title: S-adenosylmethionine prevents chronic alcohol-induced mitochondrial dysfunction in the rat liver.
abstract: 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.
authors.affiliation: Department of Environmental Health Sciences, School of Public Health, University of Alabama, Birmingham, AL 35294, USA. sbailey@uab.edu
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Bailey
authors.forename: Gloria
authors.initials: G
authors.lastname: Robinson
authors.forename: Anita
authors.initials: A
authors.lastname: Pinner
authors.forename: Laura
authors.initials: L
authors.lastname: Chamlee
authors.forename: Elena
authors.initials: E
authors.lastname: Ulasova
authors.forename: Melissa
authors.initials: M
authors.lastname: Pompilius
authors.forename: Grier P
authors.initials: GP
authors.lastname: Page
authors.forename: David
authors.initials: D
authors.lastname: Chhieng
authors.forename: Nirag
authors.initials: N
authors.lastname: Jhala
authors.forename: Aimee
authors.initials: A
authors.lastname: Landar
authors.forename: Kusum K
authors.initials: KK
authors.lastname: Kharbanda
authors.forename: Scott
authors.initials: S
authors.lastname: Ballinger
authors.forename: Victor
authors.initials: V
authors.lastname: Darley-Usmar
mesh_terms: D000818:Animals; D015153:Blotting, Western; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D008099:Liver / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008111:Liver Function Tests; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism*; D018832:Molecular Chaperones / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects; D000091402:Prohibitins; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012436:S-Adenosylmethionine / Q000494:pharmacology*
chemical_list: D004272:DNA, Mitochondrial; D018832:Molecular Chaperones; D000091402:Prohibitins; D012097:Repressor Proteins; D012436:S-Adenosylmethionine; D019392:Cytochrome P-450 CYP2E1; D052247:Nitric Oxide Synthase Type II; D003576:Electron Transport Complex IV