BAG5 protects against mitochondrial oxidative damage through regulating PINK1 degradation

Xuejing Wang; Jifeng Guo; Erkang Fei; Yingfeng Mu; Shuang He; Xiangqian Che; Jieqiong Tan; Kun Xia; Zhuohua Zhang; Guanghui Wang; Beisha Tang

doi:10.1371/journal.pone.0086276

BAG5 protects against mitochondrial oxidative damage through regulating PINK1 degradation

PLoS One. 2014 Jan 24;9(1):e86276. doi: 10.1371/journal.pone.0086276. eCollection 2014.

Authors

Xuejing Wang¹, Jifeng Guo², Erkang Fei³, Yingfeng Mu¹, Shuang He¹, Xiangqian Che¹, Jieqiong Tan⁴, Kun Xia⁴, Zhuohua Zhang⁴, Guanghui Wang³, Beisha Tang²

Affiliations

¹ Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
² Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China ; State Key Laboratory of Medical Genetics, Changsha, Hunan, People's Republic of China ; Human Key Laboratory of Neurodegenerative Disorders, Central South University, Changsha, Hunan, People's Republic of China ; Neurodegenerative Disorders Research Center, Central South University, Changsha, Hunan, People's Republic of China.
³ Laboratory of Molecular Neuropathology, National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, People's Republic of China.
⁴ State Key Laboratory of Medical Genetics, Changsha, Hunan, People's Republic of China.

Abstract

Mutations in PTEN-induced kinase 1 (PINK1) gene cause PARK6 familial Parkinsonism, and loss of the stability of PINK1 may also contribute to sporadic Parkinson's disease (PD). Degradation of PINK1 occurs predominantly through the ubiquitin proteasome system (UPS), however, to date, few of the proteins have been found to regulate the degradation of PINK1. Using the yeast two-hybrid system and pull-down methods, we identified bcl-2-associated athanogene 5 (BAG5), a BAG family member, directly interacted with PINK1. We showed that BAG5 stabilized PINK1 by decreasing the ubiquitination of PINK1. Interestingly, BAG5 rescued MPP(+)- and rotenone-induced mitochondria dysfunction by up-regulating PINK1 in vitro. In PINK1-null mice and MPTP-treated mice, BAG5 significantly increased in the substantia nigra pars compacta (SNpc) although PINK1 was decreased. Our findings indicated that BAG5, as a key protein to stabilize PINK1, is a promising therapeutic tool for preventing mitochondrial dysfunction following oxidative stress.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / pharmacology
Adaptor Proteins, Signal Transducing / genetics*
Adaptor Proteins, Signal Transducing / metabolism*
Animals
Cell Line
Humans
Mice
Mitochondria / drug effects
Mitochondria / genetics*
Mitochondria / metabolism*
Neurotoxins / toxicity
Oxidative Stress*
Protein Binding
Protein Kinases / genetics
Protein Kinases / metabolism*
Protein Stability
Proteolysis
Rotenone / pharmacology
Substantia Nigra / drug effects
Substantia Nigra / metabolism
Ubiquitination

Substances

Adaptor Proteins, Signal Transducing
BAG5 protein, human
Neurotoxins
Rotenone
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Protein Kinases
PTEN-induced putative kinase

Grants and funding

This work was supported by grant from the Major State Basic Research Development Program of China (973 Program) (2011CB510000), grant from the National Natural Science Foundation of China(30900469,81171198, 81200870, 81000542, 81130021, 81371405, 81361120404). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.