Prolonged ethanol administration depletes mitochondrial DNA in MnSOD-overexpressing transgenic mice, but not in their wild type littermates
Prolonged ethanol administration depletes mitochondrial DNA in MnSOD-overexpressing transgenic mice, but not in their wild type littermates
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DOI：
10.1016/j.taap.2008.11.004
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发表时间：
2009-02-01
影响因子：
3.8
通讯作者：
Mansouri, Abdellah
中科院分区：
文献类型：
--
作者：
Larosche, Isabelle;Chournar, Amal;Mansouri, Abdellah
酒精摄入会增加活性氧的形成和脂质过氧化，其产物会损伤线粒体DNA(MtDNA)，改变线粒体的功能。锰超氧化物歧化酶(MnSOD)在这些效应中的可能作用尚未被研究。为了测试MnSOD过表达是否调节酒精诱导的线粒体改变，我们在转基因MnSOD过表达(TgMnSOD)小鼠及其野生型(WT)仔鼠的饮用水中加入乙醇7周。在TgMnSOD小鼠中，酒精使MnSOD活性进一步升高，但降低了胞质谷胱甘肽、胞质谷胱甘肽过氧化物酶和过氧化氢酶活性。乙醇使WT和TgMnSOD小鼠的细胞色素P-4502E1和线粒体ROS生成均增加，而肝脏铁、脂质过氧化产物和呼吸复合体1蛋白羰基只在乙醇处理的TgMnSOD小鼠中增加，而在WT小鼠中不增加。在乙醇喂养的TgMnSOD小鼠，而不是乙醇喂养的WT小鼠中，mtDNA耗尽，mtDNA损伤阻止聚合酶的进展。铁络合剂DFO可防止肝脏铁蓄积、脂质过氧化。酒精处理的TgMnSOD小鼠的蛋白质羰基形成和mtDNA耗竭。酒精显著降低TgMnSOD呼吸链复合体I、IV和V的活性，而对WT小鼠无或影响较小。乙醇处理的WT和TgMnSOD小鼠未见炎症、细胞凋亡或坏死，脂肪变性相似。结论：长期饮酒可选择性地引起TgMnSOD小鼠体内铁蓄积、脂质过氧化、呼吸复合体1蛋白甲基化、线粒体DNA损伤阻碍聚合酶进展、线粒体DNA耗竭和呼吸复合体功能障碍，而在WT小鼠中无此作用。(C)2008 Elsevier Inc.保留所有权利。
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 1 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 1 protein carbonylation, mtDNA lesions blocking the progress of polymerases, mtDNA depletion and respiratory complex dysfunction in TgMnSOD mice but not in WT mice. (C) 2008 Elsevier Inc. All rights reserved.