Abstract
Joo-Yong Lee1, Yoshito Nagano1, J. Paul Taylor2, Kah Leong Lim3, and Tso-Pang Yao1
1Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710
2Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105
3National Neuroscience Institute, Singapore 308433
Correspondence to Tso-Pang Yao
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.
Footnotes
Submitted: 8 January 2010
Accepted: 16 April 2010