p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria

Genes Cells. 2010 Aug;15(8):887-900. doi: 10.1111/j.1365-2443.2010.01426.x. Epub 2010 Jul 2.

Abstract

PINK1 and Parkin were first identified as the causal genes responsible for familial forms of early-onset Parkinson's disease (PD), a prevalent neurodegenerative disorder. PINK1 encodes a mitochondrial serine/threonine protein kinase, whereas Parkin encodes an ubiquitin-protein ligase. PINK1 and Parkin cooperate to maintain mitochondrial integrity; however, the detailed molecular mechanism of how Parkin-catalyzed ubiquitylation results in mitochondrial integrity remains an enigma. In this study, we show that Parkin-catalyzed K63-linked polyubiquitylation of depolarized mitochondria resulted in ubiquitylated mitochondria being transported along microtubules to cluster in the perinuclear region, which was interfered by pathogenic mutations of Parkin. In addition, p62/SQSTM1 (hereafter referred to as p62) was recruited to depolarized mitochondria after Parkin-directed ubiquitylation. Intriguingly, deletion of p62 in mouse embryonic fibroblasts resulted in a gross loss of mitochondrial perinuclear clustering but did not hinder mitochondrial degradation. Thus, p62 is required for ubiquitylation-dependent clustering of damaged mitochondria, which resembles p62-mediated 'aggresome' formation of misfolded/unfolded proteins after ubiquitylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / deficiency
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Biocatalysis
  • Cell Nucleus / metabolism*
  • Cells, Cultured
  • DNA, Mitochondrial / genetics
  • HeLa Cells
  • Humans
  • Mitochondria / metabolism*
  • Protein Folding
  • Sequestosome-1 Protein
  • Ubiquitin / metabolism
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination

Substances

  • Adaptor Proteins, Signal Transducing
  • DNA, Mitochondrial
  • SQSTM1 protein, human
  • Sequestosome-1 Protein
  • Ubiquitin
  • Ubiquitin-Protein Ligases
  • parkin protein