The Role And Molecular Mechanism Of Prohibitin-2 In PINK1-Parkin Mediated Mitophagy

Mitophagy is selective removal of damaged or unwanted mitochondria and subsequent degradation by lysosomes.In healthy cells,PINK1(PETN-induced putative kinase 1)is continuously processed and degraded by mitochondrial proteases including mitochondrial inner protease PARL(Presenilin-associated,rhomboid-like);While,upon mitochondrial damage or uncoupling,PINK1 proteolysis is inhibited and accumulated in mitochondrial outer membrane,then recruits Parkin to mitochondrial outer membrane for ubiquitination of several mitochondrial outer membrane proteins to mediate the autophagic elimination of damaged mitochondria.However the detail mechanism of PINK1 degradation and stabilization remains unclear.Prohibitin complex consists of Prohibitin-1(PHB1)and Prohibitin2(PHB2)and function as mitochondrial scaffolding inner membrane protein.Recently,prohibitin2(PHB2),was identified as a novel inner mitochondrial membrane mitophagy receptor and plays a critical role in PINK1-Parkin mediated mitophagy.Howere,how PHB2 regulates PINK1-Parkin actvity is not clear.In this study,we found that upon mitochondrial membrane depolarization,PHB2 depletion led to decreased accumulation of PINK1 in mitochondrial outer membrane and subsequent reduced mitochondrial recruitment of Parkin,and this effect is dependent on mitochondrial proteases PARL and OMA1,which interact with PHB2 and are activated upon PHB2 depletion.Furthermore,under the condition of PHB2 silencing,PARL protein levels were significantly increased,leading to increased cleavage of PARL substrate PGAM5(phosphoglycerate mutase family member 5)which stabilize PINK1 on the mitochondrial outer membrane,while cleaved PGAM5 is responsible for PINK1 instability.Moreover,in the absence of OMA1,the effect of PHB2 on PINK1 stabilization is reversed.Therefore,besides acting as mitophagy receptor,PHB2 can promote PINK1-Parkin mediated mitophagy by stabilizing PINK1 and increasing Parkin recruitment of mitochondria.In addition,we synthesized a ligand of prohibitins,FL3,which can inhibit PHB2 mediated mitophagy and glycolysis,effectively blocks cancer cell growth.Thus,FL3 is a promising reagent for cancer therapy due to its targeting mitophagy and glycolysis in the same time.