The Effect of Mitochondrial DNA Half-Life on Deletion Mutation Proliferation in Long Lived Cells

The proliferation of mitochondrial DNA (mtDNA) with deletion mutations has been linked to aging and age related neurodegenerative conditions. In this study we model the effect of mtDNA half-life on mtDNA competition and selection. It has been proposed that mutation deletions ([Formula: see text]) have a replicative advantage over wild-type ([Formula: see text]) and that this is detrimental to the host cell, especially in post-mitotic cells. An individual cell can be viewed as forming a closed ecosystem containing a large population of independently replicating mtDNA. Within this enclosed environment a selfishly replicating [Formula: see text] would compete with the [Formula: see text] for space and resources to the detriment of the host cell. In this paper, we use a computer simulation to model cell survival in an environment where [Formula: see text] compete with [Formula: see text] such that the cell expires upon [Formula: see text] extinction. We focus on the survival time for long lived post-mitotic cells, such as neurons. We confirm previous observations that [Formula: see text] do have a replicative advantage over [Formula: see text]. As expected, cell survival times diminished with increased mutation probabilities, however, the relationship between survival time and mutation rate was non-linear, that is, a ten-fold increase in mutation probability only halved the survival time. The results of our model also showed that a modest increase in half-life had a profound affect on extending cell survival time, thereby, mitigating the replicative advantage of [Formula: see text]. Given the relevance of mitochondrial dysfunction to various neurodegenerative conditions, we propose that therapies to increase mtDNA half-life could significantly delay their onset.