How mitochondrial DNA mutations clonally expand in an individual cell is a question that has perplexed mitochondrial biologists for decades. A growing body of literature indicates that mitochondrial DNA mutations play a major role in ageing, metabolic diseases, neurodegenerative diseases, neuromuscular disorders and cancers. Importantly, this process of clonal expansion occurs for both inherited and somatic mitochondrial DNA mutations. To complicate matters further there are fundamental differences between mitochondrial DNA point mutations and deletions, and between mitotic and post-mitotic cells, that impact this pathogenic process. These differences, along with the challenges of investigating a longitudinal process occurring over decades in humans, have so far hindered progress towards understanding clonal expansion. Here we summarize our current understanding of the clonal expansion of mitochondrial DNA mutations in different tissues and highlight key unanswered questions. We then discuss the various existing biological models, along with their advantages and disadvantages. Finally, we explore what has been achieved with mathematical modelling so far and suggest future work to advance this important area of research.

中文翻译：

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线粒体 DNA 突变的不断增加。


线粒体DNA突变如何在单个细胞中克隆扩增是一个困扰线粒体生物学家数十年的问题。越来越多的文献表明，线粒体 DNA 突变在衰老、代谢疾病、神经退行性疾病、神经肌肉疾病和癌症中发挥着重要作用。重要的是，遗传性和体细胞线粒体 DNA 突变都会发生这种克隆扩增过程。使问题进一步复杂化的是，线粒体 DNA 点突变和缺失之间以及有丝分裂细胞和有丝分裂后细胞之间存在根本差异，这些差异影响了这一致病过程。这些差异，以及研究人类数十年来发生的纵向过程的挑战，迄今为止阻碍了理解克隆扩张的进展。在这里，我们总结了目前对不同组织中线粒体 DNA 突变克隆扩增的理解，并强调了尚未解答的关键问题。然后我们讨论各种现有的生物模型及其优点和缺点。最后，我们探讨了迄今为止数学建模所取得的成就，并提出了未来推动这一重要研究领域的工作建议。