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.This research was supported by Fondazione Italiana Sclerosi Multipla FIMS and Italian Multiple Sclerosis Association AISM Senior research fellowship financed or co-financed with the ‘5 per mille’ public funding 2017/B/5 (to L.P.-J.); Wellcome Trust Clinical Research Career Development Fellowship G105713 (to L.P.-J.); Isaac Newton Trust Research Grant RG 97440 (to S.P. and L.P.-J.); Fondazione Italiana Sclerosi Multipla FIMS and Italian Multiple Sclerosis Association AISM 2018/R/14 (to S.P. and L.P.-J.); National MS Society Research Grant RFA-2203-39318 (to L.P.-J.) and Grant RG 1802-30200 (to S.P. and L.P.-J.); Evelyn Trust (to S.P.); Bascule Charitable Trust (to S.P.); NIHR Cambridge BRC (to S.P.); Wings for Life RG 82921 (to S.P. and L.P.-J.), Medical Research Council UK (MC_UU_00028/4), Wellcome Trust Investigator award (220257/Z/20/Z) (to M.P.M.); Henry Wellcome Fellowship 215888/Z/19/Z (to A.E.V.); National MS Society Post-doctoral fellowship FG-2008-36954 (to C.M.W.); US National Institute of General and Medical Sciences RM1GM131968 (to A.D.); US National Heart, Lung and Blood Institute R01HL146442, R01HL149714, R01HL148151, R01HL161004 and R21HL150032 (to A.D.); European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Postdoctoral Research Fellowship Exchange Program G104956 (to A.M.N.); and Erasmus+ student internship (to A.M.R.v.d.B. and L.R.). Research in the G.B. laboratory is supported by the UK Dementia Research Institute, which receives contributions from UK DRI, the UK MRC, the Alzheimer’s Society and Alzheimer’s Research UK. Research at TINS is supported by PNRR-III-C9-2022-I8. L.P. and I.M. were funded by the Wellcome Trust (203151/Z/16/Z) and the UKRI Medical Research Council (MC_PC_17230)
