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Updated: Jul 1, 2025
Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Mitochondrial complex I activity in microglia sustains neuroinflammation
L Peruzzotti-Jametti1,2, C M Willis3, G Krzak3
1Department of Clinical Neurosciences and NIHR Biomedical Research Centre, University of Cambridge, Cambridge, UK. lp429@cam.ac.uk.
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.
Insights
Sustained myeloid cell activation in chronic neurological diseases is driven by mitochondrial complex I. Inhibiting this complex in microglia reduces neuroinflammation and damage, offering a potential therapeutic target.
Area of Science:
- Neuroscience
- Immunology
- Mitochondrial Biology
Background:
- Sustained myeloid cell activation is a hallmark of chronic neurological diseases like multiple sclerosis.
- Metabolic and mitochondrial features influence myeloid cell activation and function, but their role in perpetuating central nervous system inflammation is unclear.
Purpose of the Study:
- To identify the molecular signature sustaining microglia activation.
- To investigate the role of mitochondrial activity in neuroinflammation.
- To explore therapeutic strategies targeting microglial metabolism.
Main Methods:
- Multiomics approach to identify molecular signatures.
- Investigation of mitochondrial complex I activity in microglia.
- In vivo animal model of a central nervous system disease.
Main Results:
- A molecular signature sustaining microglia activation was identified, driven by mitochondrial complex I activity.
- This activity leads to reverse electron transport and reactive oxygen species production.
- Blocking complex I in pro-inflammatory microglia protected the central nervous system and improved functional outcomes in an animal model.
Conclusions:
- Mitochondrial complex I activity sustains microglia activation and neuroinflammation.
- Targeting complex I in microglia offers a potential therapeutic strategy for neuroprotection in chronic central nervous system inflammatory disorders.
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