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

Abstract

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 (\(\text {mtDNA}_{del}\)) have a replicative advantage over wild-type (\(\text {mtDNA}_{wild}\)) 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 \(\text {mtDNA}_{del}\) would compete with the \(\text {mtDNA}_{wild}\) 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 \(\text {mtDNA}_{wild}\) compete with \(\text {mtDNA}_{del}\) such that the cell expires upon \(\text {mtDNA}_{wild}\) extinction. We focus on the survival time for long lived post-mitotic cells, such as neurons. We confirm previous observations that \(\text {mtDNA}_{del}\) do have a replicative advantage over \(\text {mtDNA}_{wild}\). 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 \(\text {mtDNA}_{del}\). Given the relevance of mitochondrial dysfunction to various neurodegenerative conditions, we propose that therapies to increase mtDNA half-life could significantly delay their onset.