Mitochondrial complex I activity in microglia sustains neuroinflammation [bulk]

Sustained smouldering, or low grade, activation of myeloid cells is a common hallmark of several chronic neurological diseases, including multiple sclerosis (MS). Distinct metabolic and mitochondrial features guide the activation and the diverse functional states of myeloid cells. However, how these metabolic features act to perpetuate neuroinflammation is currently unknown. Using a multiomics approach, we identified a new molecular signature that perpetuates the activation of myeloid cells through mitochondrial complex I (CI) activity driving reverse electron transport (RET) and the production of reactive oxygen species (ROS). Blocking CI activity in pro-inflammatory microglia protected the central nervous system (CNS) against neurotoxic damage and improved functional outcomes in animal disease models in vivo. Our data show that mitochondrial CI in microglia is a potential new therapeutic target to foster neuroprotection in smouldering inflammatory CNS disorders. Derivation of human induced microglia (hiMG) from human induced pluripotent cells (hiPSCs)