Bryan L. Gitschlag, Cait S. Kirby, David C. Samuels, Rama D. Gangula, Simon A. Mallal, Maulik R. Patel
Why haven't deleterious mutations in mitochondrial DNA gone extinct? Naively, if a mutation has a negative impact on the fitness of an organism, then that organism may be less likely to reproduce and, in time, we expect to see fewer organisms with the mutation in nature. And yet deleterious mutations in mtDNA are still seen and passed down from generation to generation (albeit that this is often through carriers who bear such mutations at lower loads).
The authors of this study explore this simple, but fundamental, question by establishing a slightly deleterious mtDNA variant in C. elegans, called uaDF5. This is a deletion mutation which removes four protein-coding genes and seven tRNAs. The authors show that worms are still viable with a mutant load as high as 80% (but lethal at 100%), and that mtDNA copy number tended to increase in individuals with large mutant load (suggesting expansion of the total mtDNA population so that there are enough wild-type mtDNA molecules to fulfil the metabolic needs of the animal). The authors also determined that it is unlikely that the mutation has a proliferative advantage by virtue of its smaller size, through comparison with another deletion mutant which was much smaller.
In addition to mtDNA copy number control, the authors suggest an additional mechanism whereby mutant mtDNAs may proliferate. The authors find that silencing of the mitochondrial unfolded protein response (mt-UPR) causes a substantial reduction in mutant load. The mt-UPR is thought to provide a protective role against adverse conditions for mitochondria; the authors suggest here that the process inadvertently allows mutants to proliferate as it suppresses mitophagy: the mechanism by which faulty mitochondria are recycled by the cell. They show this by blocking mt-UPR and parkin-mediated mitophagy to show a recovery in mutant load.
Thoughts: A natural question to ask is, given that these heteroplasmic animals are less fit, why do cells not have a larger mitophagy rate if this allows quality control? Is there some tradeoff where wild-type mtDNAs are also consumed? Perhaps with a lower probability?