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

• Main Authors: Ren Haigang, Fu Kai, Mu Chenchen, Zhen Xuechu, Wang Guanghui
• Format: Article
• Language: English
• Published: BMC 2012-08-01
• Series: Molecular Neurodegeneration
• Subjects: Parkinson’s disease; DJ-1; L166P; Mitochondria; Apoptosis; Bcl-X_L; Bax; UVB
• Online Access: http://www.molecularneurodegeneration.com/content/7/1/40

<p>Abstract</p> <p>Background</p> <p>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-X_L 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.</p> <p>Results</p> <p>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-X_L. DJ-1(L166P) but not wild-type DJ-1 dissociates Bax from Bcl-X_L, thereby leading to Bax enrichment at outer mitochondrial membrane and promoting mitochondrial apoptosis pathway in response to UVB irradiation.</p> <p>Conclusion</p> <p>Our findings suggest that wild-type DJ-1 protects cells and DJ-1(L166P) impairs cells by differentially regulating mitochondrial Bax/Bcl-X_L functions.</p>