MnSOD Overexpression Prevents Liver Mitochondrial DNA Depletion after an Alcohol Binge but Worsens This Effect after Prolonged Alcohol Consumption in Mice
MnSOD Overexpression Prevents Liver Mitochondrial DNA Depletion after an Alcohol Binge but Worsens This Effect after Prolonged Alcohol Consumption in Mice
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DOI：
10.1159/000324284
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发表时间：
2010-01-01
影响因子：
2.3
通讯作者：
Pessayre, Dominique
中科院分区：
文献类型：
--
作者：
Mansouri, Abdellah;Tarhuni, Arige;Pessayre, Dominique
急性和慢性酒精消耗增加活性氧（ROS）的形成和脂质过氧化，其产物损伤肝线粒体DNA（mtDNA）。为了测试锰超氧化物歧化酶（MnSOD）过表达是否调节急性和慢性酒精诱导的mtDNA损伤，转基因MnSOD过表达（TgMnSOD（+））小鼠和野生型（WT）小鼠被酒精处理，无论是慢性（饮用水7周）还是急性（单次胃内剂量为5 g/kg）。急性酒精给药增加线粒体活性氧的形成，减少线粒体谷胱甘肽，耗尽和损坏的mtDNA，持久增加诱导型一氧化氮合酶（NOS）的表达，血浆亚硝酸盐/硝酸盐和硝化的复合物V蛋白中的酪氨酸残基和复合物V的活性下降在WT小鼠。这些作用在TgMnSOD（+）小鼠中被阻止。在急性酒精中毒的WT小鼠中，超氧化物清除剂tempol、两种NOS抑制剂L-NAME和1400 W或过氧亚硝酸盐清除剂尿酸可防止mtDNA耗竭。与此相反，慢性饮酒减少胞浆谷胱甘肽和增加肝脏铁，脂质过氧化产物和呼吸复合物I蛋白羰基只有乙醇处理的TgMnSOD（+++）小鼠，但在WT小鼠。在长期乙醇喂养的TgMnSOD（+）小鼠中，而不是WT小鼠，mtDNA被破坏和耗尽，铁螯合剂去铁胺（DFO）阻止了这种作用。总之，MnSOD过表达可防止急性酒精狂欢后mtDNA耗竭，但在长期饮酒后会增强这种作用，这选择性地触发TgMnSOD（+）小鼠而非WT小鼠的铁积累。在急性酒精狂欢模型中，MnSOD，tempol，NOS抑制剂和尿酸的保护作用表明超氧阴离子与NO反应形成损伤线粒体DNA的过氧亚硝酸盐的作用。在长期乙醇消耗模型中，DFO的保护作用表明铁与过氧化氢反应形成损伤线粒体DNA的羟基自由基的作用。版权所有（C）2011 S. Karger AG，巴塞尔
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 (C) 2011 S. Karger AG, Basel