PINK1 -PARKIN Interplay: Down to Ubiquitin Phosphorylation

摘要

Parkinson's disease (PD) is a chronic neuropathy characterized by a specific loss of dopaminergic neurons. Genetic evidence has shown that PINK1 (PTEN-induced putative kinase 1; PARK6) and PARKIN {PARK2) are closely linked to the pathogenesis of autosomal-recessive juvenile Parkinsonism (AR-JP). Several mutations found in PD patients result in loss of function of either of these two enzymes due to truncation, instability, impaired recruitment, or inactivation of their catalytic center. PINK1 is a mitochondria! serine/threonine kinase, while PARKIN is a cytosolic ubiquitin E3 ligase. Biochemical and molecular studies have indicated an epistatic relationship between these two genes involved in mitochondrial homeostasis (Youle and Narendra, 2011). In this pathway PINK1 acts as an upstream kinase that recruits PARKIN, in a phosphorylation-dependent manner, onto dysfunctional mitochondria. However, it is unclear how, and to what extent, PINK1 and PARKIN contribute to mitochondrial homeostasis in vivo. Is it the clearance of oxidized protein aggregates from mitochondria? Do they actively promote mitochondrial removal or are they primarily influencing fusion, fission, and transport of mitochondria (Scarffe et al., 2014)? In this issue, Ordureau et al. (2014) suggest a feedforward mechanism that explains how phosphorylation events mediated by PINK1 put defective mitochondria on an irreversible path to degradation.