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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Lee, J-Y; Nagano, Y; Taylor, JP; Lim, KL; Yao, T-P

Published Date

  • May 17, 2010

Published In

Volume / Issue

  • 189 / 4

Start / End Page

  • 671 - 679

PubMed ID

  • 20457763

Pubmed Central ID

  • 20457763

Electronic International Standard Serial Number (EISSN)

  • 1540-8140

Digital Object Identifier (DOI)

  • 10.1083/jcb.201001039

Language

  • eng

Conference Location

  • United States