Coenzyme Q regulates UCP1 expression and thermogenesis through the integrated stress responses

Coenzyme Q is an essential component of mitochondrial function and required for thermogenic activity in brown adipose tissues (BAT). BAT CoQ deficiency (50-75%) by genetic or pharmacological means does not interfere with basal or maximal mitochondrial respiration in brown adipocytes but increases mitochondrial oxidants and induces UPRmt, ISR, and repression of UCP1 expression. ATF4, the master regulator of ISR, is required for UCP1 suppression in BAT CoQ deficiency. In animals, BAT CoQ deficiency causes cold intolerance but activates compensatory thermogenic mechanisms in BAT and other tissues via greatly induced BAT FGF21 expression resulting in paradoxically upregulated whole-body respiration rates and protection from obesity at room temperature and thermoneutrality. BAT-specific loss of either ATF4 or FGF21 abolishes these metabolic benefits demonstrating a central role for CoQ in the modulation of whole-body energy expenditure and thus for the etiology of primary and secondary CoQ deficiencies. Overall design: RNAseq was used to compare gene expression in a brown adipocyte cell line treatde with vehicle control or 4CBA for 48 hours.(3 replicates per group). All data was generated using Illumina HiSeq4000.