Glucose-6-phosphate dehydrogenase regulates mitophagy by maintaining PINK1 stability

作     者：Yik-Lam Cho Hayden Weng Siong Tan Jicheng Yang Basil Zheng Mian Kuah Nicole Si Ying Lim Naiyang Fu Boon-Huat Bay Shuo-Chien Ling Han-Ming Shen 

作者机构：Department of PhysiologyYong Loo Lin School of MedicineNational University of SingaporeSingapore 117593Singapore Department of AnatomyYong Loo Lin School of MedicineNational University of SingaporeSingapore 117594Singapore Cancer and Stem Cell Biology ProgramDuke-NUS Medical SchoolSingapore 169857Singapore NUS Centre for Cancer ResearchYong Loo Lin School of MedicineNational University of SingaporeSingapore 117599Singapore Programs in Neuroscience and Behavioral DisordersDuke-NUS Medical SchoolSingapore 169857Singapore Healthy Longevity Translational Research ProgrammeYong Loo Lin School of MedicineNational University of SingaporeSingapore 117549Singapore Faculty of Health SciencesMOE Frontier Centre for Precision OncologyUniversity of MacaoMacao 999078China 

出 版 物：《Life Metabolism》 (生命代谢(英文))

年 卷 期：2025年第4卷第1期

页      面：17-34页

学科分类：0710[理学-生物学] 07[理学] 071009[理学-细胞生物学] 09[农学] 0901[农学-作物学] 090102[农学-作物遗传育种] 

基　　金：supported by grants to S.C.L.from the Swee Liew-Wadsworth Endowment fund,National University of Singapore(NUS),Ministry of Education(MOE-T2EP30220-0014),Singapore the National Research Foundation(NRF-ISF003-3221),Singapore grants to H.M.S.from University of Macao(CPG2023-0032FHS and UM-MYRG2020-00022-FHS) Macao Science and Technology Development Fund(FDCT0078/2020/A2,FDCT0031/2021/A1,FDCT0081/2022/AMJ,and FDCT 0004/2021/AKP) supported by the NUS Graduate School Research Scholarships 

主　　题：G6PD mitophagy PINK1 ROS NADPH PPP 

摘      要：Glucose-6-phosphate dehydrogenase(G6PD)is the rate-limiting enzyme in the pentose phosphate pathway(PPP)in *** metabolism is closely implicated in the regulation of mitophagy,a selective form of autophagy for the degradation of damaged *** PPP and its key enzymes such as G6PD possess important metabolic functions,including biosynthesis and maintenance of intracellular redox balance,while their implication in mitophagy is largely ***,via a whole-genome CRISPR-Cas9 screening,we identified that G6PD regulates PINK1(phosphatase and tensin homolog[PTEN]-induced kinase 1)-Parkinmediated *** function of G6PD in mitophagy was verified via multiple approaches.G6PD deletion significantly inhibited mitophagy,which can be rescued by G6PD ***,while the catalytic activity of G6PD is required,the known PPP functions per se are not involved in mitophagy ***,we found a portion of G6PD localized at mitochondria where it interacts with PINK1.G6PD deletion resulted in an impairment in PINK1 stabilization and subsequent inhibition of ubiquitin phosphorylation,a key starting point of ***,we found that G6PD deletion resulted in lower cell viability upon mitochondrial depolarization,indicating the physiological function of G6PD-mediated mitophagy in response to mitochondrial *** summary,our study reveals a novel role of G6PD as a key positive regulator in mitophagy,which bridges several important cellular processes,namely glucose metabolism,redox homeostasis,and mitochondrial quality control.