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Cited by 239Neuroinflammation and Neurodegeneration MechanismsMitochondrial Function and PathologyInflammasome and immune disorders

Mitochondrial complex I activity in microglia sustains neuroinflammation

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Peruzzotti-Jametti, L., Willis, C. M., Krzak, G., Hamel, R., Pirvan, L., Ionescu, R.-B., Reisz, J. A., Prag, H. A. +21 more·2024·Nature
DOI 10.1038/s41586-024-07167-9PMC PMC10990929
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Abstract

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.

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Crossref · 10.1038/s41586-024-07167-9

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  • Disease associated microglia upregulate mitochondrial complex 1 activity to sustain the response to pathology.

    “but it is known that disease associated microglia upregulate mitochondrial complex 1 activity to sustain the response to pathology [75], in line with our pathway analyses of ApoeCh in 5xFAD mice.”

    From APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology (2025) · cites this paper as [75]

  • JAG1 has been shown to regulate microglial function and inflammatory responses.

    “JAG1 has been shown to regulate microglial function and inflammatory responses [75].”

    From APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology (2025) · cites this paper as [75]

    The Main section reports changes in microglial states and neuroinflammation associated with mitochondrial complex I activity, but does not connect those findings to JAG1. Searches for “JAG1,” “Jag1,” and “Jagged1 Notch signaling” found no passage in our copy showing that JAG1 regulates microglial function or inflammatory responses. (LLM, conf=0.74)

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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.
Affiliations
  • University of Cambridge (GB)
  • Wellcome/MRC Cambridge Stem Cell Institute (GB)
  • University of Colorado Anschutz (US)
  • Imperial College London (GB)
  • Wellcome Centre for Mitochondrial Research (GB)
  • University Hospital Cologne (DE)
  • University of Padua (IT)
  • European Bioinformatics Institute (GB)
Corresponding author
Pluchino, S.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2024-03-13
Volume
628
Issue
8006
Pages
195-203
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-024-07167-9
PMC
PMC10990929
OpenAlex
W4392747603
Cited by
239
References
15
Citations by year
2026: 86 · 2025: 108 · 2024: 45
FWCI
37.06
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Research Explorer (The University of Manchester) (submittedVersion)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • Padua Research Archive (University of Padova) (submittedVersion, cc-by)
  • Apollo (cc-by)
Funders
  • Fondazione Italiana Sclerosi Multipla (2017/B/5)
  • Wings for Life (WFL-UK-16/20 Proj:229)
  • European Committee for Treatment and Research in Multiple Sclerosis
  • Wellcome Trust (220257/Z/20/Z, 215888/Z/19/Z, G105713, 215888, 203151/Z/16/Z, 203151)
  • UK Research and Innovation (MC_PC_17230, MC_UU_00028/4)
  • Alzheimer's Society
  • Cancer Research UK
  • National Institute for Health and Care Research
  • Rosetrees Trust (PGL23/100146)
  • Evelyn Trust
  • Isaac Newton Trust (RG 97440, 97440)
  • UK Dementia Research Institute
  • Medical Research Council (MC_PC_17230, MC_UU_00028/4, 220257/Z/20/Z, 203151/Z/16/Z)
  • Erasmus+
  • NIHR Cambridge Biomedical Research Centre
  • National Heart, Lung, and Blood Institute (R01HL148151, R21HL150032, R01HL149714, R01HL161004, R01HL146442)
  • National Institute of General Medical Sciences (RM1GM131968)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Keywords
mitochondrial complex I, microglia, neuroinflammation, reverse electron transfer, reactive oxygen species, myeloid cell activation, chronic neurological disease, multiple sclerosis, neuroprotection, mitochondrial metabolism
MeSH terms
Neuroinflammatory Diseases, Multiomics, Animals, Central Nervous System, Disease Models, Animal, Electron Transport, Female, Humans, Inflammation, Male, Mitochondria, Reactive Oxygen Species, Microglia, Myeloid Cells, Electron Transport Complex I, Mice

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