BAG2 Gene-mediated Regulation of PINK1 Protein Is Critical for Mitochondrial Translocation of PARKIN and Neuronal Survival

J Biol Chem. 2015 Dec 18;290(51):30441-52. doi: 10.1074/jbc.M115.677815. Epub 2015 Nov 4.


Emerging evidence has demonstrated a growing genetic component in Parkinson disease (PD). For instance, loss-of-function mutations in PINK1 or PARKIN can cause autosomal recessive PD. Recently, PINK1 and PARKIN have been implicated in the same signaling pathway to regulate mitochondrial clearance through recruitment of PARKIN by stabilization of PINK1 on the outer membrane of depolarized mitochondria. The precise mechanisms that govern this process remain enigmatic. In this study, we identify Bcl2-associated athanogene 2 (BAG2) as a factor that promotes mitophagy. BAG2 inhibits PINK1 degradation by blocking the ubiquitination pathway. Stabilization of PINK1 by BAG2 triggers PARKIN-mediated mitophagy and protects neurons against 1-methyl-4-phenylpyridinium-induced oxidative stress in an in vitro cell model of PD. Collectively, our findings support the notion that BAG2 is an upstream regulator of the PINK1/PARKIN signaling pathway.

Keywords: Parkinson disease; cell death; neurodegenerative disease; translocation; ubiquitylation (ubiquitination).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cell Survival
  • Mice
  • Mice, Mutant Strains
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Mitochondrial Membranes / metabolism
  • Mitophagy / genetics
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism*
  • Neurons / metabolism*
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*
  • Protein Stability
  • Protein Transport
  • Signal Transduction*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination


  • Adaptor Proteins, Signal Transducing
  • Bag2 protein, mouse
  • Molecular Chaperones
  • Ubiquitin-Protein Ligases
  • parkin protein
  • Protein Kinases
  • PTEN-induced putative kinase