Single nucleotide variant in coenzyme Q6 reprograms macrophage metabolic remodeling in response to inflammatory signals

Macrophage metabolic remodeling sustains inflammatory responses to pathogens. At homeostasis, macrophages rely on oxidative phosphorylation (OXPHOS), but during inflammation, OXPHOS is downregulated and aerobic glycolysis increases. Increased flux through the tricarboxylic acid (TCA) cycle increases the availability of substrates, such as succinate, that promote pro-inflammatory transcription. While metabolic remodeling has been extensively characterized, the mechanisms governing the shift from OXPHOS to glycolysis remain unclear. We recently identified a single nucleotide variant (SNV) in a mitochondrial protein, coenzyme Q6 (COQ6), that accelerates OXPHOS downregulation during infection with the Gram-positive organism Streptococcus pneumoniae . Because the SNV converts an aspartate residue (D) to tyrosine (Y), we denote the variant as COQ6 ^DY . Here, we now systematically compare the inflammatory responses of macrophages expressing Coq6 ^DY or Coq6 ^WT after stimulation with the S. pneumoniae -derived pneumolysin (PLY), or with lipopolysaccaharide (LPS; a toxin derived from Gram-negative bacteria). We found that Coq6 ^DY reprograms macrophage mitochondrial metabolism by changing the balance between OXPHOS and glycolytic activity and relative TCA metabolite concentrations at homeostasis. Furthermore, responses to PLY varied by host genotype and by concentration of available glucose, whereas responses to LPS were less dependent upon genotype. We therefore identify a non-canonical function of COQ6 in governing mitochondrial metabolism.