PMID:17448893

Citation	Kessova, IG and Cederbaum, AI (2007) Mitochondrial alterations in livers of Sod1-/- mice fed alcohol. Free Radic. Biol. Med. 42:1470-80
Abstract	Chronic alcohol consumption induced liver injury in Cu,Zn-superoxide dismutase-deficient mice (Sod1-/-), with extensive centrilobular necrosis and inflammation and a reduction in hepatic ATP content. Mechanisms by which ethanol decreased ATP in these mice remain unclear. We investigated alterations in mitochondria of Sod1-/- mice produced by chronic ethanol treatment. These mitochondria had an increase in State 4 oxygen consumption with succinate and especially with glutamate plus malate compared to mitochondria from pair-fed Sod1-/- mice or mitochondria from wild-type mice fed dextrose or ethanol. This uncoupling was associated with a decrease in ADP/O and respiratory control ratios, a decline in mitochondrial membrane potential, enhanced mitochondrial permeability transition, and decreased aconitase activity. Total thiols and uncoupling protein 2 levels were elevated in the pair-fed Sod1-/- mitochondria, perhaps an adaptive response to oxidant stress. However, no such increases were found with the ethanol-fed Sod1-/- mitochondria, suggesting a failure to develop these adaptations. The mitochondria from the ethanol-fed Sod1-/- mice had elevated levels of cleaved Bax, Bak, Bcl-xl, and adenine nucleotide translocator. Immunoprecipitation studies revealed increased association of Bax and Bak with the adenine nucleotide translocator. ADP-ATP exchange was very low in the ethanol-fed Sod1-/- mitochondria. These results suggest that ethanol treatment of Sod1-/- mice produces uncoupling and a decline in Deltapsi, swelling, increased association of proapoptotic proteins involved in the permeability transition, and decreased adenine nucleotide translocator activity, which may be responsible for the decline in ATP levels and development of necrosis in this model of alcohol-induced liver injury.
Links	PubMed PMC1924491 Online version:10.1016/j.freeradbiomed.2007.01.044
Keywords	Animals; Caspase 3/metabolism; DNA Fragmentation; Ethanol/toxicity; Liver/drug effects; Liver/metabolism; Liver/ultrastructure; Membrane Potentials/drug effects; Mice; Mice, Mutant Strains; Mitochondria, Liver/metabolism; Mitochondria, Liver/ultrastructure; Mitochondrial ADP, ATP Translocases/metabolism; Mitochondrial Membranes/metabolism; Mitochondrial Swelling/genetics; Oxidative Stress; Oxygen Consumption/drug effects; Permeability; Proto-Oncogene Proteins c-bcl-2/metabolism; Superoxide Dismutase/genetics; Superoxide Dismutase/physiology
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