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 production depends on oxygen-driven mitochondrial activity. To define the role of complex IV, we generated brown-adipocyte-specific Cox10-knockout mice (Cox10^BKO), as Cox10 is required for cytochrome c oxidase assembly. Cox10-deficient brown adipocytes exhibited markedly reduced complex IV activity and impaired Ucp1-dependent thermogenesis. Although ATF4 signaling was strongly induced, the alternative ATF4-dependent thermogenic pathway failed due to suppression of global protein synthesis, consistent with severe mitochondrial stress and reduced ribosomal gene expression. Unexpectedly, Cox10^BKO mice housed at room temperature or thermoneutrality were protected against high-fat-diet-induced obesity and insulin resistance. These findings demonstrate that brown adipocytes regulate systemic metabolic homeostasis independently of canonical thermogenic function and suggest that respiration-deficient brown fat may promote metabolic fitness through endocrine or metabolic signaling mechanisms.