Hepatic mitochondrial DNA depletion after an alcohol binge in mice: probable role of peroxynitrite and modulation by manganese superoxide dismutase.
Alcohol consumption increases reactive oxygen species (ROS) formation, which can damage mitochondrial DNA (mtDNA) and alter mitochondrial function. To test whether manganese superoxide dismutase (MnSOD) modulates acute alcohol-induced mitochondrial alterations, transgenic MnSOD-overexpressing (MnSOD(+++)) mice, heterozygous knockout (MnSOD(+/-)) mice, and wild-type (WT) littermates were sacrificed 2 or 24 h after intragastric ethanol administration (5 g/kg). Alcohol administration further increased MnSOD activity in MnSOD(+++) mice, but further decreased it in MnSOD(+/-) mice. In WT mice, alcohol administration transiently increased mitochondrial ROS formation, decreased mitochondrial glutathione, depleted and damaged mtDNA, and decreased complex I and V activities; alcohol durably increased inducible nitric-oxide synthase (NOS) expression, plasma nitrites/nitrates, and the nitration of tyrosine residues in complex V proteins. These effects were prevented in MnSOD(+++) mice and prolonged in MnSOD(+/-) mice. In alcoholized WT or MnSOD(+/-) mice, mtDNA depletion and the nitration of tyrosine residues in complex I and V proteins were prevented or attenuated by cotreatment with tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl), a superoxide scavenger; N(omega)-nitro-l-arginine methyl ester and N-[3-(aminomethyl)benzyl]acetamidine (1,400W), two NOS inhibitors; or uric acid, a peroxynitrite scavenger. In conclusion, MnSOD overexpression prevents, and MnSOD deficiency prolongs, mtDNA depletion after an acute alcohol binge in mice. The protective effects of MnSOD, tempol, NOS inhibitors, and uric acid point out a role of the superoxide anion reacting with NO to form mtDNA-damaging peroxynitrite.
Larosche
Isabelle
I
Institut National de la Santé et de la Recherche Médicale U773, Faculté de Médecine Xavier Bichat, 16 rue Henri Huchard, BP 416, 75018 Paris, France.
Lettéron
Philippe
P
Berson
Alain
A
Fromenty
Bernard
B
Huang
Ting-Ting
TT
Moreau
Richard
R
Pessayre
Dominique
D
Mansouri
Abdellah
A
D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004272:DNA, Mitochondrial / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D042967:Electron Transport Complex I / Q000378:metabolism; D000431:Ethanol / Q000506:poisoning*; D016166:Free Radical Scavengers / Q000494:pharmacology; D005979:Glutathione Peroxidase / Q000378:metabolism; D006609:High Mobility Group Proteins / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000502:physiology; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D030421:Peroxynitrous Acid / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013113:Spin Labels; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D014527:Uric Acid / Q000494:pharmacology
D003497:Cyclic N-Oxides; D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D016166:Free Radical Scavengers; D006609:High Mobility Group Proteins; D017382:Reactive Oxygen Species; D013113:Spin Labels; C081930:Tfam protein, mouse; D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D030421:Peroxynitrous Acid; D014527:Uric Acid; D000431:Ethanol; D007501:Iron; D005979:Glutathione Peroxidase; D052247:Nitric Oxide Synthase Type II; D013482:Superoxide Dismutase; D053148:Caspase 3; D025261:Mitochondrial Proton-Translocating ATPases; D042967:Electron Transport Complex I; C001803:tempol; D019331:NG-Nitroarginine Methyl Ester