The rise and rise of mitochondrial DNA mutations

Abstract

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.

Keywords: ageing; clonal expansion; disease; heteroplasmy; mtDNA; mutation.

Figure 1.

Theories of clonal expansion. The mechanism by which clonal expansion happens has been proposed to be explain by a number of possible theories about the mechanism. Random genetic drift suggests the accumulation happens randomly during relaxed mtDNA replication. A replicative advantage suggests that smaller deleted mtDNA genomes are replicated faster and take over the cell. Survival of the sickest suggests that the most dysfunctional mitochondria survive mitophagy due to a reduced production of ROS and therefore accumulate. A negative feedback look suggests a reduction in a mtDNA encoded protein product from a mutated mtDNA molecule drives further transcription and replication. Finally, the perinuclear niche hypothesis suggests a localized upregulation of mitochondrial biogenesis is triggered by mtDNA mutations accumulating adjacent to the myonuclei in muscle fibres.

Figure 2.

Consequences of clonally expanded mitochondrial DNA mutations. Mitochondrial DNA mutations accumulate with age and disease in both mitotic tissues such as the colon, and post-mitotic cells such as muscle fibres and neurons. At low levels the mitochondrial DNA mutation will have little functional impact (COX positive). As the percentage of mitochondrial DNA mutations within a cell accumulate they will exceed a biochemical threshold causing mitochondrial respiratory chain dysfunction (COX deficient). The transition from COX positive to COX deficient is slightly different in different tissues, with the most noticeable differences being that colonic crypts can be partially COX deficient, muscle fibres can have focal deficiency, whereas neurons are more commonly observed to have low deficiency across the full cell body (although it is never possible to view a full neuron). Scale bar, 25 µm. The images were collected from the authors' own research; see ethics statement at end of article for further details.