Mitochondrial DNA mutations may contribute to aging via cell death caused by peptides that induce cytochrome c release
Mitochondrial DNA mutations may contribute to aging via cell death caused by peptides that induce cytochrome c release
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DOI：
10.1089/rej.2007.0617
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发表时间：
2008-06-01
影响因子：
2.6
通讯作者：
Zassenhaus, H. Peter
中科院分区：
文献类型：
--
作者：
Dubec, Steven J.;Aurora, Rajeev;Zassenhaus, H. Peter
野生型线粒体 DNA 聚合酶 (pol gamma) 被校对缺陷版本取代的小鼠出生时线粒体 DNA (mtDNA) 的突变频率比老年啮齿动物或人类中通常看到的要高得多。然而，这些小鼠在出生时表型正常，这就提出了一个问题：正常衰老过程中观察到的低得多的频率如何可能导致衰老过程。相比之下，心脏特异性表达校对缺陷多聚伽玛的转基因小鼠从出生起就会积累线粒体DNA突变，达到衰老过程中通常出现的水平。但这些小鼠患上扩张型心肌病，表明与年龄相关的 mtDNA 突变具有致病性。通过计算机模拟，我们表明这两项发现都是基于以下假设预测的：（1）导致细胞凋亡的罕见致死突变是 mtDNA 突变的发病机制的基础；（2）大多数散发的 mtDNA 突变是表型隐性的，因此是非致病性的。生化证据表明，线粒体 DNA 突变的线粒体会产生一种肽，导致细胞色素 c 的释放，为衰老过程中观察到的细胞凋亡增加提供了机制。模拟还预测，正常的、与年龄相关的 mtDNA 突变积累会导致大量细胞死亡。这些发现表明线粒体DNA突变在衰老过程中发挥着重要作用，其致病机制与细胞凋亡有关。
Mice wherein the wild-type mitochondrial DNA polymerase (pol gamma) is replaced by a proofreading-deficient version are born with mutation frequencies in mitochondrial DNA (mtDNA) much higher than are ever normally seen in old rodents or humans. These mice, however, are phenotypically normal at birth, raising the question regarding how the much lower frequencies observed in normal aging could possibly contribute to the aging process. In contrast, transgenic mice with cardiac-specific expression of a proofreading-deficient poly gamma from birth onwards accumulate mtDNA mutations to levels normally seen in aging. But these mice develop dilated cardiomyopathy suggesting that age-related mtDNA mutations are pathogenic. Using computer simulation, we show that both findings are predicted based on the hypotheses that (1) rare lethal mutations that cause apoptosis underlie the pathogenesis of mutagenesis in mtDNA and (2) most sporadic mtDNA mutations are phenotypically recessive and therefore nonpathogenic. Biochemical evidence is presented that mitochondria with mtDNA mutations generate a peptide that causes the release of cytochrome c, providing a mechanism for the increased apoptosis observed in aging. Simulation also predicts that normal, age-related accumulation of mtDNA mutations causes significant levels of cell death. These findings suggest that mtDNA mutations play an important role in the aging process and that their pathogenic mechanism is linked to apoptosis.