title: The mitochondrial protein BNIP3L is the substrate of PARK2 and mediates mitophagy in PINK1/PARK2 pathway.
abstract: Mitochondrial dysfunction plays important roles in Parkinson's disease (PD) and the degradation of the damaged mitochondria by the mitochondria quality control system is important for dopaminergic (DA) neuronal survival. BNIP3L/Nix is a mitochondrial outer membrane protein that is required for the selective clearance of mitochondria. Here, we found that the mitochondrial protein BNIP3L acts downstream of the PINK1/PARK2 pathway to induce mitophagy. BNIP3L is a substrate of PARK2 to drive PARK2-mediated mitophagy. The ubiquitination of BNIP3L by PARK2 recruits NBR1 to mitochondria, thereby targeting mitochondria for degradation. BNIP3L rescues mitochondrial defects in pink1 mutant Drosophila but not in park mutant Drosophila, indicating that the clearance of mitochondria induced by BNIP3L depends on the presence of PARK2. In cells intoxicated with mitochondrial complex I inhibitors rotenone, 6-OHDA or MPP(+), the disrupted mitochondria are not appropriately eliminated by mitophagy due to the improper degradation of BNIP3L. Thus, our study demonstrates that BNIP3L, as a substrate of PARK2, promotes mitophagy in the PINK1/PARK2 pathway associated with PD pathogenesis.
authors.affiliation: Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, China, Laboratory of Molecular Neuropathology, Key Laboratory of Brain Function and Diseases and School of Life Sciences, University of Science & Technology of China, Chinese Academy of Sciences, Hefei, Anhui 230027, China and.
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.affiliation: Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Chen
authors.affiliation: Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, China, Laboratory of Molecular Neuropathology, Key Laboratory of Brain Function and Diseases and School of Life Sciences, University of Science & Technology of China, Chinese Academy of Sciences, Hefei, Anhui 230027, China and.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Si
authors.affiliation: Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, China.
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, China.
authors.forename: Zhenghong
authors.initials: Z
authors.lastname: Qin
authors.affiliation: Institute of Life Sciences, MOE Key Laboratory of Developmental Genes and Human Diseases, Southeast University, Nanjing 210096, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Fang
authors.affiliation: Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, China, wanggh@suda.edu.cn.
authors.forename: Guanghui
authors.initials: G
authors.lastname: Wang
mesh_terms: D000818:Animals; D002460:Cell Line; D042967:Electron Transport Complex I / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D063306:Mitophagy / Q000235:genetics; D008954:Models, Biological; D009132:Muscles / Q000378:metabolism / Q000648:ultrastructure; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D059748:Proteolysis; D015398:Signal Transduction; D013379:Substrate Specificity; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
chemical_list: D042967:Electron Transport Complex I; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D011494:Protein Kinases; D011506:Proteins; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C486326:Nbr1 protein, mouse; C501741:Nix protein, mouse; C111567:parkin protein