The voltage-dependent anion channel (VDAC) is a membrane channel mediating the flux of metabolites and water across the mitochondrial outer membrane. Upon lethal stress, VDAC can mediate mitochondrial membrane permeabilization and cell death. Here, we demonstrate that in mouse models of non-alcoholic fatty liver disease (NAFLD), VDAC exhibits reduced threonine phosphorylation linked to a lack of interaction with the anti-apoptotic protein Bcl- XL and the serine/threonine kinase GSK3 in mitochondrial membrane. VDAC dephosphorylation is observed in in vitro models of lipotoxicity, as well as mice with NAFLD and patients with morbid fatty liver disease. This post-translational modification increases the influx of water and calcium into mitochondria and sensitizes the organelle to matrix swelling, depolarization and cytochrome c release. Moreover, in the NAFDL models, NADH oxidase activity and channel conductance of VDAC are sensitized to calcium regulation in steatosis models. In conclusion, VDAC acts as an early sensor of lipid toxicity and its GSK3-mediated phosphorylation status controls outer mitochondrial membrane permeabilization in hepatosteatosis.
GSK3-mediated VDAC phosphorylation controls outer mitochondrial membrane permeability during lipid accumulation
CALAMITA, Giuseppe;
2013-01-01
Abstract
The voltage-dependent anion channel (VDAC) is a membrane channel mediating the flux of metabolites and water across the mitochondrial outer membrane. Upon lethal stress, VDAC can mediate mitochondrial membrane permeabilization and cell death. Here, we demonstrate that in mouse models of non-alcoholic fatty liver disease (NAFLD), VDAC exhibits reduced threonine phosphorylation linked to a lack of interaction with the anti-apoptotic protein Bcl- XL and the serine/threonine kinase GSK3 in mitochondrial membrane. VDAC dephosphorylation is observed in in vitro models of lipotoxicity, as well as mice with NAFLD and patients with morbid fatty liver disease. This post-translational modification increases the influx of water and calcium into mitochondria and sensitizes the organelle to matrix swelling, depolarization and cytochrome c release. Moreover, in the NAFDL models, NADH oxidase activity and channel conductance of VDAC are sensitized to calcium regulation in steatosis models. In conclusion, VDAC acts as an early sensor of lipid toxicity and its GSK3-mediated phosphorylation status controls outer mitochondrial membrane permeabilization in hepatosteatosis.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
