An early event that occurs in response to alcohol consumption is
mitochondrial dysfunction, which is evident in changes to the mitochondrial
proteome, respiration defects, and
mitochondrial DNA (
mtDNA) damage.
S-adenosylmethionine (SAM) has emerged as a potential therapeutic for treating
alcoholic liver disease through mechanisms that appear to involve decreases in oxidative stress and proinflammatory
cytokine production as well as the alleviation of steatosis. Because mitochondria are a source of reactive
oxygen/
nitrogen species and a target for oxidative damage, we tested the hypothesis that SAM treatment during alcohol exposure preserves organelle function. Mitochondria were isolated from livers of rats fed control and
ethanol diets with and without SAM for 5 wk. Alcohol feeding caused a significant decrease in state 3 respiration and the respiratory control ratio, whereas SAM administration prevented these alcohol-mediated defects and preserved hepatic SAM levels. SAM treatment prevented alcohol-associated increases in mitochondrial
superoxide production,
mtDNA damage, and
inducible nitric oxide synthase induction, without a significant lessening of steatosis. Accompanying these indexes of
oxidant damage, SAM prevented alcohol-mediated losses in
cytochrome c oxidase subunits as shown using blue native PAGE proteomics and immunoblot analysis, which resulted in partial preservation of complex IV activity. SAM treatment attenuated the upregulation of the mitochondrial stress chaperone
prohibitin. Although SAM supplementation did not alleviate steatosis by itself, SAM prevented several key alcohol-mediated defects to the mitochondria genome and
proteome that contribute to the bioenergetic defect in the liver after alcohol consumption. These findings reveal new molecular targets through which SAM may work to alleviate one critical component of alcohol-induced liver injury:
mitochondria dysfunction.