Mitochondrial complex I activity in microglia sustains neuroinflammation

• 成果类型: Article
• 署名作者: Peruzzotti-Jametti, L.; Willis, C. M.; Krzak, G.; Hamel, R.; Pirvan, L.; Ionescu, R. -b.; Reisz, J. A.; Prag, H. A.; Garcia-Segura, M. E.; Wu, V.; Xiang, Y.; Barlas, B.; Casey, A. M.; van den Bosch, A. M. R.; Nicaise, A. M.; Roth, L.; Bates, G. R.; Huang, H.; Prasad, P.; Vincent, A. E.; Frezza, C.; Viscomi, C.; Balmus, G.; Takats, Z.; Marioni, J. C.; D'Alessandro, A.; Murphy, M. P.; Mohorianu, I.; Pluchino, S.
• 署名单位: University of Cambridge; University of Cambridge; Imperial College London; University of Cambridge; University of Colorado System; University of Colorado Anschutz Medical Campus; University of Cambridge; University of Cambridge; Newcastle University - UK; University of Cologne; University of Padua; European Molecular Biology Laboratory (EMBL); European Bioinformatics Institute
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4858
• DOI: 10.1038/s41586-024-07167-9
• 发表日期: 2024-04-04
• 关键词: succinate-dehydrogenase; stem-cells; ndufs4

摘要

Sustained smouldering, or low-grade activation, of myeloid cells is a common hallmark of several chronic neurological diseases, including multiple sclerosis1. Distinct metabolic and mitochondrial features guide the activation and the diverse functional states of myeloid cells2. However, how these metabolic features act to perpetuate inflammation of the central nervous system is unclear. Here, using a multiomics approach, we identify a molecular signature that sustains the activation of microglia through mitochondrial complex I activity driving reverse electron transport and the production of reactive oxygen species. Mechanistically, blocking complex I in pro-inflammatory microglia protects the central nervous system against neurotoxic damage and improves functional outcomes in an animal disease model in vivo. Ccomplex I activity in microglia is a potential therapeutic target to foster neuroprotection in chronic inflammatory disorders of the central nervous system3. Blocking mitochondrial complex I in pro-inflammatory microglia protects the central nervous system against neurotoxic damage and improves functional outcomes in vivo in an animal disease model.