The rise and rise of mitochondrial DNA mutations

• Main Authors: Conor Lawless, Laura Greaves, Amy K. Reeve, Doug M. Turnbull, Amy E. Vincent
• Format: Article
• Language: English
• Published: The Royal Society 2020-05-01
• Series: Open Biology
• Subjects: clonal expansion; mtdna; ageing; disease; mutation; heteroplasmy
• Online Access: https://royalsocietypublishing.org/doi/pdf/10.1098/rsob.200061

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.