Hao Ling-Yang, Giasson Benoit I, Bonini Nancy M
Department of Biology, Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
Proc Natl Acad Sci U S A. 2010 May 25;107(21):9747-52. doi: 10.1073/pnas.0911175107. Epub 2010 May 10.
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.
帕金森病蛋白(PARKIN/PARK2)、PTEN诱导激酶1(PINK1/PARK6)和DJ-1(PARK7)中的突变或缺失会导致常染色体隐性帕金森症。在果蝇中,帕金森病蛋白和PTEN诱导激酶1的缺失会导致能量需求组织中的线粒体肿胀且功能失调。然而,DJ-1与线粒体之间的关系仍不明确。我们现在报告称,DJ-1基因的果蝇和小鼠突变体随着年龄增长线粒体功能受损。缺失DJ-1基因的果蝇表现出与PTEN诱导激酶1和帕金森病蛋白突变体类似的缺陷:雄性不育、寿命缩短以及攀爬能力下降。我们进一步发现,果蝇和小鼠DJ-1突变体的线粒体在体外偶联不佳,ATP水平降低。令人惊讶的是,上调DJ-1可以改善果蝇中PTEN诱导激酶1的突变体,但不能改善帕金森病蛋白的突变体;半胱氨酸C104(类似于人类的C106)对这种挽救作用至关重要,这表明DJ-1的氧化功能具有这种特性。这些结果表明,DJ-1对正常的线粒体功能很重要,并且在PTEN诱导激酶1的下游或与其平行发挥作用。这些发现将DJ-1、PTEN诱导激酶1和帕金森病蛋白与线粒体完整性联系起来,并为将生物能量学与帕金森症联系起来的治疗方法提供了基础。