Mitochondrial reverse electron transport in myeloid cells perpetuates neuroinflammation

Sustained smouldering, or low grade, activation of myeloid cells is a common hallmark of several chronic neurological diseases, including multiple sclerosis. Distinct metabolic and mitochondrial features of myeloid cells guide diverse functional states. How these features act to perpetuate neuroinflammation is currently unknown. Using a multiomics approach, we identify a new molecular signature that perpetuates the activation of microglia by the reverse electron transport through complex I and the subsequent production of reactive oxygen species. Blocking reverse electron transport in pro-inflammatory myeloid cells protects against neurotoxic damage and improves functional outcomes in animal disease models in vivo. Our data show that reverse electron transport in myeloid cells is a potential new therapeutic target to foster neuroprotection in smouldering inflammatory central nervous system diseases. Overall design: Resident microglia and infiltrating myeloid cells were isolated via FACS from a Cx3cr1-fate mapping mouse line at the peak or chronic phase of EAE, as well as healthy controls. Cells were then analysed via scRNAseq.