UCP3 plays a complementary role to UCP1 in brown adipose tissue mitochondrial bioenergetics

Mitochondrial uncoupling protein 3 (UCP3) plays a complementary role in uncoupling protein 1 (UCP1) dependent uncoupling in mammalian thermogenesis. Using mouse strains lacking UCP1, UCP3, and a UCP1/UCP3 double knockout, we previously demonstrated that UCP3 is necessary for sustained heat production. However, how and where UCP3 is essential for heat production remains unknown. Using brown adipocyte mitochondria from UCP1, UCP3, and UCP1/UCP3 double knockout mice, we found that in the absence of UCP1, UCP3 does not act as a free fatty acid-inducible uncoupling protein; however, it is necessary for maximal GDP sensitive respiration. Additionally, we confirm that the loss of UCP1 is a dominant regulator of mitochondrial respiratory chain activity, assembly, and composition in brown adipose tissue. Our data suggest that in the absence of UCP1 brown adipose tissue is not a significant source of heat production and that UCP3-dependent heat generation plays a regulatory role outside of adipose tissues. Together these data suggest that UCP3’s thermogenic function is independent of a role as a bona fide uncoupling protein in brown adipose tissue.