Mechanisms linking mtDNA damage and aging.
Mechanisms linking mtDNA damage and aging.
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DOI：
10.1016/j.freeradbiomed.2015.05.005
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发表时间：
2015-08
影响因子：
7.4
通讯作者：
Moraes CT
中科院分区：
文献类型：
--
作者：
Pinto M;Moraes CT
在上个世纪，人们做了大量的努力来了解线粒体DNA突变和氧化应激在衰老中的作用。经典的线粒体自由基衰老理论，其中mtDNA突变引起遗传毒性氧化应激，这反过来又产生更多的突变，几十年来一直是该领域的核心假设。然而，在过去的几年里，新的因素使这一原始理论失去了可信度。线粒体DNA突变的主要来源似乎来自复制错误和修复机制的失败，并且在衰老生物体中观察到的这些突变的积累似乎是通过克隆扩张发生的，而不是由活性氧依赖的恶性循环引起的。关于与年龄相关的线粒体功能障碍如何导致衰老的新假设是基于活性氧作为信号分子的作用以及它们在介导对年龄相关性损伤的应激反应中的作用。在这里，我们回顾了mtDNA在衰老过程中发生的变化，以及过去和最近将这些变化与衰老中观察到的组织衰竭联系起来的假设。
In the last century, considerable efforts were made to understand the role of mtDNA mutations and of oxidative stress in aging. The classic mitochondrial free radical theory of aging, in which mtDNA mutations cause genotoxic oxidative stress, which in turn creates more mutations, has been a central hypothesis in the field for decades. In the last few years, however, new elements have discredited this original theory. The major source of mitochondrial DNA mutations seems to come from replication errors and failure of the repair mechanisms, and the accumulation of these mutations as observed in aged organisms appears to occur by clonal expansion and are not caused by a reactive oxygen species-dependent vicious cycle. New hypotheses of how age-associated mitochondrial dysfunction may lead to aging are based on the role of reactive oxygen species as signaling molecules and on their role in mediating stress responses to age-dependent damage. Here, we review the changes that mtDNA undergoes during aging, and the past and most recent hypotheses linking these changes to the tissue failure observed in aging.