BNIP3 Protein Suppresses PINK1 Kinase Proteolytic Cleavage to Promote Mitophagy

Tongmei Zhang,Liang Xue,Li Li,Chengyuan Tang,Zhengqing Wan,Ruoxi Wang,Jieqiong Tan,Ya Tan,Hailong Han,Runyi Tian,Timothy R Billiar,W Andy Tao,Zhuohua Zhang

doi:10.1074/jbc.m116.733410

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.

Highlights

Mutations in PINK1 or parkin are linked to the early onset familial form of Parkinson’s disease (PD),2 the most common neurodegenerative movement disorder [1,2,3]
The results showed that immunoprecipitation of PINK1 co-precipitated BCL2/adenovirus E1B 19-kDa interacting protein 3 (BNIP3) with or without the mitochondrial uncoupling agent, carbonyl cyanide m-chlorophenylhydrazone (CCCP) (Fig. 1A)
The results suggest that PINK1 and BNIP3 interact on mitochondrial membrane

Summary

Introduction

Mutations in PINK1 or parkin are linked to the early onset familial form of Parkinson’s disease (PD), the most common neurodegenerative movement disorder [1,2,3]. PINK1 and parkin were shown to play a critical role in the clearance of damaged mitochondria via a mitophagy-mediated mechanism [12,13,14,15,16]. It is proposed that PINK1 is stabilized and accumulates on the mitochondrial outer membrane (MOM) upon mitochondrial depolarization. This subsequently recruits parkin to ubiquitinate MOM proteins followed by degradation of the damaged mitochondria via a mitophagy [15,16,17,18]. The results reveal that BNIP3 interacts with PINK1 to suppress its cleavage, resulting in the accumulation of 64-kDa full-length PINK1 on MOM, leading to increased parkin recruitment and enhanced mitochondrial clearance via mitophagy. This study identified a physiological regulatory mechanism of PINK1 and PINK1-mediated mitophagy

Objectives

Results

Conclusion