PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria

Science. 2013 Apr 26;340(6131):471-5. doi: 10.1126/science.1231031.

Abstract

Senescent and damaged mitochondria undergo selective mitophagic elimination through mechanisms requiring two Parkinson's disease factors, the mitochondrial kinase PINK1 (PTEN-induced putative kinase protein 1; PTEN is phosphatase and tensin homolog) and the cytosolic ubiquitin ligase Parkin. The nature of the PINK-Parkin interaction and the identity of key factors directing Parkin to damaged mitochondria are unknown. We show that the mitochondrial outer membrane guanosine triphosphatase mitofusin (Mfn) 2 mediates Parkin recruitment to damaged mitochondria. Parkin bound to Mfn2 in a PINK1-dependent manner; PINK1 phosphorylated Mfn2 and promoted its Parkin-mediated ubiqitination. Ablation of Mfn2 in mouse cardiac myocytes prevented depolarization-induced translocation of Parkin to the mitochondria and suppressed mitophagy. Accumulation of morphologically and functionally abnormal mitochondria induced respiratory dysfunction in Mfn2-deficient mouse embryonic fibroblasts and cardiomyocytes and in Parkin-deficient Drosophila heart tubes, causing dilated cardiomyopathy. Thus, Mfn2 functions as a mitochondrial receptor for Parkin and is required for quality control of cardiac mitochondria.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Autophagy
  • Cardiomyopathies / enzymology
  • Drosophila melanogaster
  • Fibroblasts / ultrastructure
  • GTP Phosphohydrolases / genetics
  • GTP Phosphohydrolases / metabolism*
  • HEK293 Cells
  • Humans
  • Mice
  • Mice, Mutant Strains
  • Mitochondria / enzymology
  • Mitochondria, Heart / enzymology*
  • Molecular Sequence Data
  • Myocytes, Cardiac / enzymology*
  • Myocytes, Cardiac / ultrastructure
  • Phosphorylation
  • Protein Kinases / metabolism*
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination

Substances

  • Ubiquitin-Protein Ligases
  • parkin protein
  • Protein Kinases
  • PTEN-induced putative kinase
  • GTP Phosphohydrolases
  • Mfn2 protein, mouse