title: Parkin overexpression selects against a deleterious mtDNA mutation in heteroplasmic cybrid cells.
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.
authors.affiliation: Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Der-Fen
authors.initials: DF
authors.lastname: Suen
authors.forename: Derek P
authors.initials: DP
authors.lastname: Narendra
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tanaka
authors.forename: Giovanni
authors.initials: G
authors.lastname: Manfredi
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Youle
mesh_terms: D002460:Cell Line; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D006822:Hybrid Cells; D008561:Membrane Fusion; D008928:Mitochondria / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D025261:Mitochondrial Proton-Translocating ATPases / Q000037:antagonists & inhibitors; D008954:Models, Biological; D009154:Mutation; D021381:Protein Transport; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism*
chemical_list: D004272:DNA, Mitochondrial; D011993:Recombinant Fusion Proteins; D003576:Electron Transport Complex IV; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D025261:Mitochondrial Proton-Translocating ATPases