Glutamine supplementation reverses manganese neurotoxicity by eliciting the mitochondrial unfolded protein response

Excessive exposure to manganese (Mn) can cause neurological abnormalities, but the mechanism of Mn neurotoxicity remains unclear. Previous studies have shown that abnormal mitochondrial metabolism is a crucial mechanism underlying Mn neurotoxicity. Therefore, improving neurometabolic in neuronal mitochondria may be a potential therapy for Mn neurotoxicity. Here, single-cell sequencing revealed that Mn affected mitochondrial neurometabolic pathways and unfolded protein response in zebrafish dopaminergic neurons. Metabolomic analysis indicated that Mn inhibited the glutathione metabolic pathway in human neuroblastoma (SH-SY5Y) cells. Mechanistically, Mn exposure inhibited glutathione (GSH) and mitochondrial unfolded protein response (UPR(mt)). Furthermore, supplementation with glutamine (Gln) can effectively increase the concentration of GSH and triggered UPR(mt) which can alleviate mitochondrial dysfunction and counteract the neurotoxicity of Mn. Our findings highlight that UPR(mt) is involved in Mn-induced neurotoxicity and glutathione metabolic pathway affects UPR(mt) to reverse Mn neurotoxicity. In addition, Gln supplementation may have potential therapeutic benefits for Mn-related neurological disorders.