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Mitochondrial complex I activity in microglia sustains neuroinflammation

Lookup NU author(s): Dr Amy VincentORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

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.


Publication metadata

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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Funding

Funder referenceFunder name
215888/Z/19/ZWellcome Trust
Henry Wellcome Fellowship

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