Loss of DJ-1 Does Not Affect Mitochondrial Respiration but Increases ROS Production and Mitochondrial Permeability Transition Pore Opening

被引:76
作者
Giaime, Emilie [1 ]
Yamaguchi, Hiroo [1 ]
Gautier, Clement A. [1 ]
Kitada, Tohru [1 ]
Shen, Jie [1 ]
机构
[1] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Neurol Dis,Program Neurosci, Boston, MA 02115 USA
基金
美国国家卫生研究院;
关键词
DISEASE-ASSOCIATED PROTEIN; PARKINSONS-DISEASE; CELL-DEATH; DOPAMINERGIC-NEURONS; OXIDATIVE STRESS; DROSOPHILA DJ-1; IN-VIVO; MUTATIONS; DEGENERATION; PINK1;
D O I
10.1371/journal.pone.0040501
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Background: Loss of function mutations in the DJ-1 gene have been linked to recessively inherited forms of Parkinsonism. Mitochondrial dysfunction and increased oxidative stress are thought to be key events in the pathogenesis of Parkinson's disease. Although it has been reported that DJ-1 serves as scavenger for reactive oxidative species (ROS) by oxidation on its cysteine residues, how loss of DJ-1 affects mitochondrial function is less clear. Methodology/Principal Findings: Using primary mouse embryonic fibroblasts (MEFs) or brains from DJ-1-/- mice, we found that loss of DJ-1 does not affect mitochondrial respiration. Specifically, endogenous respiratory activity as well as basal and maximal respiration are normal in intact DJ-1-/- MEFs, and substrate-specific state 3 and state 4 mitochondrial respiration are also unaffected in permeabilized DJ-1-/- MEFs and in isolated mitochondria from the cerebral cortex of DJ-1-/- mice at 3 months or 2 years of age. Expression levels and activities of all individual complexes composing the electron transport system are unchanged, but ATP production is reduced in DJ-1-/- MEFs. Mitochondrial transmembrane potential is decreased in the absence of DJ-1. Furthermore, mitochondrial permeability transition pore opening is increased, whereas mitochondrial calcium levels are unchanged in DJ-1-/- cells. Consistent with earlier reports, production of reactive oxygen species (ROS) is increased, though levels of antioxidative enzymes are unaltered. Interestingly, the decreased mitochondrial transmembrane potential and the increased mitochondrial permeability transition pore opening in DJ-1-/- MEFs can be restored by antioxidant treatment, whereas oxidative stress inducers have the opposite effects on mitochondrial transmembrane potential and mitochondrial permeability transition pore opening. Conclusions/Significance: Our study shows that loss of DJ-1 does not affect mitochondrial respiration or mitochondrial calcium levels but increases ROS production, leading to elevated mitochondrial permeability transition pore opening and reduced mitochondrial transmembrane potential.
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页数:18
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