Disassembly of ETC Complexes Drives Macrophage Inflammatory Responses by Reprogramming Cellular Metabolism and Translation

Abstract

Metabolic switch from oxidative phosphorylation (OxPhos) to glycolysis is a key feature of inflammatory macrophages, but how the switch occurs and contributes to macrophage function is obscure. Here we show that stimulation of macrophages through Toll-like receptors (TLR) disrupts the assembly of mitochondrial electron transfer chain (ETC)complexes I-V, leading to the metabolic switch by inhibiting OxPhos and inducing glycolysis through HIF-1α. Disassembly of ETC complexes also rewires the macrophage transcriptome to induce translational reprogramming via mTORC1 and ATF4, promoting global translation, cell growth, and production of inflammatory cytokines independent of glycolysis. Inhibition of OxPhos via myeloid-specific knockout of OPA1, which stimulates ETC complex assembly, exacerbates sepsis in mice while inhibition of mTORC1 reverses this effect. These findings reveal that disassembly of ETC complexes underlies macrophage metabolic switch and inflammatory responses and may be a conserved pathway to reprogram cellular anabolism and function.