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J Biol Chem. 2016 Oct 7;291(41):21616-21629. Epub 2016 Aug 15.

BNIP3 Protein Suppresses PINK1 Kinase Proteolytic Cleavage to Promote Mitophagy.

Author information

1
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.
2
the Department of Biochemistry, Purdue University, West Lafayette, Indiana 47907.
3
the Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, and.
4
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.
5
the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China.

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.

KEYWORDS:

Parkinson's disease; hypoxia; mitochondria; parkin; ubiquitin

PMID:
27528605
PMCID:
PMC5076832
DOI:
10.1074/jbc.M116.733410
[Indexed for MEDLINE]
Free PMC Article

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