Formerly: Solent University Southampton, East Park Terrace, Southampton, SO14 0YN, UK.
School of Natural and Social Sciences, University of Gloucestershire, Francis Close Hall, Swindon Road, Cheltenham GL50 4AZ, UK.
Biosci Rep. 2021 Oct 29;41(10). doi: 10.1042/BSR20211320.
Mitochondria are highly specialised organelles required for key cellular processes including ATP production through cellular respiration and controlling cell death via apoptosis. Unlike other organelles, mitochondria contain their own DNA genome which encodes both protein and RNA required for cellular respiration. Each cell may contain hundreds to thousands of copies of the mitochondrial genome, which is essential for normal cellular function - deviation of mitochondrial DNA (mtDNA) copy number is associated with cellular ageing and disease. Furthermore, mtDNA lesions can arise from both endogenous or exogenous sources and must either be tolerated or corrected to preserve mitochondrial function. Importantly, replication of damaged mtDNA can lead to stalling and introduction of mutations or genetic loss, mitochondria have adapted mechanisms to repair damaged DNA. These mechanisms rely on nuclear-encoded DNA repair proteins that are translocated into the mitochondria. Despite the presence of many known nuclear DNA repair proteins being found in the mitochondrial proteome, it remains to be established which DNA repair mechanisms are functional in mammalian mitochondria. Here, we summarise the existing and emerging research, alongside examining proteomic evidence, demonstrating that mtDNA damage can be repaired using Base Excision Repair (BER), Homologous Recombination (HR) and Microhomology-mediated End Joining (MMEJ). Critically, these repair mechanisms do not operate in isolation and evidence for interplay between pathways and repair associated with replication is discussed. Importantly, characterising non-canonical functions of key proteins and understanding the bespoke pathways used to tolerate, repair or bypass DNA damage will be fundamental in fully understanding the causes of mitochondrial genome mutations and mitochondrial dysfunction.
线粒体是高度专业化的细胞器，对于包括通过细胞呼吸产生 ATP 和通过细胞凋亡控制细胞死亡等关键细胞过程是必需的。与其他细胞器不同，线粒体含有自己的 DNA 基因组，该基因组编码细胞呼吸所需的蛋白质和 RNA。每个细胞可能包含数百到数千个线粒体基因组的副本，这对于正常的细胞功能是必不可少的——线粒体 DNA（mtDNA）拷贝数的偏差与细胞衰老和疾病有关。此外，mtDNA 损伤既可以源自内源性来源，也可以源自外源性来源，必须通过容忍或纠正来维持线粒体功能。重要的是，受损 mtDNA 的复制会导致停滞和突变或遗传损失的引入，线粒体已经适应了修复受损 DNA 的机制。这些机制依赖于核编码的 DNA 修复蛋白，这些蛋白被转运到线粒体中。尽管在线粒体蛋白质组中发现了许多已知的核 DNA 修复蛋白，但仍需要确定哪些 DNA 修复机制在哺乳动物线粒体中是功能性的。在这里，我们总结了现有的和新兴的研究，同时检查蛋白质组学证据，表明 mtDNA 损伤可以使用碱基切除修复（BER）、同源重组（HR）和微同源介导的末端连接（MMEJ）进行修复。至关重要的是，这些修复机制不是孤立运作的，并且讨论了与复制相关的途径和修复之间的相互作用的证据。重要的是，表征关键蛋白的非典型功能并理解用于容忍、修复或绕过 DNA 损伤的定制途径对于全面了解线粒体基因组突变和线粒体功能障碍的原因将是至关重要的。
