The Interaction of Mitochondrial Biogenesis and Fission/Fusion Mediated by PGC-1α Regulates Rotenone-Induced Dopaminergic Neurotoxicity
The Interaction of Mitochondrial Biogenesis and Fission/Fusion Mediated by PGC-1α Regulates Rotenone-Induced Dopaminergic Neurotoxicity
复制标题
PGC-1α 介导的线粒体生物发生和裂变/融合的相互作用调节鱼藤酮诱导的多巴胺能神经毒性
DOI：
10.1007/s12035-016-9944-9
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发表时间：
2017-07-01
影响因子：
5.1
通讯作者：
Cao, Jia
中科院分区：
文献类型：
--
作者：
Peng, Kaige;Yang, Likui;Cao, Jia
帕金森病是老年人常见的神经退行性疾病，线粒体缺陷是帕金森病发病机制的基础。线粒体稳态的损害导致活性氧的形成，这反过来又可以增强功能失调线粒体的积累，在神经元中形成恶性循环。线粒体裂变/融合和生物发生在维持线粒体稳态中起着重要作用。据报道，PGC-1 α是一种强大的转录因子，广泛参与线粒体生物发生、氧化应激等过程的调控。因此，我们探索了线粒体生物发生、线粒体裂变/融合，特别是PGC-1 α作为它们在鱼tenone诱导的多巴胺神经毒性中相互作用的信号机制的关键。结果显示，线粒体数量和质量显著减少，并伴有已知调节线粒体裂变/融合的蛋白质（MFN2, OPA1， Drp1和Fis1）和线粒体生物发生（PGC-1 α和mtTFA）的改变。进一步的实验证明，抑制线粒体裂变或促进线粒体融合对鱼藤酮诱导的神经毒性具有保护作用，并促进线粒体的生物发生。通过建立PGC-1 α过表达和过表达的细胞模型，我们发现PGC-1 α可以调节MFN2和Drp1蛋白的表达和磷酸化，从而影响线粒体的裂变/融合。综上所述，PGC-1 α介导的线粒体生物发生和裂变/融合之间的串扰参与了鱼藤酮诱导的多巴胺能神经变性。
Parkinson's disease is a common neurodegenerative disease in the elderly, and mitochondrial defects underlie the pathogenesis of PD. Impairment of mitochondrial homeostasis results in reactive oxygen species formation, which in turn can potentiate the accumulation of dysfunctional mitochondria, forming a vicious cycle in the neuron. Mitochondrial fission/fusion and biogenesis play important roles in maintaining mitochondrial homeostasis. It has been reported that PGC-1 alpha is a powerful transcription factor that is widely involved in the regulation of mitochondrial biogenesis, oxidative stress, and other processes. Therefore, we explored mitochondrial biogenesis, mitochondrial fission/fusion, and especially PGC-1 alpha as the key point in the signaling mechanism of their interaction in rotenone-induced dopamine neurotoxicity. The results showed that mitochondrial number and mass were reduced significantly, accompanied by alterations in proteins known to regulate mitochondrial fission/fusion (MFN2, OPA1, Drp1, and Fis1) and mitochondrial biogenesis (PGC-1 alpha and mtTFA). Further experiments proved that inhibition of mitochondrial fission or promotion of mitochondrial fusion has protective effects in rotenone-induced neurotoxicity and also promotes mitochondrial biogenesis. By establishing cell models of PGC-1 alpha overexpression and reduced expression, we found that PGC-1 alpha can regulate MFN2 and Drp1 protein expression and phosphorylation to influence mitochondrial fission/fusion. In summary, it can be concluded that PGC-1 alpha-mediated cross talk between mitochondrial biogenesis and fission/fusion contributes to rotenone-induced dopaminergic neurodegeneration.