Mitochondrial replacement therapy: are mito-nuclear interactions likely to be a problem?

It has been suggested that deleterious interactions between the mitochondrial and nuclear genomes could pose a problem for mitochondrial replacement therapy (MRT). This is because the mitochondrial genome is placed in a novel nuclear environment using this technique. In contrast, it is inherited with half the mother’s genome during normal reproduction, a genome which it is relatively compatible with, since the mother is alive. Here I review the evidence of whether mito-nuclear interactions are likely to pose a problem for MRT. The majority of experimental evidence, both in humans and other species suggests that MRT is not harmful. These results are consistent with population genetic theory which predicts that deleterious mito-nuclear interactions are unlikely to be much more prevalent in individuals born to MRT than normal reproduction, particularly in a species such as humans with low population differentiation. This is because selection is unlikely to be strong enough to establish significant linkage disequilibrium between the mitochondrial and nuclear genomes. These results are supported by a meta- analysis of 231 cases, from a variety of animals, in which the mtDNA from one strain has been introgressed into the nuclear background of another strain of the same species. Overall, there is little tendency for introgression of mtDNA to be harmful.