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.

骨髓细胞的持续闷烧或低度激活是包括多发性硬化症在内的多种慢性神经系统疾病的共同标志¹。独特的代谢和线粒体特征指导骨髓细胞的激活和不同的功能状态²。然而，这些代谢特征如何使中枢神经系统炎症持续存在尚不清楚。在这里，我们使用多组学方法，确定了一种分子特征，该特征通过驱动反向电子传输和活性氧产生的线粒体复合物 I 活性来维持小胶质细胞的激活。从机制上讲，阻断促炎小胶质细胞中的复合物 I 可保护中枢神经系统免受神经毒性损伤，并改善动物体内疾病模型的功能结果。小胶质细胞中的复合物 I 活性是促进中枢神经系统慢性炎症性疾病的神经保护的潜在治疗靶点³。