PINK1-parkin-mediated mitophagy generates somatic mosaicism of the mitochondrial genome

Abstract The composition of the mitochondrial DNA (mtDNA) in each cell is in constant flux through processes of mutation, replication, and degradation. In multiple species, certain tissues consistently harbour greater loads of mtDNA mutations relative to others. However, the mechanisms that drive this stereotyped distribution of mtDNA mutations within individuals are unknown. Using C. elegans as a model system, we found that mitochondrial autophagy (mitophagy), mediated through the conserved PTEN-induced putative kinase (PINK1) and the E3 ubiquitin-protein ligase parkin, selectively removes mtDNA mutations from specific tissue types. Moreover, neurons in particular were prone to accumulating mtDNA mutations when mitophagy was perturbed genetically, or through the ectopic expression of proteotoxic species that are associated with neurodegenerative diseases. These results suggest that mitophagy deterministically drives differences in heteroplasmy between tissues, and points at the existence of a causal link between proteotoxicity, mitophagy, and mtDNA mutation levels in neurons.