Mitochondrial complex I activity in microglia sustains neuroinflammation

Sustained smouldering, or low-grade activation, of myeloid cells is a common hallmark of several chronic neurological diseases, including multiple sclerosis 1 . Distinct metabolic and mitochondrial features guide the activation and the diverse functional states of myeloid cells 2 . However, how thes...

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Published in:	Nature (London) Vol. 628; no. 8006; pp. 195 - 203
Main Authors:	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.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 04-04-2024 Nature Publishing Group
Subjects:	101/58 13/106 13/31 13/51 14/63 38/91 631/378/2596/1953 631/378/371 64/60 Animal diseases Animal health Cell activation Central nervous system Datasets Disease Electron transport Electron transport chain Genes Humanities and Social Sciences Inflammatory diseases Metabolism Metabolites Microglia Mitochondria multidisciplinary Myeloid cells NADH-ubiquinone oxidoreductase Nervous system Neurological diseases Neuroprotection Neurotoxicity Oxygen Reactive oxygen species Science Science (multidisciplinary) Smoldering Spinal cord Therapeutic targets Tumor necrosis factor-TNF
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Summary:	Sustained smouldering, or low-grade activation, of myeloid cells is a common hallmark of several chronic neurological diseases, including multiple sclerosis 1 . Distinct metabolic and mitochondrial features guide the activation and the diverse functional states of myeloid cells 2 . 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. Complex I activity in microglia is a potential therapeutic target to foster neuroprotection in chronic inflammatory disorders of the central nervous system 3 . 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0028-0836 1476-4687
DOI:	10.1038/s41586-024-07167-9