RGD Reference Report - Disease-causing mutations in parkin impair mitochondrial ubiquitination, aggregation, and HDAC6-dependent mitophagy. - Rat Genome Database

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

Authors: Lee, JY  Nagano, Y  Taylor, JP  Lim, KL  Yao, TP 
Citation: Lee JY, etal., J Cell Biol. 2010 May 17;189(4):671-9. doi: 10.1083/jcb.201001039. Epub 2010 May 10.
RGD ID: 10047224
Pubmed: PMID:20457763   (View Abstract at PubMed)
PMCID: PMC2872903   (View Article at PubMed Central)
DOI: DOI:10.1083/jcb.201001039   (Journal Full-text)

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.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
mitochondrion localization involved_inIDA 10047224PMID:20457763ParkinsonsUK-UCL 
mitophagy involved_inIDA 10047224PMID:20457763ParkinsonsUK-UCL 
protein localization to mitochondrion involved_inIDA 10047224PMID:20457763ParkinsonsUK-UCL 
protein ubiquitination involved_inIDA 10047224PMID:20457763ParkinsonsUK-UCL 

Cellular Component
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
cytosol located_inIDA 10047224PMID:20457763ParkinsonsUK-UCL 
mitochondrion located_inIDA 10047224PMID:20457763ParkinsonsUK-UCL 

Objects Annotated

Genes (Rattus norvegicus)
Prkn  (parkin RBR E3 ubiquitin protein ligase)


Additional Information