Human mitochondria possess a multi-copy circular genome, mitochondrial DNA (mtDNA), that is essential for cellular energy metabolism. The number of copies of mtDNA per cell, and their integrity, are maintained by nuclear-encoded mtDNA replication and repair machineries. Aberrant mtDNA replication and mtDNA breakage are believed to cause deletions within mtDNA. The genomic location and breakpoint sequences of these deletions show similar patterns across various inherited and acquired diseases, and are also observed during normal ageing, suggesting a common mechanism of deletion formation. However, an ongoing debate over the mechanism by which mtDNA replicates has made it difficult to develop clear and testable models for how mtDNA rearrangements arise and propagate at a molecular and cellular level. These deletions may impair energy metabolism if present in a high proportion of the mtDNA copies within the cell, and can be seen in primary mitochondrial diseases, either in sporadic cases or caused by autosomal variants in nuclear-encoded mtDNA maintenance genes. These mitochondrial diseases have diverse genetic causes and multiple modes of inheritance, and show notoriously broad clinical heterogeneity with complex tissue specificities, which further makes establishing genotype-phenotype relationships challenging. In this review, we aim to cover our current understanding of how the human mitochondrial genome is replicated, the mechanisms by which mtDNA replication and repair can lead to mtDNA instability in the form of large-scale rearrangements, how rearranged mtDNAs subsequently accumulate within cells, and the pathological consequences when this occurs.

中文翻译：

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人类线粒体DNA复制和缺失形成的机制和病理学


人类线粒体拥有多拷贝环状基因组，即线粒体 DNA (mtDNA)，它对于细胞能量代谢至关重要。每个细胞的线粒体 DNA 拷贝数及其完整性由核编码的线粒体 DNA 复制和修复机制维持。异常的 mtDNA 复制和 mtDNA 断裂被认为会导致 mtDNA 内的缺失。这些缺失的基因组位置和断点序列在各种遗传性和获得性疾病中显示出相似的模式，并且也在正常衰老过程中观察到，这表明缺失形成的共同机制。然而，关于 mtDNA 复制机制的持续争论使得开发清晰且可测试的模型来解释 mtDNA 重排如何在分子和细胞水平上产生和传播变得困难。如果细胞内 mtDNA 拷贝的高比例存在，这些缺失可能会损害能量代谢，并且可以在原发性线粒体疾病中看到，无论是散发病例还是由核编码 mtDNA 维持基因的常染色体变异引起。这些线粒体疾病具有不同的遗传原因和多种遗传模式，并且表现出众所周知的广泛的临床异质性和复杂的组织特异性，这进一步使得建立基因型-表型关系具有挑战性。在这篇综述中，我们的目标是涵盖我们目前对人类线粒体基因组如何复制的理解，mtDNA复制和修复可能导致大规模重排形式的mtDNA不稳定的机制，重排的mtDNA随后如何在细胞内积累，以及发生这种情况时的病理后果。