Microglia are necessary for central nervous system (CNS) function during development and play roles in ageing, Alzheimer’s disease and the response to demyelinating injury^1,2,3,4,5. The mitochondrial respiratory chain (RC) is necessary for conventional T cell proliferation⁶ and macrophage-dependent immune responses^7,8,9,10. However, whether mitochondrial RC is essential for microglia proliferation or function is not known. We conditionally deleted the mitochondrial complex III subunit Uqcrfs1 (Rieske iron-sulfur polypeptide 1) in the microglia of adult mice to assess the requirement of microglial RC for survival, proliferation and adult CNS function in vivo. Notably, mitochondrial RC function was not required for survival or proliferation of microglia in vivo. RNA sequencing analysis showed that loss of RC function in microglia caused changes in gene expression distinct from aged or disease-associated microglia. Microglia-specific loss of mitochondrial RC function is not sufficient to induce cognitive decline. Amyloid-β plaque coverage decreased and microglial interaction with amyloid-β plaques increased in the hippocampus of 5xFAD mice with mitochondrial RC-deficient microglia. Microglia-specific loss of mitochondrial RC function did impair remyelination following an acute, reversible demyelinating event. Thus, mitochondrial respiration in microglia is dispensable for proliferation but is essential to maintain a proper response to CNS demyelinating injury.

小胶质细胞是发育过程中中枢神经系统 (CNS) 功能所必需的，并在衰老、阿尔茨海默病和脱髓鞘损伤反应中发挥作用^1,2,3,4,5 。线粒体呼吸链 (RC) 对于传统 T 细胞增殖⁶和巨噬细胞依赖性免疫反应^7,8,9,10是必需的。然而，线粒体 RC 是否对小胶质细胞增殖或功能至关重要尚不清楚。我们有条件地删除了成年小鼠小胶质细胞中的线粒体复合物 III 亚基Uqcrfs1 （Rieske 铁硫多肽 1），以评估小胶质细胞 RC 对体内存活、增殖和成体中枢神经系统功能的需求。值得注意的是，线粒体 RC 功能并不是小胶质细胞体内存活或增殖所必需的。 RNA测序分析表明，小胶质细胞中RC功能的丧失导致了与衰老或疾病相关的小胶质细胞不同的基因表达变化。小胶质细胞特异性线粒体 RC 功能丧失不足以引起认知能力下降。在线粒体 RC 缺陷小胶质细胞的 5xFAD 小鼠的海马中，淀粉样蛋白 β 斑块覆盖率降低，小胶质细胞与淀粉样蛋白 β 斑块的相互作用增加。小胶质细胞特异性线粒体 RC 功能丧失确实会在急性、可逆性脱髓鞘事件后损害髓鞘再生。因此，小胶质细胞中的线粒体呼吸对于增殖来说是可有可无的，但对于维持对中枢神经系统脱髓鞘损伤的适当反应至关重要。