Context-Dependent Role of Mitochondrial Fusion-Fission in Clonal Expansion of mtDNA Mutations

http://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1004183

Zhi Yang Tam, Jan Gruber, Barry Halliwell and Rudiyanto Gunawan

Mitochondria possess quality-control mechanisms, to degrade defective organelles. The authors consider two kinds of quality control: mitophagy, where defective mitochondria are removed from the cell; and fission/fusion, where mitochondrial units leave or join the mitochondrial network. Using computational modelling, the authors consider a cell where mitochondria are allowed to fuse and fisson, and each mitochondrion contains multiple copies of its genome (mtDNA). The mtDNA can either be wild-type (W) or mutant (M).

The effect of increased mutant load per mitochondrion, was modelled to sigmoidally increase its level of defectiveness. The authors show that faster fusion/fission causes clearance of mitochondrial mutation to become faster, when fusion and mitophagy are selective against mutants. However, when mitophagy and fusion are only weakly selective, if mutants have a replicative advantage, then these molecules are able to proliferate faster, as fusion/fission rate increases.

This is supported by findings from a recent study in our group (see here and here), which showed that selective mitochondrial fusion is sufficient to clear mutants, even if mitophagy does not directly target mutant haplotypes (rather, it targets small mitochondria). Increasing fission/fusion rate increases the strength of the effect.