Sciences, Lipid Droplets, Lipid Metabolism, medicine.disease, Invertebrates, Ecology, Evolution, Behavior and Systematic, Mice, Inbred C57BL, 030104 developmental biology, age, Eyes, Reactive Oxygen Species, 030217 neurology & neurosurgery, Neuroscience, Photoreceptors, 0301 basic medicine, [SDV]Life Sciences [q-bio], Mitochondrion, souris, medicine.disease_cause, retine, Animals, Genetically Modified, Lipid droplet, Medicine and Health Sciences, Drosophila Proteins, Ecology, neurodegeneration, Animal Models, Mitochondria, Insects, medicine.anatomical_structure, Experimental Organism Systems, Drosophila, Sensory Perception, Anatomy, Research Article, Signal Transduction, Programmed cell death, Arthropoda, lcsh:QH426-470, Bioenergetics, Biology, Research and Analysis Methods, visual cycle, storage, Model Organisms, Behavior and Systematics, Ocular System, Coenzyme A Ligases, medicine, Animals, programmed cell-death, disease, acid transport proteins, Afferent Neurons, Lipid metabolism, Cell Biology, pigment epithelium, Oxidative Stress, lcsh:Genetics, rôle physiologique, Cellular Neuroscience, sense organs, Energy Metabolism, Head, Oxidative stress
Abstract

Increasing evidence suggests that dysregulation of lipid metabolism is associated with neurodegeneration in retinal diseases such as age-related macular degeneration and in brain disorders such as Alzheimer’s and Parkinson’s diseases. Lipid storage organelles (lipid droplets, LDs), accumulate in many cell types in response to stress, and it is now clear that LDs function not only as lipid stores but also as dynamic regulators of the stress response. However, whether these LDs are always protective or can also be deleterious to the cell is unknown. Here, we investigated the consequences of LD accumulation on retinal cell homeostasis under physiological and stress conditions in Drosophila and in mice. In wild-type Drosophila, we show that dFatp is required and sufficient for expansion of LD size in retinal pigment cells (RPCs) and that LDs in RPCs are required for photoreceptor survival during aging. Similarly, in mice, LD accumulation induced by RPC-specific expression of human FATP1 was non-toxic and promoted mitochondrial energy metabolism in RPCs and non-autonomously in photoreceptor cells. In contrast, the inhibition of LD accumulation by dFatp knockdown suppressed neurodegeneration in Aats-metFB Drosophila mutants, which carry elevated levels of reactive oxygen species (ROS). This suggests that abnormal turnover of LD may be toxic for photoreceptors cells of the retina under oxidative stress. Collectively, these findings indicate that FATP-mediated LD formation in RPCs promotes RPC and neuronal homeostasis under physiological conditions but could be deleterious for the photoreceptors under pathological conditions., Author summary Lipids are major cell constituents and are present in the membranes, as free lipids in the cytoplasm, or stored in vesicles called lipid droplets (LDs). Under conditions of stress, lipids stored in LDs can be released to serve as substrates for energy metabolism by mitochondria. However, lipid storage is dysregulated in many degenerative disorders such as age-related macular degeneration, Parkinson’s and Alzheimer’s diseases. Thus, it is unclear whether accumulation of LDs is protective or toxic for neuronal cells. To address this question, we examined the consequences of removal or enforced LD accumulation on the health of retinal cells in flies and mice. Like humans, fly and mouse retinas contain retinal pigment cells (RPC) that support the functions of neighboring photoreceptor cells. We found that overexpression of the fatty acid transport protein (FATP) in RPCs induced accumulation of LDs in both transgenic flies and mice. Moreover, LD accumulation in RPCs was not harmful for juxtaposed photoreceptors during aging, but was toxic under stress conditions. We propose that lipid storage promotes cellular communication that affects photoreceptor health.

Published
2018

5. Metformin reverses cardiac SR/ER-mitochondria remodeling and mitochondrial complex I dysfunction in Dystrophin-deficient mice

Author

Jérémy Fauconnier, M. Lacote, Alain Lacampagne, and Claire Angebault-Prouteau

Subjects
medicine.medical_specialty, biology, business.industry, Superoxide, Duchenne muscular dystrophy, Cardiomyopathy, Proximity ligation assay, Mitochondrion, medicine.disease, Metformin, chemistry.chemical_compound, Endocrinology, chemistry, Internal medicine, biology.protein, medicine, Cardiology and Cardiovascular Medicine, Dystrophin, business, VDAC1, medicine.drug
Abstract

Introduction Besides skeletal and diaphragmatic muscle dysfunction, Duchenne muscular dystrophy (DMD) exhibit a progressive cardiomyopathy with an altered Ca2 + handling and a defect in mitochondrial respiration capacity. Aim The aim of the present study was to determine if the sarco-endoplasmic reticulum (SR/ER)-mitochondria interaction and mitochondrial Ca2 + homeostasis contribute to the progression of the cardiomyopathy. Methods and results Ventricular myocytes were isolated from 3-month old Dystrophin-deficient mice (mdx mice). Using proximity ligation assay, we observed an increase interaction between the SR/ER Ca2 + release channels, IP3R1, and the porine of the mitochondria, VDAC1, associated with an increase expression levels of IP3R1 and SIGMA1R. Similarly, the mitochondrial Ca2 + uniporter (MCU) and its regulated subunit, MICU1, expressions levels were enhanced in mdx heart. Furthermore the mitochondrial Ca2 + uptake kinetics and the mitochondrial Ca2 + content were significantly increased. Using oxygraphy experiment, we observed a severe decrease in respiration driven by the complex I with a stimulation in anion superoxide production measured with Mitosox red fluorescent dye. Finally, mdx mice were treated with the complex I modulator metformin at 200 mg/kg/day during one month. Metformin normalize the SR/ER-mitochondria interaction, decreases MICU1 expression and mitochondrial Ca2 + content and tends to restore complex I alteration in cardiomyocytes. Conclusions In summary, our data demonstrate for the first time that in the DMD heart the mitochondrial dysfunction is linked to an excessive SR/ER-mitochondria coupling with an increase in mitochondrial Ca2 + uptake and complex I dysfunction. Such remodeling could be reversed by metformin providing a novel therapeutic perspective in DMD.

Published
2019

6. ER stress disturbs SR/ER-mitochondria Ca2+transfer: Implications in Duchenne muscular dystrophy

Author

Marion Pauly, Haikel Dridi, Claire Angebault-Prouteau, Stefan Matecki, Cécile Notarnicola, Jérémy Fauconnier, Valérie Scheuermann, Alain Lacampagne, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), and roussel, pascale

Subjects
0301 basic medicine, medicine.medical_specialty, Duchenne muscular dystrophy, [SDV]Life Sciences [q-bio], Diaphragm, UPR, Biology, Mitochondrion, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, medicine, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Calcium signaling, ATF6, Autophagy, Tunicamycin, medicine.disease, [SDV] Life Sciences [q-bio], 030104 developmental biology, Endocrinology, chemistry, Unfolded protein response, Molecular Medicine, mdx, 030217 neurology & neurosurgery, Homeostasis
Abstract

Besides its role in calcium (Ca2 +) homeostasis, the sarco-endoplamic reticulum (SR/ER) controls protein folding and is tethered to mitochondria. Under pathophysiological conditions the unfolded protein response (UPR) is associated with disturbance in SR/ER-mitochondria crosstalk. Here, we investigated whether ER stress altered SR/ER-mitochondria links, Ca2 + handling and muscle damage in WT (Wild Type) and mdx mice, the murine model of Duchenne Muscular Dystrophy (DMD). In WT mice, the SR/ER-mitochondria links were decreased in isolated FDB muscle fibers after injection of ER stress activator tunicamycin (TM). Ca2 + imaging revealed an increase of cytosolic Ca2 + transient and a decrease of mitochondrial Ca2 + uptake. The force generating capacity of muscle dropped after TM. This impaired contractile function was accompanied by an increase in autophagy markers and calpain-1 activation. Conversely, ER stress inhibitors restored SR/ER-mitochondria links, mitochondrial Ca2 + uptake and improved diaphragm contractility in mdx mice. Our findings demonstrated that ER stress-altered SR/ER-mitochondria links, disturbed Ca2 + handling and muscle function in WT and mdx mice. Thus, ER stress may open up a prospect of new therapeutic targets in DMD.

Published
2017

7. ER stress disturbs SR/ER-mitochondria Ca

Author

Marion, Pauly, Claire, Angebault-Prouteau, Haikel, Dridi, Cécile, Notarnicola, Valérie, Scheuermann, Alain, Lacampagne, Stefan, Matecki, and Jérémy, Fauconnier

Subjects
Male, Calpain, Endoplasmic Reticulum Stress, Mitochondria, Muscle, Muscular Dystrophy, Duchenne, Disease Models, Animal, Mice, Sarcoplasmic Reticulum, Autophagy, Mice, Inbred mdx, Animals, Calcium, Calcium Signaling, Muscle Contraction
Abstract

Besides its role in calcium (Ca

Published
2017

8. Non-enzymatic oxidized metabolite of DHA, 4( RS )-4-F 4t -neuroprostane protects the heart against reperfusion injury

Author

Claire Angebault-Prouteau, Thierry Durand, Valérie Scheuermann, Valérie Bultel-Poncé, Jetty Chung-Yung Lee, Jean-Yves Le Guennec, Jérôme Thireau, Marie Demion, Jérôme Roy, Jean-Marie Galano, Camille Oger, Charlotte Farah, Patrice Bideaux, Jérémy Fauconnier, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Physiopathologie des adaptations cardiovasculaires à l'Exercice, Avignon Université (AU), Physiopathologie cardiovasculaire, Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM), and School of Biological Sciences

Subjects
0301 basic medicine, Mitochondrial ROS, medicine.medical_specialty, Ischemia/reperfusion, n-3 polyunsaturated fatty acids, Cardioprotection, Mitochondrion, Biology, medicine.disease_cause, mPTP, Biochemistry, Lipid peroxidation, 03 medical and health sciences, chemistry.chemical_compound, Physiology (medical), Internal medicine, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Neuroprostanes, ComputingMilieux_MISCELLANEOUS, [SDV.BA]Life Sciences [q-bio]/Animal biology, medicine.disease, Mitochondria, 030104 developmental biology, Endocrinology, Mitochondrial permeability transition pore, chemistry, Docosahexaenoic acid, Reperfusion injury, Oxidative stress
Abstract

International audience; Acute myocardial infarction leads to an increase in oxidative stress and lipid peroxidation. 4(RS)-4-F4t-Neuroprostane (4-F4t-NeuroP) is a mediator produced by non-enzymatic free radical peroxidation of thecardioprotective polyunsaturated fatty acid, docosahexaenoic acid (DHA). In this study, we investigated whetherintra-cardiac delivery of 4-F4t-NeuroP (0.03 mg/kg) prior to occlusion (ischemia) prevents and protects ratmyocardium from reperfusion damages.Using a rat model of ischemic-reperfusion (I/R), we showed that intra-cardiac infusion of 4-F4t-NeuroPsignificantly decreased infarct size following reperfusion (−27%) and also reduced ventricular arrhythmia scoreconsiderably during reperfusion (−41%). Most notably, 4-F4t-NeuroP decreased ventricular tachycardia andpost-reperfusion lengthening of QT interval. The evaluation of the mitochondrial homeostasis indicates alimitation of mitochondrial swelling in response to Ca2+by decreasing the mitochondrial permeability transitionpore opening and increasing mitochondria membrane potential. On the other hand, mitochondrial respirationmeasured by oxygraphy, and mitochondrial ROS production measured with MitoSox red®were unchanged. Wefound decreased cytochrome c release and caspase 3 activity, indicating that 4-F4t-NeuroP prevented reperfusiondamages and reduced apoptosis. In conclusion, 4-F4t-NeuroP derived from DHA was able to protect I/R cardiacinjuries by regulating the mitochondrial homeostasis

Published
2017

9. Non-enzymatic oxidized metabolite of DHA, 4(RS)-4-F

Author

Jérôme, Roy, Jérémy, Fauconnier, Camille, Oger, Charlotte, Farah, Claire, Angebault-Prouteau, Jérôme, Thireau, Patrice, Bideaux, Valérie, Scheuermann, Valérie, Bultel-Poncé, Marie, Demion, Jean-Marie, Galano, Thierry, Durand, Jetty Chung-Yung, Lee, and Jean-Yves, Le Guennec

Subjects
Docosahexaenoic Acids, Myocardium, Myocardial Infarction, Heart, Myocardial Reperfusion Injury, Protective Agents, Mitochondria, Heart, Rats, Oxidative Stress, Tachycardia, Ventricular, Animals, Humans, Neuroprostanes, Lipid Peroxidation, Reactive Oxygen Species
Abstract

Acute myocardial infarction leads to an increase in oxidative stress and lipid peroxidation. 4(RS)-4-F

Published
2016

10. Cardiac mitochondrial complex I dysfunction is associated with an increase in sarcoplasmic reticulum leak in a Duchenne muscular dystrophy

Author

Alain Lacampagne, Claire Angebault-Prouteau, M. Pauly, Valérie Scheuermann, M. Lacote, and Jérémy Fauconnier

Subjects
Leak, medicine.medical_specialty, Endocrinology, business.industry, Endoplasmic reticulum, Duchenne muscular dystrophy, Internal medicine, Medicine, Cardiology and Cardiovascular Medicine, business, medicine.disease, Mitochondrial Complex I
Published
2017

11. Neuroradiological findings expand the phenotype of OPA1-related mitochondrial dysfunction

Author

Michel Pagès, Catherine Blanchet, Christian P. Hamel, H. Brunel, Agathe Roubertie, Gaël Manes, Emmanuelle Le Bars, Michel Mondain, Marie Christine Picot, Guy Lenaers, Claire Angebault Prouteau, Nicolas Leboucq, Erika Nogue, Hugues Chevassus, Emmanuelle Sarzi, Isabelle Meunier, Max Villain, Patrizia Amati-Bonneau, Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), CHU de Montpellier, and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)

Subjects
Male, Pathology, medicine.medical_specialty, Magnetic Resonance Spectroscopy, Visual acuity, Mitochondrial Diseases, Adolescent, Optic nerve, [SDV]Life Sciences [q-bio], Brain imaging, Neurological examination, Fluid-attenuated inversion recovery, Motor Activity, OPA1, Retinal ganglion, GTP Phosphohydrolases, White matter, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Atrophy, Optic Atrophy, Autosomal Dominant, medicine, Humans, dominant optic atrophy, Child, Hearing Loss, 030304 developmental biology, Neurologic Examination, Mitochondrial disorders, 0303 health sciences, medicine.diagnostic_test, business.industry, Brain, medicine.disease, Magnetic Resonance Imaging, eye diseases, 3. Good health, medicine.anatomical_structure, Neurology, Child, Preschool, Cerebellar atrophy, Female, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery
Abstract

International audience; OBJECTIVE: OPA1 mutations are responsible for more than half of autosomal dominant optic atrophy (ADOA), a blinding disease affecting the retinal ganglion neurons. In most patients the clinical presentation is restricted to the optic nerve degeneration, albeit in 20% of them, additional neuro-sensorial symptoms might be associated to the loss of vision, as frequently encountered in mitochondrial diseases. This study describes clinical and neuroradiological features of OPA1 patients.METHODS: Twenty two patients from 17 families with decreased visual acuity related to optic atrophy and carrying an OPA1 mutation were enrolled. Patients underwent neuro-ophthalmological examinations. Brain magnetic resonance imaging (T1, T2 and flair sequences) was performed on a 1.5-Tesla MR Unit. Twenty patients underwent 2-D proton spectroscopic imaging.RESULTS: Brain imaging disclosed abnormalities in 12 patients. Cerebellar atrophy mainly involving the vermis was observed in almost a quarter of the patients; other abnormalities included unspecific white matter hypersignal, hemispheric cortical atrophy, and lactate peak. Neurological examination disclosed one patient with a transient right hand motor deficit and ENT examination revealed hearing impairment in 6 patients. Patients with abnormal MRI were characterized by: (i) an older age (ii) more severe visual impairment with chronic visual acuity deterioration, and (iii) more frequent associated deafness.CONCLUSIONS: Our results demonstrate that brain imaging abnormalities are common in OPA1 patients, even in those with normal neurological examination. Lactate peak, cerebellar and cortical atrophies are consistent with the mitochondrial dysfunction related to OPA1 mutations and might result from widespread neuronal degeneration.

Published
2014

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