AIMP2 TARGETS PINK1 FOR PROTEOSOMAL DEGRADATION: INSIGHT INTO MITOCHONDRIAL MAINTENANCE AND PARKINSON’S DISEASE

[摘要] A mitochondrial serine/threonine kinase, PINK1, is a common genetic risk factor that has been implicated in the pathology of autosomal recessive Parkinson’s disease (PD). PINK1 identifies damaged mitochondria and recruits another PD-related E3 ubiquitin ligase parkin to trigger the autophagic clearance of the impaired mitochondria: mitophagy. The tight regulation of PINK1 protein expression in mitochondria as well as in cytoplasm is important for this process because loss of function of PINK1 leads to failure in mitophagy. However, the exact mechanisms by which the steady-state level of PINK1 is maintained are poorly understood. Here, we show that AIMP2, previously found as a pathogenic substrate of parkin, functions as a novel regulator for ubiquitin-proteasome-dependent degradation of PINK1. AIMP2 interacts with both PINK1 and 26S proteasome regulatory subunits, RPN1 and RPN3 subunits to promote PINK1 degradation through the ubiquitin-proteosome system. Overexpression of AIMP2 decreases PINK1 levels, whereas depletion of AIMP2 increases PINK1 levels both in vitro and in vivo. Moreover, AIMP2-mediated regulation of PINK1 leads to differential kinetics of parkin recruitment onto CCCP-induced damaged mitochondria. These results suggest that AIMP2 serves as a key regulator of PINK1 expression and PINK1-induced parkin recruitment for mitophagy.

[发布机构] Johns Hopkins University

[效力级别] PINK1

[关键词] AIMP2;PINK1;parkin;mitochondria;mitophagy;ubiquitin proteasome degradation;Parkinson’s disease;Biology