Department of Environmental Health, School of Public Health, China Medical University, China.
Department of Environmental Health, School of Public Health, China Medical University, China.
Sci Total Environ. 2022 Oct 20;844:157134. doi: 10.1016/j.scitotenv.2022.157134. Epub 2022 Jul 2.
Manganese (Mn) toxicity is mainly caused by excessive Mn content in drinking water and occupational exposure. Moreover, overexposure to Mn can impair mental, cognitive, memory, and motor capacities. Although melatonin (Mel) can protect against Mn-induced neuronal damage and mitochondrial fragmentation, the underlying mechanism remains elusive. Here, we examined the related molecular mechanisms underlying Mel attenuating Mn-induced mitochondrial fragmentation through the mammalian sterile 20-like kinase-1 (Mst1)/JNK signaling path. To test the role of Mst1 in mitochondrial fragmentation, we treated mouse primary neurons overexpressing Mst1 with Mel and Mn stimulation. In normal neurons, 10 μM Mel reduced the effects of Mn (200 μM) on Mst1 expression at the mRNA and protein levels and on phosphorylation of JNK and Drp1, Drp1 mitochondrial translocation, and mitochondrial fragmentation. Conversely, overexpression of Mst1 hindered the protective effect of Mel (10 μM) against Mn-induced mitochondrial fragmentation. Anisomycin (ANI), an activator of JNK signaling, was similarly found to inhibit the protective effect of Mel on mitochondria, while Mst1 levels were not significantly changed. Thus, our results demonstrated that 10 μM Mel negatively regulated the Mst1-JNK pathway, thereby reducing excessive mitochondrial fission, maintaining the mitochondrial network, and alleviating Mn-induced mitochondrial dysfunction.
锰（Mn）毒性主要是由饮用水和职业暴露中过量的 Mn 含量引起的。此外，过量的 Mn 会损害精神、认知、记忆和运动能力。虽然褪黑素（Mel）可以保护神经元免受 Mn 诱导的损伤和线粒体碎片化，但潜在的机制仍不清楚。在这里，我们通过哺乳动物 sterile 20-like kinase-1（Mst1）/JNK 信号通路研究了 Mel 减轻 Mn 诱导的线粒体碎片化的相关分子机制。为了测试 Mst1 在线粒体碎片化中的作用，我们用 Mel 和 Mn 刺激处理过表达 Mst1 的小鼠原代神经元。在正常神经元中，10 μM Mel 降低了 Mn（200 μM）对 Mst1 表达的 mRNA 和蛋白水平以及 JNK 和 Drp1 的磷酸化、Drp1 线粒体易位和线粒体碎片化的影响。相反，Mst1 的过表达阻碍了 Mel（10 μM）对 Mn 诱导的线粒体碎片化的保护作用。促分裂原激活的蛋白激酶（JNK）信号的激活剂 anisomycin（ANI）也被发现抑制了 Mel 对线粒体的保护作用，而 Mst1 水平没有明显变化。因此，我们的结果表明，10 μM Mel 负调控 Mst1-JNK 通路，从而减少过度的线粒体分裂，维持线粒体网络，并减轻 Mn 诱导的线粒体功能障碍。
