The study investigates the role of mitochondrial complex I (CI) activity in microglia and its impact on neuroinflammation in chronic neurological diseases, particularly multiple sclerosis (MS). Using a multiomics approach, including single-cell RNA sequencing (scRNA-seq) and liquid chromatography–mass spectrometry (LC–MS), the researchers identified a molecular signature that sustains microglial activation through CI-driven reverse electron transport and reactive oxygen species (ROS) production. Mechanistically, blocking CI in pro-inflammatory microglia protects the central nervous system from neurotoxic damage and improves functional outcomes in an animal model of MS-like disease. The findings suggest that targeting CI activity in myeloid cells could be a potential therapeutic strategy to foster neuroprotection in chronic inflammatory disorders of the central nervous system. The study also highlights the importance of CI in maintaining a balanced state of microglial activation and preventing oxidative stress and neurotoxicity.The study investigates the role of mitochondrial complex I (CI) activity in microglia and its impact on neuroinflammation in chronic neurological diseases, particularly multiple sclerosis (MS). Using a multiomics approach, including single-cell RNA sequencing (scRNA-seq) and liquid chromatography–mass spectrometry (LC–MS), the researchers identified a molecular signature that sustains microglial activation through CI-driven reverse electron transport and reactive oxygen species (ROS) production. Mechanistically, blocking CI in pro-inflammatory microglia protects the central nervous system from neurotoxic damage and improves functional outcomes in an animal model of MS-like disease. The findings suggest that targeting CI activity in myeloid cells could be a potential therapeutic strategy to foster neuroprotection in chronic inflammatory disorders of the central nervous system. The study also highlights the importance of CI in maintaining a balanced state of microglial activation and preventing oxidative stress and neurotoxicity.