Parkinson's disease-associated kinase PINK1 regulates Miro protein level and axonal transport of mitochondria.
Parkinson's disease-associated kinase PINK1 regulates Miro protein level and axonal transport of mitochondria.
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DOI：
10.1371/journal.pgen.1002537
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Lu B
中科院分区：
文献类型：
--
作者：
Liu S;Sawada T;Lee S;Yu W;Silverio G;Alapatt P;Millan I;Shen A;Saxton W;Kanao T;Takahashi R;Hattori N;Imai Y;Lu B
Pten诱导激酶1(PINK1)的突变与早发性家族性帕金森病(FPD)有关。此前，PINK1与线粒体分裂/融合动力学、质量控制和电子传输链功能有关。然而，目前还不清楚这些过程是如何相互联系的，以及它们是否足以解释PINK1发病的所有方面。在这里，我们展示了PINK1也控制线粒体的运动。在果蝇中，dMiro或线粒体运输机制的其他组成部分的下调拯救了肌肉和多巴胺(DA)神经元中的dPINK1突变表型，而dMiro的过度表达单独导致DA神经元的丢失。DPINK1突变体的dMiro蛋白水平升高，而dPINK1或dParkin过表达条件下dMiro蛋白水平降低。在果蝇幼虫运动神经元中，dPINK1的过表达抑制了轴突线粒体的顺行和逆行运输，而dPINK1基因敲除则促进了顺行运输。在HeLa细胞中，过表达的hPINK1与另一个FPD基因hParkin一起调节hMiro1和hMiro2的泛素化和降解，显然是以Ser-156磷酸化不依赖的方式。同样在HeLa细胞中，hMiro的丢失促进了线粒体的核周聚集，并促进了受损线粒体的自噬，这一效应以前与PINK1/Parkin通路的激活有关。这些新发现的PINK1/Parkin和Miro在线粒体转运和有丝分裂中的功能有助于我们理解线粒体质量控制中复杂的相互作用，这些相互作用在PD的发病机制中至关重要，它们可能解释一些携带特定PINK1或Parkin突变的PD患者的周围神经病症状。此外，PINK1功能丧失对果蝇和小鼠细胞MIRO蛋白水平的不同影响可能为这两个物种中PINK1突变体的不同表型表现提供了一种解释。帕金森病(PD)是第二常见的神经退行性疾病。它主要影响老年人的运动，传统上被认为是一种原因不明的零星疾病。家族性帕金森病(FPD)相关基因的发现表明，个体的遗传构成可以显著影响帕金森病的发病机制。了解这些FPD基因的功能将有助于更好地了解散发性PD病例。PINK1和Parkin是与FPD相关的基因，会影响早期患者。由于线粒体质量控制系统的损伤，PINK1和Parkin的突变会导致受损的线粒体积累，线粒体是细胞的动力源。然而，PINK1/Parkin的作用机制仍然知之甚少。在这里，我们展示了PINK1和Parkin共同作用来调节线粒体运输机制的关键组成部分Miro，并且PINK1的活动改变导致了线粒体的异常运输。线粒体转运的调节可能是PINK1/Parkin通路控制线粒体质量的机制中的一个重要方面。这一过程的功能障碍可能导致帕金森病的基本特征--DA神经元的丧失，以及与特定的PINK1或Parkin突变相关的周围神经病症状。
Mutations in Pten-induced kinase 1 (PINK1) are linked to early-onset familial Parkinson's disease (FPD). PINK1 has previously been implicated in mitochondrial fission/fusion dynamics, quality control, and electron transport chain function. However, it is not clear how these processes are interconnected and whether they are sufficient to explain all aspects of PINK1 pathogenesis. Here we show that PINK1 also controls mitochondrial motility. In Drosophila, downregulation of dMiro or other components of the mitochondrial transport machinery rescued dPINK1 mutant phenotypes in the muscle and dopaminergic (DA) neurons, whereas dMiro overexpression alone caused DA neuron loss. dMiro protein level was increased in dPINK1 mutant but decreased in dPINK1 or dParkin overexpression conditions. In Drosophila larval motor neurons, overexpression of dPINK1 inhibited axonal mitochondria transport in both anterograde and retrograde directions, whereas dPINK1 knockdown promoted anterograde transport. In HeLa cells, overexpressed hPINK1 worked together with hParkin, another FPD gene, to regulate the ubiquitination and degradation of hMiro1 and hMiro2, apparently in a Ser-156 phosphorylation-independent manner. Also in HeLa cells, loss of hMiro promoted the perinuclear clustering of mitochondria and facilitated autophagy of damaged mitochondria, effects previously associated with activation of the PINK1/Parkin pathway. These newly identified functions of PINK1/Parkin and Miro in mitochondrial transport and mitophagy contribute to our understanding of the complex interplays in mitochondrial quality control that are critically involved in PD pathogenesis, and they may explain the peripheral neuropathy symptoms seen in some PD patients carrying particular PINK1 or Parkin mutations. Moreover, the different effects of loss of PINK1 function on Miro protein level in Drosophila and mouse cells may offer one explanation of the distinct phenotypic manifestations of PINK1 mutants in these two species. Parkinson's disease (PD) is the second most common neurodegenerative disease. It mainly affects movement in elderly people and was traditionally considered a sporadic disease with no known cause. Discoveries of genes associated with familial PD (FPD) have demonstrated that PD pathogenesis can be significantly influenced by an individual's genetic makeup. Understanding the functions of these FPD genes will allow better understanding of the sporadic PD cases. PINK1 and Parkin are genes associated with FPD that affect patients at an early age. Mutations in PINK1 and Parkin lead to the accumulation of damaged mitochondria, the powerhouse of the cell, as a result of impairments of the mitochondrial quality control system. However, the mechanism of PINK1/Parkin action remains poorly understood. Here we show that PINK1 and Parkin act together to regulate Miro, a key component of the mitochondrial transport machinery, and that altered activities of PINK1 cause aberrant mitochondrial transport. Regulation of mitochondrial transport may be a critical aspect of the mechanisms by which the PINK1/Parkin pathway governs mitochondrial quality control. Dysfunction of this process could contribute to the loss of DA neurons, the cardinal feature of PD, as well as the peripheral neuropathy symptom associated with particular PINK1 or Parkin mutations.
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影响因子：
4.5
作者：
Imai Y;Kanao T;Sawada T;Kobayashi Y;Moriwaki Y;Ishida Y;Takeda K;Ichijo H;Lu B;Takahashi R
通讯作者：
Takahashi R
影响因子：
3.7
作者：
Akundi RS;Huang Z;Eason J;Pandya JD;Zhi L;Cass WA;Sullivan PG;Büeler H
通讯作者：
Büeler H
影响因子：
3.6
作者：
Fernandes C;Rao Y
通讯作者：
Rao Y
DOI：
10.1146/annurev.pathol.3.121806.151529
发表时间：
2009
期刊：
Annual review of pathology
影响因子：
--
作者：
Lu B;Vogel H
通讯作者：
Vogel H
影响因子：
5.7
作者：
Imai Y;Lu B
通讯作者：
Lu B