线粒体DNA复制机制在线粒体DNA诱变、衰老及衰老相关疾病中的作用。
Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases.
作者信息
DeBalsi Karen L, Hoff Kirsten E, Copeland William C
机构信息
Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
出版信息
Ageing Res Rev. 2017 Jan;33:89-104. doi: 10.1016/j.arr.2016.04.006. Epub 2016 Apr 30.
As regulators of bioenergetics in the cell and the primary source of endogenous reactive oxygen species (ROS), dysfunctional mitochondria have been implicated for decades in the process of aging and age-related diseases. Mitochondrial DNA (mtDNA) is replicated and repaired by nuclear-encoded mtDNA polymerase γ (Pol γ) and several other associated proteins, which compose the mtDNA replication machinery. Here, we review evidence that errors caused by this replication machinery and failure to repair these mtDNA errors results in mtDNA mutations. Clonal expansion of mtDNA mutations results in mitochondrial dysfunction, such as decreased electron transport chain (ETC) enzyme activity and impaired cellular respiration. We address the literature that mitochondrial dysfunction, in conjunction with altered mitochondrial dynamics, is a major driving force behind aging and age-related diseases. Additionally, interventions to improve mitochondrial function and attenuate the symptoms of aging are examined.
作为细胞生物能量学的调节因子和内源性活性氧（ROS）的主要来源，功能失调的线粒体数十年来一直被认为与衰老及年龄相关疾病的发生过程有关。线粒体DNA（mtDNA）由核编码的mtDNA聚合酶γ（Pol γ）和其他几种相关蛋白进行复制和修复，这些蛋白共同构成了mtDNA复制机制。在此，我们综述了相关证据，即这种复制机制所导致的错误以及未能修复这些mtDNA错误会引发mtDNA突变。mtDNA突变的克隆性扩增会导致线粒体功能障碍，如电子传递链（ETC）酶活性降低和细胞呼吸受损。我们探讨了相关文献，这些文献表明线粒体功能障碍与线粒体动力学改变共同作用，是衰老和年龄相关疾病背后的主要驱动力。此外，还研究了改善线粒体功能和减轻衰老症状的干预措施。
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