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Lookup NU author(s): Dr Amy VincentORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
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. Complex I activity in microglia is a potential therapeutic target to foster neuroprotection in chronic inflammatory disorders of the central nervous system3.
Author(s): Peruzzotti-Jametti L, Willis CM, Kzrak G, Hamel R, Pirva L, Ionescu RB, Reisz JA, Prag HA, Garcia-Sergura ME, Wu V, Xiang Y, Barlas B, Casy AM, van der Bosch AMR, Nicaise AM, Roth L, Batces GR, Huang H, Prasad P, Vincent AE, Frezza C, Viscomi C, Balmus G, Takats Z, Marioni JC, D'Alessandro A, Murphy MP, Mohorianu I, Pluchino S
Publication type: Article
Publication status: Published
Journal: Nature
Year: 2024
Volume: 628
Pages: 195–203
Print publication date: 04/04/2024
Online publication date: 13/03/2024
Acceptance date: 06/02/2024
Date deposited: 05/04/2024
ISSN (print): 0028-0836
ISSN (electronic): 1476-4687
Publisher: Nature Publishing Group
URL: https://doi.org/10.1038/s41586-024-07167-9
DOI: 10.1038/s41586-024-07167-9
Data Access Statement: The bulk and single-cell RNA-seq datasets are publicly available in raw (fastq) and processed (expression matrix) format at the Gene Expression Omnibus (GSE248175).[Further details at https://www.nature.com/articles/s41586-024-07167-9#data-availability ] Source data are provided with this paper.
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