title: Genome-wide RNAi screen identifies ATPase inhibitory factor 1 (ATPIF1) as essential for PARK2 recruitment and mitophagy.
abstract: Mitochondrial dysfunction is a hallmark of aging and numerous human diseases, including Parkinson disease (PD). Multiple homeostatic mechanisms exist to ensure mitochondrial integrity, including the selective autophagic program mitophagy, that is activated during starvation or in response to mitochondrial dysfunction. Following prolonged loss of potential across the inner mitochondrial membrane (ΔΨ), PTEN-induced putative kinase 1 (PINK1) and the E3-ubiquitin ligase PARK2 work in the same pathway to trigger mitophagy of dysfunctional mitochondria. Mutations in PINK1 and PARK2, as well as PARK7/DJ-1, underlie autosomal recessive Parkinsonism and impair mitochondrial function and morphology. In a genome-wide RNAi screen searching for genes that are required for PARK2 translocation to the mitochondria, we identified ATPase inhibitory factor 1 (ATPIF1/IF1) as essential for PARK2 recruitment and mitophagy in cultured cells. During uncoupling, ATPIF1 promotes collapse of ΔΨ and activation of the PINK-PARK2 mitophagy pathway by blocking the ATPase activity of the F 1-Fo ATP synthase. Restoration of ATPIF1 in Rho0 cells, which lack mtDNA and a functional electron transport chain, lowers ΔΨ and triggers PARK2 recruitment. Our findings identified ATPIF1 and the ATP synthase as novel components of the PINK1-PARK2 mitophagy pathway and provide genetic evidence that loss of ΔΨ is an essential trigger for mitophagy.
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute; Ottawa, ON Canada; Department of Cellular and Molecular Medicine; University of Ottawa; Ottawa, ON Canada.
authors.forename: Valerie
authors.initials: V
authors.lastname: Lefebvre
authors.forename: Qiujiang
authors.initials: Q
authors.lastname: Du
authors.forename: Stephen
authors.initials: S
authors.lastname: Baird
authors.forename: Andy Cheuk-Him
authors.initials: AC
authors.lastname: Ng
authors.forename: Mirna
authors.initials: M
authors.lastname: Nascimento
authors.forename: Michelangelo
authors.initials: M
authors.lastname: Campanella
authors.forename: Heidi M
authors.initials: HM
authors.lastname: McBride
authors.forename: Robert A
authors.initials: RA
authors.lastname: Screaton
mesh_terms: D004579:Electron Transport; D015894:Genome, Human; D006367:HeLa Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D063306:Mitophagy; D011506:Proteins / Q000378:metabolism*; D034622:RNA Interference; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D000097795:ATPase Inhibitory Protein
chemical_list: D011506:Proteins; D044767:Ubiquitin-Protein Ligases; D000097795:ATPase Inhibitory Protein; C111567:parkin protein
keywords: ATPIF1; F1-Fo ATP synthase; IF1; PARK2; PINK1; mitochondria; mitophagy