Richard Youle's lab pioneered an understanding of how a mitochondrial ubiquitin ligase that is genetically linked to an autosomal recessive form of Parkinson's Disease, Parkin, regulates a pathway of mitochondrial quality control through selective autophagy.
The products of two genes mutated in autosomal recessive forms of Parkinson’s disease, Pink1 and Parkin, have been identified in Drosophila to work in the same pathway to maintain healthy flight muscles and dopaminergic neurons. PINK1 is a kinase located on mitochondria whereas Parkin is an E3 ubiquitin ligase located in the cytosol. Normally, the protein level of PINK1 is maintained at low to undetectable levels because PINK1 is constitutively imported to the inner membrane of healthy mitochondria where it is cleaved by the rhomboid protease PARL and then degraded in the cytosol by the proteosome through the N-end rule. When mitochondrial import is impaired PINK1 accumulates on the outer mitochondrial membrane where it can recruit Parkin from the cytosol and activate Parkin’s E3 ubiquitin ligase activity. Parkin in turn ubiquitinates mitochondrial proteins to trigger autophagic elimination of the damaged mitochondrion. Thus PINK1 represents a sensing mechanism to allow detection of individual damaged mitochondria and Parkin mediates their removal through mitophagy. Recent results reveal how mitochondria outer membrane proteins guide autophagosomal membrane encapsulation following Parkin ubiquitination. How PINK1 recruits Parkin to mitochondria and the kinase substrate of PINK1 involved in Parkin activation will be presented. These results indicate that the maintenance of mitochondrial quality control may be disrupted in patients with PINK1 and Parkin mutations and lead to parkinsonism.