title: Glycogen synthase kinase 3-mediated voltage-dependent anion channel phosphorylation controls outer mitochondrial membrane permeability during lipid accumulation.
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.
  
  
  CONCLUSIONS
  VDAC acts as an early sensor of lipid toxicity and its GSK3-mediated phosphorylation status controls outer mitochondrial membrane permeabilization in hepatosteatosis.
authors: INSERM U769, LabEx LERMIT, Université Paris-Sud, Faculté de Pharmacie, Châtenay-Malabry, France.
authors: Cecile
authors: C
authors: Martel
authors: Maya
authors: M
authors: Allouche
authors: Davide Degli
authors: DD
authors: Esposti
authors: Elena
authors: E
authors: Fanelli
authors: Céline
authors: C
authors: Boursier
authors: Céline
authors: C
authors: Henry
authors: Joel
authors: J
authors: Chopineau
authors: Giuseppe
authors: G
authors: Calamita
authors: Guido
authors: G
authors: Kroemer
authors: Antoinette
authors: A
authors: Lemoine
authors: Catherine
authors: C
authors: Brenner
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D005234:Fatty Liver / Q000378:metabolism*; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051336:Mitochondrial Membranes / Q000378:metabolism*; D010766:Phosphorylation; D050994:Voltage-Dependent Anion Channels / Q000378:metabolism*; D051020:bcl-X Protein / Q000378:metabolism*
chemical_list: C494812:Bcl2l1 protein, mouse; D050994:Voltage-Dependent Anion Channels; D051020:bcl-X Protein; D038362:Glycogen Synthase Kinase 3; D002118:Calcium