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首页> 外文期刊>Molecular and Cellular Biology >Mitochondrial Dysfunction Due to Oxidative Mitochondrial DNA Damage Is Reduced through Cooperative Actions of Diverse Proteins
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Mitochondrial Dysfunction Due to Oxidative Mitochondrial DNA Damage Is Reduced through Cooperative Actions of Diverse Proteins

机译：氧化性线粒体DNA损伤导致的线粒体功能障碍通过多种蛋白质的协同作用而减少

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The mitochondrial genome is a significant target of exogenous and endogenous genotoxic agents; however, the determinants that govern this susceptibility and the pathways available to resist mitochondrial DNA (mtDNA) damage are not well characterized. Here we report that oxidative mtDNA damage is elevated in strains lacking Ntg1p, providing the first direct functional evidence that this mitochondrion-localized, base excision repair enzyme functions to protect mtDNA. However, ntg1 null strains did not exhibit a mitochondrial respiration-deficient (petite) phenotype, suggesting that mtDNA damage is negotiated by the cooperative actions of multiple damage resistance pathways. Null mutations in ABF2 or PIF1, two genes implicated in mtDNA maintenance and recombination, exhibit a synthetic-petite phenotype in combination with ntg1 null mutations that is accompanied by enhanced mtDNA point mutagenesis in the corresponding double-mutant strains. This phenotype was partially rescued by malonic acid, indicating that reactive oxygen species generated by the electron transport chain contribute to mitochondrial dysfunction in abf2Δ strains. In contrast, when two other genes involved in mtDNA recombination, CCE1 and NUC1, were inactivated a strong synthetic-petite phenotype was not observed, suggesting that the effects mediated by Abf2p and Pif1p are due to novel activities of these proteins other than recombination. These results document the existence of recombination-independent mechanisms in addition to base excision repair to cope with oxidative mtDNA damage in Saccharomyces cerevisiae. Such systems are likely relevant to those operating in human cells where mtDNA recombination is less prevalent, validating yeast as a model system in which to study these important issues.
机译：线粒体基因组是外源和内源遗传毒性剂的重要靶点。然而，决定这种敏感性的决定因素和抵抗线粒体DNA（mtDNA）损伤的途径尚不清楚。在这里，我们报告说，缺乏Ntg1p的菌株中mtDNA的氧化损伤增加，提供了第一个直接的功能证据，表明这种线粒体定位的碱基切除修复酶具有保护mtDNA的功能。然而， ntg1 无效菌株没有表现出线粒体呼吸缺陷（娇小）表型，这表明mtDNA损伤是通过多种抗药性途径的协同作用来协商的。与mtDNA维持和重组有关的两个基因 ABF2 或 PIF1 中的空突变，与 ntg1 空突变结合在一起，表现出合成的小表型在相应的双突变株中伴随着增强的mtDNA点诱变。该表型被丙二酸部分挽救，表明由电子传输链产生的活性氧导致abf2Δ菌株的线粒体功能障碍。相反，当其他两个参与mtDNA重组的基因 CCE1 和 NUC1 失活时，未观察到强烈的合成小表型，表明由Abf2p和Pif1p是由于这些蛋白质的新活性而不是重组引起的。这些结果证明了除碱基切除修复以外还存在重组独立机制，以应对啤酒酵母中的线粒体DNA氧化损伤。此类系统可能与在mtDNA重组不那么普遍的人细胞中运行的系统有关，从而验证了酵母是研究这些重要问题的模型系统。

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