DJ-1 is critical for mitochondrial function and rescues PINK1 loss of function
DJ-1 is critical for mitochondrial function and rescues PINK1 loss of function
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DOI：
10.1073/pnas.0911175107
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发表时间：
2010-05-25
影响因子：
11.1
通讯作者：
Bonini, Nancy M.
中科院分区：
文献类型：
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作者：
Hao, Ling-Yang;Giasson, Benoit I.;Bonini, Nancy M.
PARKIN/PARK 2、PINK 1/PARK 6和DJ-1/PARK 7的突变或缺失导致常染色体隐性帕金森综合征。在果蝇中，parkin和pink 1的缺失导致能量需求组织中线粒体肿胀和功能障碍。然而，DJ-1和线粒体之间的关系仍不清楚。我们现在报告说，果蝇和小鼠的DJ-1突变体显示受损的线粒体功能随着年龄的增长。DJ-1基因缺失的果蝇表现出与pink 1和parkin突变体相似的缺陷：雄性不育、寿命缩短和攀爬能力降低。我们进一步发现体外线粒体偶联不良，果蝇和小鼠DJ-1突变体中ATP水平降低。令人惊讶的是，DJ-1的上调可以改善果蝇中的pink 1突变体，但不能改善parkin突变体;半胱氨酸C104（类似于人类中的C106）对于这种拯救至关重要，这表明DJ-1的氧化功能与此有关。这些结果表明，DJ-1是重要的适当的线粒体功能和下游的行为，或平行，粉红色1。这些发现将DJ-1，pink 1和parkin与线粒体完整性联系起来，并为将生物能量学和帕金森症联系起来的治疗方法提供了基础。
Mutations or deletions in PARKIN/PARK2, PINK1/PARK6, and DJ-1/PARK7 lead to autosomal recessive parkinsonism. In Drosophila, deletions in parkin and pink1 result in swollen and dysfunctional mitochondria in energy-demanding tissues. The relationship between DJ-1 and mitochondria, however, remains unclear. We now report that Drosophila and mouse mutants in DJ-1 show compromised mitochondrial function with age. Flies deleted for DJ-1 manifest similar defects as pink1 and parkin mutants: male sterility, shortened lifespan, and reduced climbing ability. We further found poorly coupled mitochondria in vitro and reduced ATP levels in fly and mouse DJ-1 mutants. Surprisingly, up-regulation of DJ-1 can ameliorate pink1, but not parkin, mutants in Drosophila; cysteine C104 (analogous to C106 in human) is critical for this rescue, implicating the oxidative functions of DJ-1 in this property. These results suggest that DJ-1 is important for proper mitochondrial function and acts downstream of, or in parallel to, pink1. These findings link DJ-1, pink1, and parkin to mitochondrial integrity and provide the foundation for therapeutics that link bioenergetics and parkinsonism.