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

Haigang Ren, Kai Fu, Chenchen Mu, Xuechu Zhen, Guanghui Wang

Research output: Contribution to journalArticle

Abstract

Background: Mutations or deletions in DJ-1/PARK7 gene are causative for recessive forms of early onset Parkinsons 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-X L 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.

Original languageEnglish (US)
Article number40
JournalMolecular Neurodegeneration
Volume7
Issue number1
DOIs
Publication statusPublished - Aug 17 2012
Externally publishedYes

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Keywords

  • Apoptosis
  • Bax
  • Bcl-X
  • DJ-1
  • L166P
  • Mitochondria
  • Parkinsons disease
  • UVB

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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