Genome-wide RNAi screen identifies ATPase inhibitory factor 1 (ATPIF1) as essential for PARK2 recruitment and mitophagy

Autophagy. 2013 Nov 1;9(11):1770-9. doi: 10.4161/auto.25413. Epub 2013 Aug 7.

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.

Keywords: ATPIF1; F1-Fo ATP synthase; IF1; PARK2; PINK1; mitochondria; mitophagy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Electron Transport
  • Genome, Human*
  • HeLa Cells
  • Humans
  • Membrane Potential, Mitochondrial
  • Mitophagy*
  • Proteins / metabolism*
  • RNA Interference*
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • ATPase inhibitory protein
  • Proteins
  • Ubiquitin-Protein Ligases
  • parkin protein