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Mitochondrial complex I activity in microglia sustains neuroinflammation

Author

Listed:
  • L. Peruzzotti-Jametti

    (University of Cambridge
    Imperial College London)

  • C. M. Willis

    (University of Cambridge)

  • G. Krzak

    (University of Cambridge)

  • R. Hamel

    (University of Cambridge)

  • L. Pirvan

    (University of Cambridge)

  • R.-B. Ionescu

    (University of Cambridge)

  • J. A. Reisz

    (University of Colorado School of Medicine)

  • H. A. Prag

    (University of Cambridge, Cambridge Biomedical Campus)

  • M. E. Garcia-Segura

    (University of Cambridge)

  • V. Wu

    (Imperial College London)

  • Y. Xiang

    (Imperial College London)

  • B. Barlas

    (University of Cambridge
    University of Cambridge)

  • A. M. Casey

    (University of Cambridge, Cambridge Biomedical Campus)

  • A. M. R. Bosch

    (University of Cambridge)

  • A. M. Nicaise

    (University of Cambridge)

  • L. Roth

    (University of Cambridge)

  • G. R. Bates

    (University of Cambridge, Cambridge Biomedical Campus)

  • H. Huang

    (Imperial College London)

  • P. Prasad

    (University of Cambridge)

  • A. E. Vincent

    (Newcastle University)

  • C. Frezza

    (University Hospital Cologne)

  • C. Viscomi

    (University of Padua)

  • G. Balmus

    (University of Cambridge
    University of Cambridge
    Transylvanian Institute of Neuroscience)

  • Z. Takats

    (Imperial College London)

  • J. C. Marioni

    (European Bioinformatics Institute, EMBL-EBI, Wellcome Genome Campus)

  • A. D’Alessandro

    (University of Colorado School of Medicine)

  • M. P. Murphy

    (University of Cambridge, Cambridge Biomedical Campus)

  • I. Mohorianu

    (University of Cambridge)

  • S. Pluchino

    (University of Cambridge)

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.

Suggested Citation

  • L. Peruzzotti-Jametti & C. M. Willis & G. Krzak & R. Hamel & L. Pirvan & R.-B. Ionescu & J. A. Reisz & H. A. Prag & M. E. Garcia-Segura & V. Wu & Y. Xiang & B. Barlas & A. M. Casey & A. M. R. Bosch & , 2024. "Mitochondrial complex I activity in microglia sustains neuroinflammation," Nature, Nature, vol. 628(8006), pages 195-203, April.
    • Handle: RePEc:nat:nature:v:628:y:2024:i:8006:d:10.1038_s41586-024-07167-9
    DOI: 10.1038/s41586-024-07167-9
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