Pink1 regulates mitochondrial dynamics through interaction with the fission/fusion machinery
Pink1 regulates mitochondrial dynamics through interaction with the fission/fusion machinery
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DOI：
10.1073/pnas.0711845105
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发表时间：
2008-05-13
影响因子：
11.1
通讯作者：
Lu, Bingwei
中科院分区：
文献类型：
--
作者：
Yang, Yufeng;Ouyang, Yingshi;Lu, Bingwei
线粒体通过分裂和融合形成动态的管状网络，通过分裂和融合发生频繁的形态变化，这种不平衡会影响细胞的存活，特别是影响神经元的突触传递和可塑性。线粒体分裂/融合机制的一些核心组件已经被鉴定，包括动力蛋白样GTP酶Drp1、Mitofusin、OPA1和Drp1相互作用蛋白Fis1。在正常情况下，线粒体的分裂和融合过程是如何调节的，以及线粒体分裂/融合缺陷在不同的疾病条件下所涉及的程度还知之甚少。线粒体功能障碍往往会导致具有脑和骨骼肌症状的疾病，并与帕金森氏病(PD)等神经退行性疾病有关。线粒体的异常分裂或融合是否在帕金森病的发病机制中起作用尚未得到证实。在这里，我们展示了PINK1，一种线粒体靶向的丝氨酸/苏氨酸激酶，与家族性PID连锁，在基因上与线粒体分裂/融合机制相互作用，并调节线粒体的动力学。促进线粒体分裂的基因操作抑制了果蝇间接飞行肌肉和多巴胺神经元中PINK1突变的表型，而减少分裂则有相反的效果。在果蝇和哺乳动物细胞中，PINK1的过度表达促进线粒体的分裂，而抑制PINK1则导致过度融合。我们的遗传交互作用结果表明，Fis1可能在PINK1和Drp1之间发挥作用，控制线粒体的分裂。这些结果揭示了PINK1的细胞生物学作用，并建立了线粒体分裂/融合作为PID研究的范例。调节线粒体分裂/融合的化合物可能在帕金森病干预中具有治疗价值。
Mitochondria form dynamic tubular networks that undergo frequent morphological changes through fission and fusion, the imbalance of which can affect cell survival in general and impact synaptic transmission and plasticity in neurons in particular. Some core components of the mitochondrial fission/fusion machinery, including the dynamin-like GTPases Drp1, Mitofusin, Opa1, and the Drp1-interacting protein Fis1, have been identified. How the fission and fusion processes are regulated under normal conditions and the extent to which defects in mitochondrial fission/fusion are involved in various disease conditions are poorly understood. Mitochondrial malfunction tends to cause diseases with brain and skeletal muscle manifestations and has been implicated in neurodegenerative diseases such as Parkinson's disease (PD). Whether abnormal mitochondrial fission or fusion plays a role in PD pathogenesis has not been shown. Here, we show that Pink1, a mitochondria-targeted Ser/Thr kinase linked to familial PID, genetically interacts with the mitochondrial fission/fusion machinery and modulates mitochondrial dynamics. Genetic manipulations that promote mitochondrial fission suppress Drosophila Pink1 mutant phenotypes in indirect flight muscle and dopamine neurons, whereas decreased fission has opposite effects. In Drosophila and mammalian cells, overexpression of Pink1 promotes mitochondrial fission, whereas inhibition of Pink1 leads to excessive fusion. Our genetic interaction results suggest that Fis1 may act in-between Pink1 and Drp1 in controlling mitochondrial fission. These results reveal a cell biological role for Pink1 and establish mitochondrial fission/fusion as a paradigm for PID research. Compounds that modulate mitochondrial fission/fusion could have therapeutic value in PD intervention.