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Excessive manganese (Mn) exposure can cause nerve damage and mitochondrial dysfunction, which may involve defects in mitochondrial dynamics. Resveratrol (RSV) exerts a wide range of beneficial effects via activation of sirtuin 1 (SIRT1) and thus may positively impact Mn-induced mitochondrial damage through the regulation of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α) by SIRT1. In this study, we investigated the molecular mechanisms by which RSV alleviates the nerve injury and mitochondrial fragmentation caused by Mn in C57 BL/6 mice. Our results demonstrated that RSV activated the deacetylase activity of SIRT1 and protected against the surge of mitochondrial reactive oxygen species, the loss of mitochondrial membrane potential, and the attenuation of ATP caused by Mn. RSV, therefore, inhibits mitochondrial fragmentation and safeguards neural cells. Increased deacetylase activity led to a reduction in the acetylation of PGC-1α, which directly regulates DRP1 expression by binding to the DRP1 promoter. The resultant attenuation of DRP1-mediated mitochondrial fragmentation in RSV-pretreated mice was abolished by the addition of the SIRT1 inhibitor EX527. Taken together, these findings indicate that RSV alleviates Mn-induced mitochondrial dysfunction mediated by DRP1 by modulating the SIRT1/PGC-1α signaling pathway.

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.

Exposure to excess levels of manganese (Mn) leads to neurotoxicity. Increasing evidence demonstrates that oxidative stress and neuroinflammation are important pathological causes of neurotoxicity. Resveratrol (Rsv), a sirtuin-1 (SIRT1) activator, plays an important role in neuroprotection. However, the molecular mechanisms of Rsv alleviating Mn-induced oxidative stress and neuroinflammation are not fully understood. To evaluate whether Rsv treatment relieves the oxidative stress and neuroinflammation in the hippocampus after Mn exposure through SIRT1 signaling, C57BL/6 adult mice were exposed to MnCl2 (200 μmol/kg), Rsv (30 mg/kg), and EX527 (5 mg/kg). Our results showed that administering MnCl2 for 6 weeks caused behavioral impairment and nerve cell injury in hippocampal tissue, which was related to oxidative stress and neuroinflammation. Activating Mn-induced JNK and inhibiting SIRT1 increased the phosphorylated and acetylated levels of NF-κB and STAT3, respectively. However, Rsv reduced the phosphorylated and acetylated levels of NF-κB and STAT3, and attenuated Mn-induced oxidative stress and inflammatory cytokines by activating SIRT1 signaling. Most importantly, EX527, a potent SIRT1 inhibitor, inactivated SIRT1, which prevented Rsv from exerting its beneficial effects. Taken together, our findings revealed that Rsv alleviated Mn-induced oxidative stress and neuroinflammation in adult mice by activating SIRT1.

Chronic manganese (Mn) exposure is related to elevated risks of neurodegenerative diseases, and mitochondrial dysfunction is considered a critical pathophysiological feature of Mn neurotoxicity. Although previous research has demonstrated Mn-induced alpha-synuclein (α-Syn) overexpression, the role of α-Syn in mitochondrial dysfunction remains unclear. Here, we used Wistar rats and human neuroblastoma cells (SH-SY5Y cells) to elucidate the molecular mechanisms underlying how α-Syn overexpression induced by different doses of Mn (15, 30, and 60 mg/kg) results in mitochondrial dysfunction. We found that Mn-induced neural cell injury was associated with mitochondrial damage. Furthermore, Mn upregulated α-Syn protein levels and increased the interaction between α-Syn and mitochondria. We then used a lentivirus vector containing α-Syn shRNA to examine the effect of Mn-induced α-Syn protein on PINK1/Parkin-mediated mitophagy in SH-SY5Y cells. Our data demonstrated that the knockdown of α-Syn decreased the interaction between α-Syn and PINK1. The enhanced level of phosphorylated Parkin (p-Parkin) was due to the decrease of the interaction between α-Syn and PINK1. Moreover, the knockdown of α-Syn increased recruitment of p-Parkin to mitochondria. Collectively, these observations revealed that Mn-induced α-Syn overexpression repressed PINK1/Parkin-mediated mitophagy and exacerbated mitochondrial damage.