The Parkinson's disease genes pink1 and parkin promote mitochondrial fission and/or inhibit fusion in Drosophila
The Parkinson's disease genes pink1 and parkin promote mitochondrial fission and/or inhibit fusion in Drosophila
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DOI：
10.1073/pnas.0803998105
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发表时间：
2008-09-23
影响因子：
11.1
通讯作者：
Guo, Ming
中科院分区：
文献类型：
--
作者：
Deng, Hansong;Dodson, Mark W.;Guo, Ming
PTEN诱导的激酶1（pink 1）或parkin的突变导致常染色体隐性遗传和一些散发形式的帕金森病。pink 1在果蝇中在一个共同的遗传途径中作用于parkin的上游，以调节线粒体的完整性。线粒体形态通过线粒体融合（mfn）和视神经萎缩1（opal）控制的线粒体融合与drp 1控制的线粒体分裂的相反作用之间的动态平衡来维持。在这里，我们探讨pink 1/parkin和线粒体融合/裂变机制之间的相互作用。肌肉特异性敲除Mfn（Marf）或蛋白石的果蝇同源物，或过表达drp 1，导致显著的线粒体片段化。mfn基因敲除的果蝇也表现出嵴形态的改变。有趣的是，敲低Mfn或蛋白石或过表达drp 1，挽救了pink 1或parkin突变体的肌肉变性，细胞死亡和线粒体异常的表型。在雄性生殖系中，我们也观察到pink 1和测试特异性mfn同源物模糊洋葱之间的遗传相互作用，以及pink 1和drp 1之间的遗传相互作用。我们的数据表明pink 1/parkin通路通过负调节mfn和opal功能和/或正调节drp 1促进线粒体分裂和/或抑制融合。然而，pink 1和parkin突变果蝇显示出与drp 1突变果蝇不同的线粒体表型，并且携带drp 1杂合突变的果蝇增强了pink 1-null表型，导致致死性。这些结果表明pink 1和parkin可能不是drp 1介导的线粒体分裂机制的核心成分。融合和裂变的修饰可能代表帕金森病的新治疗策略。
Mutations in PTEN-induced kinase 1 (pink1) or parkin cause autosomal-recessive and some sporadic forms of Parkinson's disease. pink1 acts upstream of parkin in a common genetic pathway to regulate mitochondrial integrity in Drosophila. Mitochondrial morphology is maintained by a dynamic balance between the opposing actions of mitochondrial fusion, controlled by Mitofusin (mfn) and Optic atrophy 1 (opal), and mitochondrial fission, controlled by drp1. Here, we explore interactions between pink1/parkin and the mitochondrial fusion/fission machinery. Muscle-specific knockdown of the fly homologue of Mfn (Marf) or opal, or overexpression of drp1, results in significant mitochondrial fragmentation. Mfn-knockdown flies also display altered cristae morphology. Interestingly, knockdown of Mfn or opal or overexpression of drp1, rescues the phenotypes of muscle degeneration, cell death, and mitochondrial abnormalities in pink1 or parkin mutants. In the male germline, we also observe genetic interactions between pink1 and the testes-specific mfn homologue fuzzy onion, and between pink1 and drp1. Our data suggest that the pink1/parkin pathway promotes mitochondrial fission and/or inhibits fusion by negatively regulating mfn and opal function, and/or positively regulating drp1. However, pink1 and parkin mutant flies show distinct mitochondrial phenotypes from drp1 mutant flies, and flies carrying a heterozygous mutation in drp1 enhance the pink1-null phenotype, resulting in lethality. These results suggest that pink1 and parkin are likely not core components of the drp1-mediated mitochondrial fission machinery. Modification of fusion and fission may represent a novel therapeutic strategy for Parkinson's disease.