L166P mutant DJ-1 promotes cell death by dissociating Bax from mitochondrial Bcl-XL

Mol Neurodegener. 2012 Aug 14;7:40. doi: 10.1186/1750-1326-7-40.

Abstract

Background: Mutations or deletions in DJ-1/PARK7 gene are causative for recessive forms of early onset Parkinson's disease (PD). Wild-type DJ-1 has cytoprotective roles against cell death through multiple pathways. The most commonly studied mutant DJ-1(L166P) shifts its subcellular distribution to mitochondria and renders cells more susceptible to cell death under stress stimuli. We previously reported that wild-type DJ-1 binds to Bcl-XL and stabilizes it against ultraviolet B (UVB) irradiation-induced rapid degradation. However, the mechanisms by which mitochondrial DJ-1(L166P) promotes cell death under death stimuli are largely unknown.

Results: We show that DJ-1(L166P) is more prone to localize in mitochondria and it binds to Bcl-XL more strongly than wild-type DJ-1. In addition, UVB irradiation significantly promotes DJ-1(L166P) translocation to mitochondria and binding to Bcl-XL. DJ-1(L166P) but not wild-type DJ-1 dissociates Bax from Bcl-XL, thereby leading to Bax enrichment at outer mitochondrial membrane and promoting mitochondrial apoptosis pathway in response to UVB irradiation.

Conclusion: Our findings suggest that wild-type DJ-1 protects cells and DJ-1(L166P) impairs cells by differentially regulating mitochondrial Bax/Bcl-XL functions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Death / physiology
  • Gene Knockdown Techniques
  • HEK293 Cells
  • Humans
  • Immunohistochemistry
  • Immunoprecipitation
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mitochondria / metabolism*
  • Mutation*
  • Oncogene Proteins / genetics*
  • Oncogene Proteins / metabolism
  • Protein Deglycase DJ-1
  • bcl-2-Associated X Protein / genetics
  • bcl-2-Associated X Protein / metabolism*
  • bcl-X Protein / genetics
  • bcl-X Protein / metabolism*

Substances

  • BAX protein, human
  • BCL2L1 protein, human
  • Intracellular Signaling Peptides and Proteins
  • Oncogene Proteins
  • bcl-2-Associated X Protein
  • bcl-X Protein
  • PARK7 protein, human
  • Protein Deglycase DJ-1