A study published in Nature (DOI: 10.1038/s41586-024-07167-9) reveals that sustained mitochondrial complex I activity in microglia contributes to neuroinflammation in chronic neurological diseases, such as multiple sclerosis (MS). The research shows that microglia, the primary immune cells in the central nervous system (CNS), maintain a low-grade activation state through mitochondrial complex I activity, which drives reverse electron transport and the production of reactive oxygen species (ROS). This process promotes neurotoxicity and exacerbates disease progression. Using a multiomics approach, the study identifies a molecular signature that sustains microglial activation through mitochondrial complex I activity. Mechanistically, blocking complex I in pro-inflammatory microglia protects the CNS against neurotoxic damage and improves functional outcomes in an animal model of MS. The study also shows that mitochondrial complex I activity in microglia is a potential therapeutic target for neuroprotection in chronic inflammatory disorders of the CNS. In MS, chronic active, slowly expanding lesions are associated with brain atrophy and irreversible disability. These lesions are characterized by the accumulation of myeloid cells at the lesion edge, which continuously produce neurotoxic factors such as TNF, IL-1β, NO, and ROS, leading to remyelination failure and secondary neuronal/axonal damage. In MS-like disease models, axonal injury is followed by a compensatory response, where mitochondrial content and activity increase in demyelinated axons to promote neuroprotection. However, deficits in neuronal mitochondrial complexes and energy metabolism are associated with persistent axonal damage, grey-matter atrophy, and MS disease progression. The study also shows that mitochondrial respiratory complexes and metabolites control myeloid immune responses. Under inflammatory conditions, elevated intracellular succinate levels in myeloid cells promote a switch from forward to reverse electron transport through mitochondrial complex I, which generates ROS. Inhibiting succinate dehydrogenase limits this process and promotes anti-inflammatory effects in myeloid cells. The study used ex vivo single-cell RNA-sequencing and LC-MS analysis to identify the molecular mechanisms through which microglia and CNS-infiltrating myeloid cells sustain CNS inflammation. The results show that microglia display increased mitochondrial complex I expression during EAE, and that disease-associated microglia (DAMs) are characterized by the increased expression of genes related to glycolysis, oxidative phosphorylation, and myeloid activation. The study also shows that targeting mitochondrial complex I activity in myeloid cells during the transition from acute to chronic EAE reduces neuroinflammation and neurotoxicity. In vivo, daily intraperitoneal injections of 4-octyl itaconate or DMM only did not ameliorate EAE in mice. However, the combination of DMM and metformin led toA study published in Nature (DOI: 10.1038/s41586-024-07167-9) reveals that sustained mitochondrial complex I activity in microglia contributes to neuroinflammation in chronic neurological diseases, such as multiple sclerosis (MS). The research shows that microglia, the primary immune cells in the central nervous system (CNS), maintain a low-grade activation state through mitochondrial complex I activity, which drives reverse electron transport and the production of reactive oxygen species (ROS). This process promotes neurotoxicity and exacerbates disease progression. Using a multiomics approach, the study identifies a molecular signature that sustains microglial activation through mitochondrial complex I activity. Mechanistically, blocking complex I in pro-inflammatory microglia protects the CNS against neurotoxic damage and improves functional outcomes in an animal model of MS. The study also shows that mitochondrial complex I activity in microglia is a potential therapeutic target for neuroprotection in chronic inflammatory disorders of the CNS. In MS, chronic active, slowly expanding lesions are associated with brain atrophy and irreversible disability. These lesions are characterized by the accumulation of myeloid cells at the lesion edge, which continuously produce neurotoxic factors such as TNF, IL-1β, NO, and ROS, leading to remyelination failure and secondary neuronal/axonal damage. In MS-like disease models, axonal injury is followed by a compensatory response, where mitochondrial content and activity increase in demyelinated axons to promote neuroprotection. However, deficits in neuronal mitochondrial complexes and energy metabolism are associated with persistent axonal damage, grey-matter atrophy, and MS disease progression. The study also shows that mitochondrial respiratory complexes and metabolites control myeloid immune responses. Under inflammatory conditions, elevated intracellular succinate levels in myeloid cells promote a switch from forward to reverse electron transport through mitochondrial complex I, which generates ROS. Inhibiting succinate dehydrogenase limits this process and promotes anti-inflammatory effects in myeloid cells. The study used ex vivo single-cell RNA-sequencing and LC-MS analysis to identify the molecular mechanisms through which microglia and CNS-infiltrating myeloid cells sustain CNS inflammation. The results show that microglia display increased mitochondrial complex I expression during EAE, and that disease-associated microglia (DAMs) are characterized by the increased expression of genes related to glycolysis, oxidative phosphorylation, and myeloid activation. The study also shows that targeting mitochondrial complex I activity in myeloid cells during the transition from acute to chronic EAE reduces neuroinflammation and neurotoxicity. In vivo, daily intraperitoneal injections of 4-octyl itaconate or DMM only did not ameliorate EAE in mice. However, the combination of DMM and metformin led to