Mitigating Mutational Meltdown in Mammalian Mitochondria

M itochondria are remarkable microorganisms. About two billion years ago, their distant free-living ancestors hooked up with a truly foreign lineage of archaebacteria and started a genomic merger that led to the most successful coevolved mutualism on the planet: the eukaryotic cell. Along the way, evolving mitochondria lost a lot of genomic baggage, entrusted their emerging hosts with their own replication, sorted out genomic conflicts by following maternal inheritance, and have mostly abstained from sex and recombination. What mitochondria did retain was a subset of genes that encode critical components of the electron transport chain and ATP synthesis enzymes that carry out oxidative phosphorylation. Because mitochondria house the biochemical machinery that requires us to breathe oxygen, it was first assumed that mitochondrial genes would show very slow rates of molecular evolution. So it was big news almost 30 years ago when mitochondrial DNA (mtDNA) evolution was observed to be quite rapid [1]. How could the genes for a highly conserved and critical function sustain the consequences of high mutation pressure and permit rapid rates of nucleotide substitution between species? Without the benefits of recombination, where offspring can carry fewer mutations than either parent, mutations should accumulate in mitochondrial genomes through the random loss of less-mutated genomes, a process referred to as Muller's ratchet [2,3]. How have mitochondria avoided a mutational meltdown, or at least significant declines in fitness? In many ways, these questions were set aside by researchers to capitalize on the tremendous opportunity that a rapidly evolving, nonrecombining, maternally inherited, easily sequenced set of homologous genes could provide: a window into the evolutionary history of populations and closely related species [4]. Indeed, mtDNA is still the first marker of choice for evolutionary analysis. It has played a major role in uncovering the evolutionary histories of a wide diversity of organisms, most notably our own origin and evolution from African roots [5,6]. The high rate of mtDNA evolution may have led to the assumption that most mtDNA mutations are essentially neutral and not subject to the effects of natural selection. But in recent years, there has been great interest in returning to the question of how mitochondria sustain themselves in the face of high mutation pressure and critically examining the evidence for the variety of ways that natural selection can shape the evolution of mtDNA [7–9]. It is now clear that mitochondrial mutations are a significant factor in many mitochondrial …