Prolonged ethanol administration depletes mitochondrial DNA in MnSOD-overexpressing transgenic mice, but not in their wild type littermates.
Alcohol consumption increases reactive oxygen species formation and lipid peroxidation, whose products can damage mitochondrial DNA (mtDNA) and alter mitochondrial function. A possible role of manganese superoxide dismutase (MnSOD) on these effects has not been investigated. To test whether MnSOD overexpression modulates alcohol-induced mitochondrial alterations, we added ethanol to the drinking water of transgenic MnSOD-overexpressing (TgMnSOD) mice and their wild type (WT) littermates for 7 weeks. In TgMnSOD mice, alcohol administration further increased the activity of MnSOD, but decreased cytosolic glutathione as well as cytosolic glutathione peroxidase activity and peroxisomal catalase activity. Whereas ethanol increased cytochrome P-450 2E1 and mitochondrial ROS generation in both WT and TgMnSOD mice, hepatic iron, lipid peroxidation products and respiratory complex I protein carbonyls were only increased in ethanol-treated TgMnSOD mice but not in WT mice. In ethanol-fed TgMnSOD mice, but not ethanol-fed WT mice, mtDNA was depleted, and mtDNA lesions blocked the progress of polymerases. The iron chelator, DFO prevented hepatic iron accumulation, lipid peroxidation, protein carbonyl formation and mtDNA depletion in alcohol-treated TgMnSOD mice. Alcohol markedly decreased the activities of complexes I, IV and V of the respiratory chain in TgMnSOD, with absent or lesser effects in WT mice. There was no inflammation, apoptosis or necrosis, and steatosis was similar in ethanol-treated WT and TgMnSOD mice. In conclusion, prolonged alcohol administration selectively triggers iron accumulation, lipid peroxidation, respiratory complex I protein carbonylation, mtDNA lesions blocking the progress of polymerases, mtDNA depletion and respiratory complex dysfunction in TgMnSOD mice but not in WT mice.
Larosche
Isabelle
I
INSERM, U773, Centre de Recherche Biomédicale Bichat Beaujon (CRB3), Equipe Mitochondries et Foie, F75018, Paris, France.
Choumar
Amal
A
Fromenty
Bernard
B
Lettéron
Philippe
P
Abbey-Toby
Adjé
A
Van Remmen
Holly
H
Epstein
Charles J
CJ
Richardson
Arlan
A
Feldmann
Gérard
G
Pessayre
Dominique
D
Mansouri
Abdellah
A
D000428:Alcohol Drinking / Q000009:adverse effects*; D000818:Animals; D001835:Body Weight; D053148:Caspase 3 / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D003676:Deferoxamine / Q000494:pharmacology; D015536:Down-Regulation; D042967:Electron Transport Complex I / Q000378:metabolism; D000431:Ethanol / Q000097:blood / Q000378:metabolism / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D006609:High Mobility Group Proteins / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D050050:Protein Carbonylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation; D000099156:Superoxide Dismutase 2
D053148:Caspase 3; D002374:Catalase; D019392:Cytochrome P-450 CYP2E1; D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D003676:Deferoxamine; D042967:Electron Transport Complex I; D000431:Ethanol; D005978:Glutathione; D005979:Glutathione Peroxidase; D006609:High Mobility Group Proteins; D007501:Iron; D007502:Iron Chelating Agents; D052247:Nitric Oxide Synthase Type II; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D017392:Thiobarbituric Acid Reactive Substances; D014157:Transcription Factors; D000099156:Superoxide Dismutase 2; C081930:Tfam protein, mouse; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; C496317:Nos2 protein, mouse; C505409:Casp3 protein, mouse