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The Parkinson's disease genes pink1 and parkin promote mitochondrial fission and/or inhibit fusion in Drosophila

机译:帕金森氏病基因pink1和parkin促进果蝇的线粒体分裂和/或抑制融合

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摘要

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 (opa1), 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 opa1, or overexpression of drp1, results in significant mitochondrial fragmentation. Mfn-knockdown flies also display altered cristae morphology. Interestingly, knockdown of Mfn or opa1 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 opa1 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.
机译:PTEN诱导的激酶1(pink1)或派克蛋白的突变会导致常染色体隐性和帕金森氏病的一些散发性形式。 pink1在常见的遗传途径中调节parkin的上游,以调节果蝇的线粒体完整性。线粒体形态由线粒体融合蛋白(mfn)和视神经萎缩1(opa1)控制的线粒体融合的相反作用与drp1控制的线粒体裂变之间的动态平衡保持。在这里,我们探索粉红色1 / parkin和线粒体融合/裂变机制之间的相互作用。 Mfn(Marf)或opa1的蝇蝇同源物的肌肉特异性敲低或drp1的过度表达导致明显的线粒体片段化。 Mfn-nockdown苍蝇也显示出cr形态的改变。有趣的是,敲低Mfn或opa1或drp1的过度表达,可以挽救pink1或parkin突变体中的肌肉变性,细胞死亡和线粒体异常的表型。在雄性种系中,我们还观察到pink1和睾丸特异性mfn同源模糊洋葱之间以及pink1和drp1之间的遗传相互作用。我们的数据表明pink1 / parkin途径通过负调节mfn和opa1功能和/或正调节drp1促进线粒体裂变和/或抑制融合。但是,pink1和parkin突变体蝇显示出与drp1突变体蝇不同的线粒体表型,并且在drp1中携带杂合突变的蝇增强了pink1无效表型,导致致死性。这些结果表明pink1和parkin可能不是drp1介导的线粒体分裂机制的核心组成部分。融合和裂变的改变可能代表了帕金森氏病的一种新颖的治疗策略。

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