![]() In this study, we show that PINK1 is rapidly and constitutively degraded under steady-state conditions in a mitochondrial membrane potential–dependent manner and that a loss in mitochondrial membrane potential stabilizes PINK1 mitochondrial accumulation. Furthermore, PINK1 recruits Parkin from the cytoplasm to mitochondria with low membrane potential to initiate the autophagic degradation of damaged mitochondria. Interestingly, the ubiquitin ligase activity of Parkin is repressed in the cytoplasm under steady-state conditions however, PINK1-dependent mitochondrial localization liberates the latent enzymatic activity of Parkin. Some pathogenic mutations of PINK1 and Parkin interfere with the aforementioned events, suggesting an etiological importance. These results provide crucial insight into the pathogenic mechanisms of PD. Parkinson's disease (PD) is a very common movement disorder characterized by dopaminergic neuronal loss. ![]() The majority of PD cases are sporadic however, the discovery of genes linked to rare familial forms of this disease has provided important insight into the molecular mechanisms of disease pathogenesis ( Moore et al., 2005 Hardy et al., 2006). In 2000, we and others found that dysfunction of an E3 ubiquitin ligase ( Imai et al., 2000 Shimura et al., 2000 Zhang et al., 2000) termed Parkin causes autosomal recessive juvenile Parkinsonism ( Kitada et al., 1998). ![]()
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