Glycogen synthase kinase 3-mediated voltage-dependent anion channel phosphorylation controls outer mitochondrial membrane permeability during lipid accumulation§

Authors

  • Cecile Martel,

    1. INSERM U769, LabEx LERMIT, Université Paris-Sud, Faculté de Pharmacie, Châtenay-Malabry, France
    2. INSERM U1004, Université de Paris-Sud, PRES UniverSud Paris, Hôpital Paul Brousse, Villejuif, France
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  • Maya Allouche,

    1. Institut Charles Gerhardt, UMR 5253 CNRS, Equipe MACS, UFR des Sciences Pharmaceutiques et Biologiques, Montpellier, France
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  • Davide Degli Esposti,

    1. INSERM U1004, Université de Paris-Sud, PRES UniverSud Paris, Hôpital Paul Brousse, Villejuif, France
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  • Elena Fanelli,

    1. Dipartimento di Fisiologia Generale ed Ambientale, Università degli Studi di Bari, Aldo Moro, Bari, Italy
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  • Céline Boursier,

    1. INSERM IFR 141, Université Paris-Sud, Faculté de Pharmacie, Châtenay-Malabry, France
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  • Céline Henry,

    1. INRA, UMR 1319 Micalis, PAPPSO, Jouy-en-Josas, France
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  • Joel Chopineau,

    1. Institut Charles Gerhardt, UMR 5253 CNRS, Equipe MACS, UFR des Sciences Pharmaceutiques et Biologiques, Montpellier, France
    2. Université de Nîmes, Nîmes, France
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  • Giuseppe Calamita,

    1. Dipartimento di Fisiologia Generale ed Ambientale, Università degli Studi di Bari, Aldo Moro, Bari, Italy
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  • Guido Kroemer,

    1. INSERM, U848, Villejuif, France
    2. Metabolomics Platform, Institut Gustave Roussy, Villejuif, France
    3. Centre de Recherche des Cordeliers, Paris, France
    4. Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France
    5. Université Paris Descartes, Faculté de Médecine, Paris, France
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  • Antoinette Lemoine,

    1. INSERM U1004, Université de Paris-Sud, PRES UniverSud Paris, Hôpital Paul Brousse, Villejuif, France
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  • Catherine Brenner

    Corresponding author
    1. INSERM U769, LabEx LERMIT, Université Paris-Sud, Faculté de Pharmacie, Châtenay-Malabry, France
    • INSERM U769, LabEx LERMIT, Université Paris-Sud, 5 Rue J.-B. Clément, 92290 Châtenay-Malabry Cedex, France
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    • fax: 33-1 46 83 54 75


  • Potential conflict of interest: Nothing to report.

  • C.B. is supported by the University of Paris Sud (grant attractivité), Institut National pour le Cancer (INCa, 2008-1-PL BIO-04-CNRS ON1), and LabEx LERMIT. C.B. and A.L. are supported by the PRES UniverSud Paris. C.M. received a fellowship from Association pour la Recherche sur le Cancer. C.B., M.A., and J.C. are supported by ANR (ANR-08PCVI-0008-01). G.C. received support from MIUR (PRIN20089SRS2X_003) and Fondazione Cassa di Risparmio di Puglia.

  • §

    Senior coauthors.

Abstract

Nonalcoholic steatosis is a liver pathology characterized by fat accumulation and severe metabolic alterations involving early mitochondrial impairment and late hepatocyte cell death. However, mitochondrial dysfunction mechanisms remain elusive. Using four models of nonalcoholic steatosis, i.e., livers from patients with fatty liver disease, ob/ob mice, mice fed a high-fat diet, and in vitro models of lipotoxicity, we show that outer mitochondrial membrane permeability is altered and identified a posttranslational modification of voltage-dependent anion channel (VDAC), a membrane channel and NADH oxidase, as a cause of early mitochondrial dysfunction. Thus, in nonalcoholic steatosis VDAC exhibits reduced threonine phosphorylation, which increases the influx of water and calcium into mitochondria, sensitizes the organelle to matrix swelling, depolarization, and cytochrome c release without inducing cell death. This also amplifies VDAC enzymatic and channel activities regulation by calcium and modifies its interaction with proteic partners. Moreover, lipid accumulation triggers a rapid lack of VDAC phosphorylation by glycogen synthase kinase 3 (GSK3). Pharmacological and genetic manipulations proved GSK3 to be responsible for VDAC phosphorylation in normal cells. Notably, VDAC phosphorylation level correlated with steatosis severity in patients. Conclusion: VDAC acts as an early sensor of lipid toxicity and its GSK3-mediated phosphorylation status controls outer mitochondrial membrane permeabilization in hepatosteatosis. (HEPATOLOGY 2013)

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