The PINK1/Parkin pathway regulates mitochondrial dynamics and function in mammalian hippocampal and dopaminergic neurons
The PINK1/Parkin pathway regulates mitochondrial dynamics and function in mammalian hippocampal and dopaminergic neurons
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DOI：
10.1093/hmg/ddr235
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发表时间：
2011-08-15
影响因子：
3.5
通讯作者：
Lu, Bingwei
中科院分区：
文献类型：
--
作者：
Yu, Wendou;Sun, Yaping;Lu, Bingwei
PTEN诱导的推定激酶1（PINK1）和Parkin在调节线粒体动力学的共同途径中起作用，其在帕金森病（PD）的发病机制中的参与越来越受到重视。然而，PINK1/Parkin通路如何影响线粒体功能还没有很好地理解，并且该通路在控制线粒体动力学中的确切作用仍然存在争议。在这里，我们使用哺乳动物原代神经元来检查PINK1/Parkin通路在调节线粒体动力学和功能中的功能。在大鼠海马神经元中，PINK1或Parkin过表达导致线粒体数量增加，线粒体尺寸减小，神经元过程的线粒体占用减少，表明线粒体分裂/融合动力学的平衡倾向于更多的分裂。相反，PINK1的失活导致线粒体延长，表明线粒体分裂/融合动力学的平衡倾向于更多的融合。此外，过表达分裂蛋白Drp1（动力蛋白相关蛋白1）或敲低融合蛋白OPA1（视神经萎缩1）抑制PINK1 RNAi诱导的线粒体形态缺陷，过表达PINK1或Parkin抑制由Drp1 RNAi引起的延长线粒体表型。在功能上，PINK1敲低和过表达对树突棘形成和神经元对兴奋性毒性的脆弱性具有相反的影响。最后，我们发现PINK1/Parkin类似地影响大鼠中脑多巴胺能神经元的线粒体动力学。这些结果，连同先前在果蝇多巴胺能神经元中的发现，表明PINK1/Parkin通路在调节神经元线粒体动力学和功能中起保守作用。
PTEN-induced putative kinase 1 (PINK1) and Parkin act in a common pathway to regulate mitochondrial dynamics, the involvement of which in the pathogenesis of Parkinson's disease (PD) is increasingly being appreciated. However, how the PINK1/Parkin pathway influences mitochondrial function is not well understood, and the exact role of this pathway in controlling mitochondrial dynamics remains controversial. Here we used mammalian primary neurons to examine the function of the PINK1/Parkin pathway in regulating mitochondrial dynamics and function. In rat hippocampal neurons, PINK1 or Parkin overexpression resulted in increased mitochondrial number, smaller mitochondrial size and reduced mitochondrial occupancy of neuronal processes, suggesting that the balance of mitochondrial fission/fusion dynamics is tipped toward more fission. Conversely, inactivation of PINK1 resulted in elongated mitochondria, indicating that the balance of mitochondrial fission/fusion dynamics is tipped toward more fusion. Furthermore, overexpression of the fission protein Drp1 (dynamin-related protein 1) or knocking down of the fusion protein OPA1 (optical atrophy 1) suppressed PINK1 RNAi-induced mitochondrial morphological defect, and overexpression of PINK1 or Parkin suppressed the elongated mitochondria phenotype caused by Drp1 RNAi. Functionally, PINK1 knockdown and overexpression had opposite effects on dendritic spine formation and neuronal vulnerability to excitotoxicity. Finally, we found that PINK1/Parkin similarly influenced mitochondrial dynamics in rat midbrain dopaminergic neurons. These results, together with previous findings in Drosophila dopaminergic neurons, indicate that the PINK1/Parkin pathway plays conserved roles in regulating neuronal mitochondrial dynamics and function.