Most of the genetic information has been lost or transferred to the nucleus during the evolution of mitochondria. Neverthelss, mitochondria have retained their own genome that is essential for oxidative phosphorylation (OXPHOS). In mammals, a gene-dense circular mitochondrial DNA (mtDNA) of about 16.5kb encodes 13 proteins, which constitute only 1% of the mitochondrial proteome. Mammalian mtDNA is present in thousands of copies per cell and mutations often affect only a fraction of them. Most pathogenic human mtDNA mutations are recessive and only cause OXPHOS defects if present above a certain critical threshold. However, emerging evidence strongly suggests that the proportion of mutated mtDNA copies is not the only determinant of disease but that also the absolute copy number matters. In this review, we critically discuss current knowledge of the role of mtDNA copy number regulation in various types of human diseases, including mitochondrial disorders, neurodegenerative disorders, and cancer, and during ageing. We also provide an overview of new exciting therapeutic strategies to directly manipulate mtDNA to restore OXPHOS in mitochondrial diseases.

中文翻译：

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人类疾病中的线粒体DNA拷贝数：越多越好？

大多数遗传信息在线粒体进化过程中已经丢失或转移到细胞核中。尽管如此，线粒体保留了自己的基因组，这对氧化磷酸化 (OXPHOS) 至关重要。在哺乳动物中，约 16.5kb 的基因密集环状线粒体 DNA (mtDNA) 编码 13 种蛋白质，仅占线粒体蛋白质组的 1%。哺乳动物 mtDNA 在每个细胞中存在数千个拷贝，而突变通常只影响其中的一小部分。大多数致病性人类 mtDNA 突变是隐性的，只有在高于某个临界阈值时才会导致 OXPHOS 缺陷。然而，新出现的证据强烈表明，突变 mtDNA 拷贝的比例并不是疾病的唯一决定因素，绝对拷贝数也很重要。在这次审查中，我们批判性地讨论了当前关于 mtDNA 拷贝数调节在各种类型的人类疾病中的作用的知识，包括线粒体疾病、神经退行性疾病和癌症，以及在衰老过程中。我们还概述了直接操纵 mtDNA 以恢复线粒体疾病中的 OXPHOS 的新的令人兴奋的治疗策略。