Contribution of mitochondrial DNA repair to cell resistance from oxidative stress
Contribution of mitochondrial DNA repair to cell resistance from oxidative stress
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DOI：
10.1074/jbc.m413022200
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发表时间：
2005-03-11
影响因子：
4.8
通讯作者：
LeDoux, SP
中科院分区：
文献类型：
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作者：
Grishko, VI;Rachek, LI;LeDoux, SP
许多研究表明，细胞对慢性氧化应激反应的一部分涉及增加抗氧化能力。然而，另一种受到较少关注的防御机制是DNA修复。由于线粒体的重要稳态作用和线粒体DNA（mtDNA）对氧化损伤的敏感性，我们假设mtDNA修复在抗氧化应激中起着重要作用。为了验证这一假设，在正常的HA 1中国仓鼠成纤维细胞和抗氧化应激的变异体慢性暴露于H2 O2或95%O-2后分离的mtDNA损伤和修复进行了评价。利用黄嘌呤氧化酶和次黄嘌呤酶促产生活性氧。当用黄嘌呤氧化酶处理时，相对于亲本细胞系，在来自抗氧化应激变体的细胞中观察到初始mtDNA损伤水平降低和mtDNA修复增强。这种增强的mtDNA修复与线粒体脱嘌呤/脱嘧啶核酸内切酶活性的增加在H2 O2和O-2抗性HA 1变体。这是第一个报告显示增强mtDNA修复细胞对慢性氧化应激的反应。这些结果为mtDNA修复途径在保护细胞免受活性氧的有害影响方面发挥的关键作用提供了进一步的证据。
Numerous studies have revealed that a part of the cellular response to chronic oxidative stress involves increased antioxidant capacity. However, another defense mechanism that has received less attention is DNA repair. Because of the important homeostatic role of mitochondria and the exquisite sensitivity of mitochondrial DNA (mtDNA) to oxidative damage, we hypothesized that mtDNA repair plays an important role in the protection against oxidative stress. To test this hypothesis mtDNA damage and repair was evaluated in normal HA1 Chinese hamster fibroblasts and oxidative stress-resistant variants isolated following chronic exposure to H2O2 or 95% O-2. Reactive oxygen species were generated enzymatically using xanthine oxidase and hypoxanthine. When treated with xanthine oxidase reduced levels of initial mtDNA damage and enhanced mtDNA repair were observed in the cells from the oxidative stress-resistant variants, relative to the parental cell line. This enhanced mtDNA repair correlated with an increase in mitochondrial apurinic/apyrimidinic endonuclease activity in both H2O2- and O-2-resistant HA1 variants. This is the first report showing enhanced mtDNA repair in the cellular response to chronic oxidative stress. These results provide further evidence for the crucial role that mtDNA repair pathways play in protecting cells against the deleterious effects of reactive oxygen species.