Pathomechanisms of Alcohol-Induced Damage

MnSOD Overexpression Prevents Liver Mitochondrial DNA Depletion after an Alcohol Binge but Worsens This Effect after Prolonged Alcohol Consumption in Mice
Abdellah Mansouri, Arige Tarhuni, Isabelle Larosche, Florence Reyl-Desmars, Christine Demeilliers, Françoise Degoul, Pierre Nahon, Angela Sutton, Richard Moreau, Bernard Fromenty, Dominique Pessayre

INSERM U773, Centre de Recherche Biomédicale Bichat Beaujon (CRB3), Université Paris 7 Denis Diderot, site Bichat, Paris, France

Address of Corresponding Author

Dig Dis 2010;28:756-775 (DOI: 10.1159/000324284)

  Key Words

• Mitochondria
• Liver
• Alcohol
• Oxidative stress
• Manganese superoxide dismutase
• Mitochondrial DNA

  Abstract

Both acute and chronic alcohol consumption increase reactive oxygen species (ROS) formation and lipid peroxidation, whose products damage hepatic mitochondrial DNA (mtDNA). To test whether manganese superoxide dismutase (MnSOD) overexpression modulates acute and chronic alcohol-induced mtDNA lesions, transgenic MnSOD-overexpressing (TgMnSOD⁺⁺⁺) mice and wild-type (WT) mice were treated by alcohol, either chronically (7 weeks in drinking water) or acutely (single intragastric dose of 5 g/kg). Acute alcohol administration increased mitochondrial ROS formation, decreased mitochondrial glutathione, depleted and damaged mtDNA, durably increased inducible nitric oxide synthase (NOS) expression, plasma nitrites/nitrates and the nitration of tyrosine residues in complex V proteins and decreased complex V activity in WT mice. These effects were prevented in TgMnSOD⁺⁺⁺ mice. In acutely alcoholized WT mice, mtDNA depletion was prevented by tempol, a superoxide scavenger, L-NAME and 1400W, two NOS inhibitors, or uric acid, a peroxynitrite scavenger. In contrast, chronic alcohol consumption decreased cytosolic glutathione and increased hepatic iron, lipid peroxidation products and respiratory complex I protein carbonyls only in ethanol-treated TgMnSOD⁺⁺⁺ mice but not in WT mice. In chronic ethanol-fed TgMnSOD⁺⁺⁺ mice, but not WT mice, mtDNA was damaged and depleted, and the iron chelator, deferoxamine (DFO), prevented this effect. In conclusion, MnSOD overexpression prevents mtDNA depletion after an acute alcohol binge but aggravates this effect after prolonged alcohol consumption, which selectively triggers iron accumulation in TgMnSOD⁺⁺⁺ mice but not in WT mice. In the model of acute alcohol binge, the protective effects of MnSOD, tempol, NOS inhibitors and uric acid suggested a role of the superoxide anion reacting with NO to form mtDNA-damaging peroxynitrite. In the model of prolonged ethanol consumption, the protective effects of DFO suggested the role of iron reacting with hydrogen peroxide to form mtDNA-damaging hydroxyl radical.

Copyright © 2011 S. Karger AG, Basel

  Author Contacts

A. Mansouri
INSERM U773, Faculté de Médecine Xavier Bichat
16, rue Henri Huchard, BP 416
FR–75018 Paris (France)
Tel. +33 157 277 512, E-Mail abdel.mansouri@inserm.fr

  Article Information

Published online: April 27, 2011
Number of Print Pages : 20
Number of Figures : 8, Number of Tables : 2, Number of References : 76