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

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.