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Melatonin attenuates manganese-induced mitochondrial fragmentation by suppressing the Mst1/JNK signaling pathway in
Zhuo-Fan Liu1, Kuan Liu1, Zhi-Qi Liu1
1Department of Environmental Health, School of Public Health, China Medical University, China.
Abstract:
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.
Insights
Melatonin (Mel) protects against manganese (Mn) toxicity by inhibiting the Mst1-JNK pathway, reducing mitochondrial fragmentation and dysfunction. This study elucidates the molecular mechanism behind Mel
Area of Science:
- Neuroscience
- Toxicology
- Cell Biology
Background:
- Manganese (Mn) toxicity from drinking water and occupational exposure impairs cognitive and motor functions.
- Melatonin (Mel) shows neuroprotective effects against Mn-induced neuronal damage and mitochondrial fragmentation, but the mechanism is unclear.
Purpose of the Study:
- To investigate the molecular mechanisms by which Mel attenuates Mn-induced mitochondrial fragmentation.
- To examine the role of the mammalian sterile 20-like kinase-1 (Mst1)/JNK signaling pathway in Mel's protective effects against Mn toxicity.
Main Methods:
- Primary mouse neurons were treated with Mel and Mn.
- Mst1 overexpression and JNK signaling activator (Anisomycin) were used to test pathway involvement.
- Mst1 expression, JNK phosphorylation, Drp1 translocation, and mitochondrial morphology were analyzed.
Main Results:
- Mel (10 μM) reduced Mn-induced effects on Mst1 expression, JNK phosphorylation, Drp1 mitochondrial translocation, and fragmentation in normal neurons.
- Mst1 overexpression blocked Mel's protective effects against Mn-induced mitochondrial fragmentation.
- Anisomycin inhibited Mel's protective effect on mitochondria, without altering Mst1 levels.
Conclusions:
- Melatonin negatively regulates the Mst1-JNK pathway to mitigate Mn-induced mitochondrial fragmentation and dysfunction.
- Melatonin preserves mitochondrial networks by reducing excessive mitochondrial fission.
- The findings provide insight into the molecular basis of melatonin's neuroprotective action against manganese toxicity.
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