Parkin overexpression selects against a deleterious mtDNA mutation in heteroplasmic cybrid cells

TLDR

Mitochondrial genomes with deleterious mutations can coexist with wild‑type genomes in heteroplasmy, causing severe inherited syndromes, while the E3 ligase Parkin is known to target depolarized mitochondria for autophagic elimination, hinting at a role in selective removal of defective mitochondria. Long‑term Parkin overexpression in heteroplasmic cybrid cells eliminates COXI‑mutant mitochondria, enriches wild‑type mtDNA, restores cytochrome c oxidase activity, and maintains a favorable genome ratio after withdrawal, supporting Parkin’s mitochondrial quality‑control function and suggesting transient Parkin elevation could ameliorate certain mitochondrial diseases.

Abstract

Mitochondrial genomes with deleterious mutations can replicate in cells along with wild-type genomes in a state of heteroplasmy, and are a cause of severe inherited syndromes, such as mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS), neuropathy, ataxia, retinitis pigmentosa-maternally inherited Leigh syndrome (NARP-MILS), and Leber's hereditary optic neuropathy (LHON). The cytosolic E3 ligase, Parkin, commonly mutated in recessive familial parkinsonism, translocates to depolarized mitochondria and induces their autophagic elimination, suggesting that Parkin may signal the selective removal of defective mitochondria within the cell. We report that long-term overexpression of Parkin can eliminate mitochondria with deleterious COXI mutations in heteroplasmic cybrid cells, thereby enriching cells for wild-type mtDNA and restoring cytochrome c oxidase activity. After relieving cybrid cells of Parkin overexpression, a more favorable wild-type to mutant mitochondrial genome ratio is stably maintained. These data support the model that Parkin functions in a mitochondrial quality control pathway. Additionally, they suggest that transiently increasing levels of Parkin expression might ameliorate certain mitochondrial diseases.