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VDAC phosphorylation impairment causes mitochondrial membrane permeability during lipid accumulation
Ist Teil von
FASEB Journal, 2013, Vol.27 (S1)
Ort / Verlag
Federation of American Society of Experimental Biology
Erscheinungsjahr
2013
Link zum Volltext
Quelle
Wiley Online Library - AutoHoldings Journals
Beschreibungen/Notizen
Non‐alcoholic steatosis is a chronic disease characterized by lipid accumulation in the cytoplasm of hepatocytes involving early mitochondrial impairment and late hepatocyte cell death. The voltage‐dependent anion channel (VDAC) is a mitochondrial membrane channel mediating the flux of metabolites, calcium and water across the mitochondrial outer membrane. Upon lethal stress, VDAC can mediate mitochondrial membrane permeabilization (MMP) and cell death. Combination of four experimental models of steatosis (human biopsies, isolated mitochondria from ob/ob obese mice, high fat diet‐fed mice or immortalized cell lines) displayed, in steatotic livers, favored calcium‐induced MMP induction and permeability of VDAC. Thus, lipid accumulation increased the influx of water and calcium into mitochondria and sensitized the organelle to matrix swelling, depolarization and cytochrome c release. Moreover, NADH oxidase activity and channel properties of VDAC are sensitized to calcium regulation in steatosis models. These findings are associated with the hypophosphorylation of VDAC on a threonine residue and the loss of its interaction with the anti‐apoptotic Bcl‐XL and GSK3 kinase. In conclusion, VDAC acts as an early sensor of lipid toxicity and its GSK3‐mediated phosphorylation status controls outer mitochondrial membrane permeabilization in steatosis.