Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India.
Department of Life Sciences, School of Life and Environmental Sciences, University of Lincoln, Lincoln LN6 7TS, United Kingdom.
Biochim Biophys Acta Bioenerg. 2022 Jun 1;1863(5):148554. doi: 10.1016/j.bbabio.2022.148554. Epub 2022 Mar 24.
Mitochondria is a unique cellular organelle involved in multiple cellular processes and is critical for maintaining cellular homeostasis. This semi-autonomous organelle contains its circular genome - mtDNA (mitochondrial DNA), that undergoes continuous cycles of replication and repair to maintain the mitochondrial genome integrity. The majority of the mitochondrial genes, including mitochondrial replisome and repair genes, are nuclear-encoded. Although the repair machinery of mitochondria is quite efficient, the mitochondrial genome is highly susceptible to oxidative damage and other types of exogenous and endogenous agent-induced DNA damage, due to the absence of protective histones and their proximity to the main ROS production sites. Mutations in replication and repair genes of mitochondria can result in mtDNA depletion and deletions subsequently leading to mitochondrial genome instability. The combined action of mutations and deletions can result in compromised mitochondrial genome maintenance and lead to various mitochondrial disorders. Here, we review the mechanism of mitochondrial DNA replication and repair process, key proteins involved, and their altered function in mitochondrial disorders. The focus of this review will be on the key genes of mitochondrial DNA replication and repair machinery and the clinical phenotypes associated with mutations in these genes.
线粒体是一种参与多种细胞过程的独特细胞细胞器，对于维持细胞内环境稳定至关重要。这个半自主细胞器包含其环状基因组 - 线粒体 DNA（mtDNA），它经历连续的复制和修复循环，以维持线粒体基因组的完整性。大多数线粒体基因，包括线粒体复制体和修复基因，都是由核编码的。尽管线粒体的修复机制相当高效，但由于缺乏保护性组蛋白以及它们与主要 ROS 产生位点的接近，线粒体基因组极易受到氧化损伤和其他类型的外源和内源性物质诱导的 DNA 损伤。线粒体复制和修复基因的突变可导致 mtDNA 耗竭，随后导致线粒体基因组不稳定。突变和缺失的综合作用可导致线粒体基因组维持受损，并导致各种线粒体疾病。在这里，我们综述了线粒体 DNA 复制和修复过程的机制、涉及的关键蛋白及其在线粒体疾病中的改变功能。本综述的重点将放在线粒体 DNA 复制和修复机制的关键基因上，以及这些基因的突变与相关临床表型上。
