Characterizing the function of PARL in PINK1 regulation

The close relationship between pathogenesis of Parkinson's disease (PD) and mitochondrial dysfunction has been established by various studies. PINK1, a mitochondrial kinase, is genetically linked to PD and known to be involved in maintaining proper mitochondrial function. PINK1 is post‐translationally processed into two cleaved forms whose levels are tightly regulated; however, the regulation of PINK1 is not completely understood. Using PARL knockout mouse embryonic fibroblasts (MEFs), we demonstrate that the mitochondrial protease PARL can affect the proteolytic processing of PINK1 and its protease activity is required for PINK1's normal cellular localization. Recent functional studies have revealed that PINK1 recruits Parkin, an E3 ubiquitin ligase, to mitochondria to initiate mitophagy, an important mitochondrial quality control mechanism that eliminates damaged mitochondria. Using MEFs, we show that PARL deficiency impairs Parkin recruitment to mitochondria suggesting PINK1's processing and localization are important in determining its interaction with Parkin. These findings reveal a potential regulatory mechanism of PINK1 function, which may provide valuable insight into disease mechanisms in PD. Sources of research support: Canadian Institute of Health Research, Parkinson Society of Canada