PTENα regulates mitophagy and maintains mitochondrial quality control

PTEN plays an important role in tumor suppression, and PTEN family members are involved in multiple biological processes in various subcellular locations. Here we report that PTEN, the first identified PTEN isoform, regulates mitophagy through promotion of PARK2 recruitment to damaged mitochondria. We show that PTEN alpha-deficient mice exhibit accumulation of cardiac mitochondria with structural and functional abnormalities, and PTEN alpha-deficient mouse hearts are more susceptible to injury induced by isoprenaline and ischemia-reperfusion. Mitochondrial clearance by mitophagy is also impaired in PTEN alpha-deficient cardiomyocytes. In addition, we found PTEN alpha physically interacts with the E3 ubiquitin ligase PRKN, which is an important mediator of mitophagy. PTEN alpha binds PRKN through the membrane binding helix in its N-terminus, and promotes PRKN mitochondrial translocation through enhancing PRKN self-association in a phosphatase-independent manner. Loss of PTEN alpha compromises mitochondrial translocation of PRKN and resultant mitophagy following mitochondrial depolarization. We propose that PTEN alpha functions as a mitochondrial quality controller that maintains mitochondrial function and cardiac homeostasis.