fax: 33-1 46 83 54 75
Steatohepatitis/Metabolic Liver Disease
Article first published online: 7 JAN 2013
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 57, Issue 1, pages 93–102, January 2013
How to Cite
Martel, C., Allouche, M., Esposti, D. D., Fanelli, E., Boursier, C., Henry, C., Chopineau, J., Calamita, G., Kroemer, G., Lemoine, A. and Brenner, C. (2013), Glycogen synthase kinase 3-mediated voltage-dependent anion channel phosphorylation controls outer mitochondrial membrane permeability during lipid accumulation. Hepatology, 57: 93–102. doi: 10.1002/hep.25967
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.
- Issue published online: 7 JAN 2013
- Article first published online: 7 JAN 2013
- Accepted manuscript online: 19 JUL 2012 05:45AM EST
- Manuscript Accepted: 6 JUL 2012
- Manuscript Revised: 21 JUN 2012
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)