Mitochondrial complex I activity in microglia sustains neuroinflammation

Nature. 2024 Apr;628(8006):195-203. doi: 10.1038/s41586-024-07167-9. Epub 2024 Mar 13.


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.

MeSH terms

  • Animals
  • Central Nervous System / drug effects
  • Central Nervous System / metabolism
  • Central Nervous System / pathology
  • Disease Models, Animal
  • Electron Transport / drug effects
  • Electron Transport Complex I* / antagonists & inhibitors
  • Electron Transport Complex I* / metabolism
  • Female
  • Humans
  • Inflammation* / drug therapy
  • Inflammation* / metabolism
  • Inflammation* / pathology
  • Male
  • Mice
  • Microglia* / drug effects
  • Microglia* / metabolism
  • Microglia* / pathology
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Multiomics
  • Myeloid Cells / metabolism
  • Myeloid Cells / pathology
  • Neuroinflammatory Diseases* / drug therapy
  • Neuroinflammatory Diseases* / metabolism
  • Neuroinflammatory Diseases* / pathology
  • Reactive Oxygen Species / metabolism


  • Electron Transport Complex I
  • Reactive Oxygen Species