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Glutamine supplementation reverses manganese neurotoxicity by eliciting the mitochondrial unfolded protein response
Shixuan Zhang1,2,3, Junrou Zhang1,2, Luli Wu1,2
1Department of Occupational and Environmental Health, School of Public Health, Capital Medical University, Beijing 100069, China.
Abstract:
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 (UPRmt). Furthermore, supplementation with glutamine (Gln) can effectively increase the concentration of GSH and triggered UPRmt which can alleviate mitochondrial dysfunction and counteract the neurotoxicity of Mn. Our findings highlight that UPRmt is involved in Mn-induced neurotoxicity and glutathione metabolic pathway affects UPRmt to reverse Mn neurotoxicity. In addition, Gln supplementation may have potential therapeutic benefits for Mn-related neurological disorders.
Insights
Manganese (Mn) neurotoxicity disrupts mitochondrial function and glutathione metabolism. Glutamine (Gln) supplementation boosts glutathione (GSH) and mitochondrial unfolded protein response (UPRmt), offering a potential therapy for Mn-related neurological disorders.
Area of Science:
- Neuroscience
- Toxicology
- Mitochondrial Biology
Background:
- Manganese (Mn) exposure causes neurological issues, with unclear mechanisms.
- Abnormal mitochondrial metabolism is implicated in Mn neurotoxicity.
- Therapies targeting neuronal mitochondrial metabolism are promising.
Purpose of the Study:
- Investigate Mn's impact on mitochondrial neurometabolic pathways.
- Elucidate the role of glutathione and mitochondrial unfolded protein response (UPRmt) in Mn neurotoxicity.
- Evaluate glutamine (Gln) as a potential therapeutic agent.
Main Methods:
- Single-cell sequencing in zebrafish dopaminergic neurons.
- Metabolomic analysis in human neuroblastoma (SH-SY5Y) cells.
- Assessment of glutathione (GSH) and UPRmt levels following Mn exposure and Gln supplementation.
Main Results:
- Mn exposure altered mitochondrial pathways and UPRmt in zebrafish.
- Mn inhibited the glutathione metabolic pathway and GSH levels in human cells.
- Glutamine (Gln) supplementation increased GSH, triggered UPRmt, and alleviated Mn-induced mitochondrial dysfunction and neurotoxicity.
Conclusions:
- Mitochondrial unfolded protein response (UPRmt) is crucial in Mn neurotoxicity.
- The glutathione metabolic pathway influences UPRmt to counteract Mn neurotoxicity.
- Glutamine (Gln) shows therapeutic potential for Mn-related neurological disorders.
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