MitoQ protects dopaminergic neurons in a 6-OHDA induced PD model by enhancing Mfn2-dependent mitochondrial fusion via activation of PGC-1α.
MitoQ protects dopaminergic neurons in a 6-OHDA induced PD model by enhancing Mfn2-dependent mitochondrial fusion via activation of PGC-1α.
复制标题
MitoQ 通过激活 PGC-1α 来增强 Mfn2 依赖性线粒体融合，从而保护 6-OHDA 诱导的 PD 模型中的多巴胺能神经元。
DOI：
10.1016/j.bbadis.2018.05.018
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发表时间：
2018-09
期刊：
影响因子：
--
通讯作者：
Zhao G
中科院分区：
文献类型：
--
作者：
Xi Y;Feng D;Tao K;Wang R;Shi Y;Qin H;Murphy MP;Yang Q;Zhao G
帕金森病(PD)是以黑质致密质多巴胺能神经元变性为特征的疾病。虽然线粒体功能障碍是帕金森病发病的关键因素，但其潜在的分子机制尚不清楚，因此缺乏有效的医学干预措施。线粒体的分裂和融合在维持线粒体功能和细胞活力方面起着重要作用。在这里，我们研究了线粒体靶向抗氧化剂MitoQ在6-羟基多巴胺(6-OHDA)诱导的体外和活体PD模型中的作用。我们观察到，6-OHDA通过降低Mfn1、Mfn2和OPA1的表达以及增加Drp1的表达来促进多巴胺能(DA)细胞系SN4741的线粒体分裂。值得注意的是，MitoQ处理特别上调了Mfn2的蛋白和mRNA水平，并以Mfn2依赖的方式促进了6-OHDA存在下的线粒体融合。此外，MitoQ还在6-OHDA存在下稳定了线粒体的形态和功能，进一步抑制了活性氧物种(ROS)的形成，并改善了线粒体的碎裂和细胞凋亡。此外，过氧化体增殖物激活受体γ辅活化子1α(PGC-1α)的激活归因于MitoQ诱导的Mfn2表达上调。与这些发现一致的是，在6-OHDA处理的小鼠中，给予MitoQ显著挽救了黑质Mfn2表达的减少和黑质DA神经元的丢失。综上所述，我们的发现表明，MitoQ通过激活pGC-1α促进依赖于mfn2的线粒体融合来保护6-羟基多巴胺诱导的帕金森病模型中的DA神经元。
Parkinson's disease (PD) is characterized by the degeneration of dopaminergic neurons in the substantia nigra compacta (SNc). Although mitochondrial dysfunction is the critical factor in the pathogenesis of PD, the underlying molecular mechanisms are not well understood, and as a result, effective medical interventions are lacking. Mitochondrial fission and fusion play important roles in the maintenance of mitochondrial function and cell viability. Here, we investigated the effects of MitoQ, a mitochondria-targeted antioxidant, in 6-hydroxydopamine (6-OHDA)-inducedin vitroandin vivoPD models. We observed that 6-OHDA enhanced mitochondrial fission by decreasing the expression of Mfn1, Mfn2 and OPA1 as well as by increasing the expression of Drp1 in the dopaminergic (DA) cell line SN4741. Notably, MitoQ treatment particularly upregulated the Mfn2 protein and mRNA levels and promoted mitochondrial fusion in the presence of 6-OHDA in a Mfn2-dependent manner. In addition, MitoQ also stabilized mitochondrial morphology and function in the presence of 6-OHDA, which further suppressed the formation of reactive oxygen species (ROS), as well as ameliorated mitochondrial fragmentation and cellular apoptosis. Moreover, the activation of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) was attributed to the upregulation of Mfn2 induced by MitoQ. Consistent with these findings, administration of MitoQ in 6-OHDA-treated mice significantly rescued the decrease of Mfn2 expression and the loss of DA neurons in the SNc. Taken together, our findings suggest that MitoQ protects DA neurons in a 6-OHDA induced PD model by activating PGC-1α to enhance Mfn2-dependent mitochondrial fusion.
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DOI：
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发表时间：
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影响因子：
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作者：
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