title: BNIP3 Protein Suppresses PINK1 Kinase Proteolytic Cleavage to Promote Mitophagy.
abstract: Mutations in PINK1 (PTEN-induced putative kinase 1) cause early onset familial Parkinson's disease (PD). PINK1 accumulates on the outer membrane of damaged mitochondria followed by recruiting parkin to promote mitophagy. Here, we demonstrate that BCL2/adenovirus E1B 19-kDa interacting protein 3 (BNIP3), a mitochondrial BH3-only protein, interacts with PINK1 to promote the accumulation of full-length PINK1 on the outer membrane of mitochondria, which facilitates parkin recruitment and PINK1/parkin-mediated mitophagy. Inactivation of BNIP3 in mammalian cells promotes PINK1 proteolytic processing and suppresses PINK1/parkin-mediated mitophagy. Hypoxia-induced BNIP3 expression results in increased expression of full-length PINK1 and mitophagy. Consistently, expression of BNIP3 in Drosophila suppresses muscle degeneration and the mitochondrial abnormality caused by PINK1 inactivation. Together, the results suggest that BNIP3 plays a vital role in regulating PINK1 mitochondrial outer membrane localization, the proteolytic process of PINK1 and PINK1/parkin-mediated mitophagy under physiological conditions. Functional up-regulation of BNIP3 may represent a novel therapeutic strategy to suppress the progression of PD.
authors.affiliation: From the Institute of Precision Medicine, the Xiangya Hospital and State Key Laboratory of Medical Genetics, the Xiangya Medical School, Central South University, Changsha, Hunan 410078, China.
authors.forename: Tongmei
authors.initials: T
authors.lastname: Zhang
authors.affiliation: the Department of Biochemistry, Purdue University, West Lafayette, Indiana 47907.
authors.forename: Liang
authors.initials: L
authors.lastname: Xue
authors.affiliation: From the Institute of Precision Medicine, the Xiangya Hospital and State Key Laboratory of Medical Genetics, the Xiangya Medical School, Central South University, Changsha, Hunan 410078, China.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: From the Institute of Precision Medicine, the Xiangya Hospital and State Key Laboratory of Medical Genetics, the Xiangya Medical School, Central South University, Changsha, Hunan 410078, China.
authors.forename: Chengyuan
authors.initials: C
authors.lastname: Tang
authors.affiliation: From the Institute of Precision Medicine, the Xiangya Hospital and State Key Laboratory of Medical Genetics, the Xiangya Medical School, Central South University, Changsha, Hunan 410078, China.
authors.forename: Zhengqing
authors.initials: Z
authors.lastname: Wan
authors.affiliation: From the Institute of Precision Medicine, the Xiangya Hospital and State Key Laboratory of Medical Genetics, the Xiangya Medical School, Central South University, Changsha, Hunan 410078, China.
authors.forename: Ruoxi
authors.initials: R
authors.lastname: Wang
authors.affiliation: From the Institute of Precision Medicine, the Xiangya Hospital and State Key Laboratory of Medical Genetics, the Xiangya Medical School, Central South University, Changsha, Hunan 410078, China.
authors.forename: Jieqiong
authors.initials: J
authors.lastname: Tan
authors.affiliation: From the Institute of Precision Medicine, the Xiangya Hospital and State Key Laboratory of Medical Genetics, the Xiangya Medical School, Central South University, Changsha, Hunan 410078, China.
authors.forename: Ya
authors.initials: Y
authors.lastname: Tan
authors.affiliation: From the Institute of Precision Medicine, the Xiangya Hospital and State Key Laboratory of Medical Genetics, the Xiangya Medical School, Central South University, Changsha, Hunan 410078, China.
authors.forename: Hailong
authors.initials: H
authors.lastname: Han
authors.affiliation: From the Institute of Precision Medicine, the Xiangya Hospital and State Key Laboratory of Medical Genetics, the Xiangya Medical School, Central South University, Changsha, Hunan 410078, China.
authors.forename: Runyi
authors.initials: R
authors.lastname: Tian
authors.affiliation: From the Institute of Precision Medicine, the Xiangya Hospital and State Key Laboratory of Medical Genetics, the Xiangya Medical School, Central South University, Changsha, Hunan 410078, China.|the Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, and.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
authors.affiliation: the Department of Biochemistry, Purdue University, West Lafayette, Indiana 47907.
authors.forename: W Andy
authors.initials: WA
authors.lastname: Tao
authors.affiliation: From the Institute of Precision Medicine, the Xiangya Hospital and State Key Laboratory of Medical Genetics, the Xiangya Medical School, Central South University, Changsha, Hunan 410078, China zhangzhuohua@sklmg.edu.cn.|the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China.
authors.forename: Zhuohua
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D018345:Mice, Knockout; D051336:Mitochondrial Membranes / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D063306:Mitophagy; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
chemical_list: D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D011494:Protein Kinases; D011518:Proto-Oncogene Proteins; D000099202:PTEN-Induced Putative Kinase; C090121:BNIP3 protein, human; C508686:BNip3 protein, mouse
keywords: Parkinson's disease; hypoxia; mitochondria; parkin; ubiquitin