Cox10-mediated mitochondrial respiration in brown adipocytes regulates adaptive thermogenesis and systemic metabolism

Mitochondrial respiration is essential for Ucp1-mediated thermogenesis in brown adipocytes, where heat is produced through oxygen-dependent mitochondrial activity. To investigate the role of complex IV in this process, we generated brown adipocyte–specific Cox10 knockout mice (Cox10BKO), as COX10 is required for the assembly of cytochrome c oxidase (complex IV). Cox10-deficient brown adipocytes displayed markedly reduced complex IV activity and were unable to support Ucp1-dependent thermogenesis. Previous studies have shown that disruption of mtDNA-encoded electron transport chain (ETC) gene expression abolishes the Ucp1-mediated thermogenesis but induces an alternative, ATF4-driven thermogenic program involving increased protein turnover. In Cox10-deficient brown adipocytes, ATF4 target genes were strongly induced; however, this alternative thermogenic pathway did not occur because global protein synthesis was suppressed, likely reflecting severe mitochondrial stress. Interestingly, the Cox10BKO mice were protected against high-fat-diet-induced metabolic abnormalities. These findings reveal that brown adipocytes can influence whole-body metabolic homeostasis independently of their canonical thermogenic function, suggesting previously unrecognized endocrine or metabolic roles for brown fat.