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

Abstract

In multiple species, certain tissue types are prone to acquiring greater loads of mitochondrial genome (mtDNA) mutations relative to others, however the mechanisms that drive these heteroplasmy differences are unknown. We found that the conserved PTEN-induced putative kinase (PINK1/PINK-1) and the E3 ubiquitin-protein ligase parkin (PDR-1), which are required for mitochondrial autophagy (mitophagy), underlie stereotyped differences in heteroplasmy of a deleterious mitochondrial genome mutation ({Delta}mtDNA) between major somatic tissues types in Caenorhabditis elegans. We demonstrate that tissues prone to accumulating {Delta}mtDNA have lower mitophagy responses than those with low mutation levels, such as neurons. Moreover, we show that {Delta}mtDNA heteroplasmy increases when proteotoxic species that are associated with neurodegenerative disease and mitophagy inhibition are overexpressed in the nervous system. Together, these results suggest that PINK1 and parkin drive organism-wide patterns of heteroplasmy and provide evidence of a causal link between proteotoxicity, mitophagy, and mtDNA mutation levels in neurons.