Modeling selection mechanisms for for quality control of mitochondrial DNA

Mitochondria in each cell have many copies of their own DNA, known as mtDNA, which exhibit high mutation rates. Despite high mutation rates, mtDNA mutation levels remain relatively low, indicating the existence of a quality control process to reduce mutations. While the mechanisms of quality control are unknown, recent experimental work ties the turnover of mitochondria through the mitophagy pathway in germline cells to maintenance of low mtDNA mutation levels and thus to mtDNA quality control. We use theoretical methods to compare experimental data, including generational mutation levels from fruit flies, to predictions from proposed quality control mechanisms. We determine generational mutation levels with replication-based models via solution of a system of coupled differential equations, and for degradation-based models with mean-field statistical mechanics along with experimentally-measured mtDNA distributions among mitochondria. We find that a degradation-based model is the closest match to experimental data. We explore with agent-based simulations how so-called piecemeal mitophagy events can facilitate accelerated selection of mitochondria harboring mutant mtDNA, finding that this mechanism can temporally separate the selection of distinct mitochondrial populations.