What cost mitochondria? The maintenance of functional mitochondrial DNA within and across generations

Abstract

The peculiar biology of mitochondrial DNA (mtDNA) potentially has detrimental consequences for organismal health and lifespan. Typically, eukaryotic cells contain multiple mitochondria, each with multiple mtDNA genomes. The high copy number of mtDNA implies that selection on mtDNA functionality is relaxed. Furthermore, because mtDNA replication is not strictly regulated, within-cell selection may favour mtDNA variants with a replication advantage, but a deleterious effect on cell fitness. The opportunities for selfish mtDNA mutations to spread are restricted by various organism-level adaptations, such as uniparental transmission, germline mtDNA bottlenecks, germline selection and, during somatic growth, regular alternation between fusion and fission of mitochondria. These mechanisms are all hypothesized to maintain functional mtDNA. However, the strength of selection for maintenance of functional mtDNA progressively declines with age, resulting in age-related diseases. Furthermore, organismal adaptations that most probably evolved to restrict the opportunities for selfish mtDNA create secondary problems. Owing to predominantly maternal mtDNA transmission, recombination among mtDNA from different individuals is highly restricted or absent, reducing the scope for repair. Moreover, maternal inheritance precludes selection against mtDNA variants with male-specific effects. We finish by discussing the consequences of life-history differences among taxa with respect to mtDNA evolution and make a case for the use of microorganisms to experimentally manipulate levels of selection.

Keywords: evolution; genetic conflict; mitochondria; mitochondrial DNA; mitochondrial disease.

Figure 1.

Levels of selection affecting mitochondrial evolution. (a) In the vast majority of sexually reproducing eukaryotes, mtDNA is inherited uniparentally, usually maternally. (b) Selection on mtDNA acts on two time scales: among generations, when mtDNA mutations in the germline are passed on to offspring, and within an individual, when mtDNA mutations accumulate during somatic growth. Thus, natural selection acts on mtDNA at four levels of selection: among individuals, among cells, among mitochondria within cells and among mtDNAs within mitochondria.