Melatonin attenuates manganese-induced mitochondrial fragmentation by suppressing the Mst1/JNK signaling pathway in primary mouse neurons

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 mito-chondrial 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 mu M Mel reduced the effects of Mn (200 mu M) 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 mu M) 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 mu M Mel negatively regulated the Mst1-JNK pathway, thereby reducing excessive mitochondrial fission, maintaining the mitochondrial network, and alleviating Mn-induced mitochondrial dysfunction.

Automated summary

Excessive manganese exposure can lead to manganese toxicity, which can be alleviated by melatonin through regulating the Mst1-JNK signaling pathway, reducing manganese-induced mitochondrial fragmentation, and maintaining mitochondrial network.