Mitochondrial depolarization in yeast zygotes inhibits clonal expansion of selfish mtDNA

Abstract

Non-identical copies of mitochondrial DNA (mtDNA) compete with each other within a cell and the result depends on their replication rates. Using yeast Saccharomyces cerevisiae cells as a model, we studied the effects of mitochondrial inhibitors on the competition between wild type mtDNA and mutant selfish mtDNA in heteroplasmic zygotes. We found that decreasing mitochondrial transmembrane potential by adding uncouplers or valinomycin changes the competition outcomes in favor of the wild type mtDNA. This effect was significantly lower in the cells with disrupted mitochondria fission or repressed autophagy-related genes ATG8, ATG32 or ATG33 implying that heteroplasmic zygotes activate mitochondrial degradation in response to the depolarization. Moreover, the rate of mitochondrially-targeted GFP turnover was higher in zygotes treated with FCCP than in haploid cells or untreated zygotes. Finally, we showed that vacuoles of the zygotes with uncoupler-activated autophagy contained DNA. Together, our data demonstrate that mitochondrial depolarization inhibits clonal expansion of selfish mtDNA and this effect depends on mitochondrial fission and autophagy. These observations suggest an activation of mitochondria quality control mechanisms in heteroplasmic yeast zygotes.