Disease-causing mutations in parkin impair mitochondrial ubiquitination, aggregation, and HDAC6-dependent mitophagy

J Cell Biol. 2010 May 17;189(4):671-9. doi: 10.1083/jcb.201001039. Epub 2010 May 10.

Abstract

Mutations in parkin, a ubiquitin ligase, cause early-onset familial Parkinson's disease (AR-JP). How parkin suppresses parkinsonism remains unknown. Parkin was recently shown to promote the clearance of impaired mitochondria by autophagy, termed mitophagy. Here, we show that parkin promotes mitophagy by catalyzing mitochondrial ubiquitination, which in turn recruits ubiquitin-binding autophagic components, HDAC6 and p62, leading to mitochondrial clearance. During the process, juxtanuclear mitochondrial aggregates resembling a protein aggregate-induced aggresome are formed. The formation of these "mito-aggresome" structures requires microtubule motor-dependent transport and is essential for efficient mitophagy. Importantly, we show that AR-JP-causing parkin mutations are defective in supporting mitophagy due to distinct defects at recognition, transportation, or ubiquitination of impaired mitochondria, thereby implicating mitophagy defects in the development of parkinsonism. Our results show that impaired mitochondria and protein aggregates are processed by common ubiquitin-selective autophagy machinery connected to the aggresomal pathway, thus identifying a mechanistic basis for the prevalence of these toxic entities in Parkinson's disease.

Publication types

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

MeSH terms

  • Animals
  • Autophagy / genetics*
  • Cells, Cultured
  • Histone Deacetylase 6
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism*
  • Mice
  • Mitochondria / metabolism*
  • Mutation*
  • Parkinson Disease / genetics*
  • Parkinson Disease / metabolism
  • Transfection
  • Ubiquitin-Protein Ligases / genetics*
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination / genetics

Substances

  • Ubiquitin-Protein Ligases
  • parkin protein
  • Hdac6 protein, mouse
  • Histone Deacetylase 6
  • Histone Deacetylases