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首页> 外文期刊>American Journal of Physiology >Mitochondrial DNA damage triggers mitochondrial-superoxide generation and apoptosis
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Mitochondrial DNA damage triggers mitochondrial-superoxide generation and apoptosis

机译：线粒体DNA损伤触发线粒体超氧化物的产生和凋亡

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First published December 12, 2007; doi:10.1152/ajpcell.00362.2007.-Recently, it has become apparent that mitochondrial DNA (mtDNA) damage can rapidly initiate apoptosis independent of mutations, although the mechanism involved remains unclear. To elucidate this mechanism, angiotensin II-mediated apoptosis was studied in cells that were transduced with a lentiviral vector to overexpress the DNA repair enzyme 8-oxogua-nine glycosylase or were treated with inhibitors known to block angiotensin E-induced mtDNA damage. Cells exhibiting angiotensin II-induced mtDNA damage showed two phases of superoxide generation, the first derived from NAD(P)H oxidase and the second of mitochondrial origin, whereas cells prevented from experiencing mtDNA damage importantly exhibited only the first phase. Furthermore, cells with mtDNA damage demonstrated impairments in mitochondrial protein expression, cellular respiration, and complex 1 activity before the onset of the second phase of oxidation. After the second phase, themitochondrial membrane potential collapsed, cytochrome c was released, and the cells underwent apoptosis, all of which were prevented by disrupting mtDNA damage. Collectively, these data reveal a novel mechanism of apoptosis that is initiated when mtDNA damage triggers mitochondrial superoxide generation and ultimately the activation of the mitochondrial permeability transition. This novel mechanism may play an important pathological role.
机译：首次发布于2007年12月12日; doi：10.1152 / ajpcell.00362.2007.-最近，尽管所涉及的机制仍不清楚，但线粒体DNA（mtDNA）损伤可迅速引发细胞凋亡，而与突变无关。为了阐明该机制，在用慢病毒载体转导以过表达DNA修复酶8-氧瓜氨酸-糖基化酶的细胞中研究了血管紧张素II介导的凋亡，或用已知阻断血管紧张素E引起的mtDNA损伤的抑制剂对其进行了处理。表现出血管紧张素II诱导的mtDNA损伤的细胞表现出两个阶段的超氧化物生成，第一个阶段来自NAD（P）H氧化酶，第二个阶段是线粒体起源，而阻止遭受mtDNA破坏的细胞重要地只显示了第一阶段。此外，在第二阶段氧化开始之前，具有mtDNA损伤的细胞在线粒体蛋白表达，细胞呼吸和复合物1活性方面表现出损伤。第二阶段后，线粒体膜电位崩溃，细胞色素c释放，细胞发生凋亡，所有这些都可以通过破坏mtDNA损伤来预防。总的来说，这些数据揭示了一种新的细胞凋亡机制，该机制在mtDNA损伤触发线粒体超氧化物生成并最终激活线粒体通透性转变时启动。这种新颖的机制可能发挥重要的病理作用。

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