Mitochondrial respiration in microglia is essential for response to demyelinating injury but not proliferation

Microglia are necessary for CNS function during development and play roles in aging, Alzheimer’s Disease (AD) and the response to demyelinating injury. Mitochondrial respiratory chain (RC) is necessary for conventional T cell proliferation6 and macrophage-dependent immune responses. However, whether mitochondrial RC is essential for microglia proliferation or function is not known. We conditionally deleted the mitochondrial complex III subunit Rieske Iron-Sulfur Protein (RISP) in the microglia of adult mice to assess the requirement of microglial RC for survival, proliferation, and adult CNS function in vivo. Surprisingly, mitochondrial RC function was not required for survival or proliferation of microglia in vivo. RNA-seq analysis showed that loss of RC function in microglia caused changes in gene expression distinct from aged or disease-associated microglia (DAM). 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.