Mitochondria use energy derived from fuel combustion to create a proton electrochemical gradient across the mitochondrial inner membrane. This intermediate form of energy is then used by ATP synthase to synthesize ATP. Uncoupling protein-1 (UCP1) is a brown fat-specific mitochondrial inner membrane protein with proton transport activity. UCP1 catalyzes a highly regulated proton leak, converting energy stored within the mitochondrial proton electrochemical potential gradient to heat. This uncouples fuel oxidation from conversion of ADP to ATP. In rodents, UCP1 activity and brown fat contribute importantly to whole-body energy expenditure. Recently, two additional mitochondrial carriers with high similarity to UCP1 were molecularly cloned. In contrast to UCP1, UCP2 is expressed widely, and UCP3 is expressed preferentially in skeletal muscle. Biochemical studies indicate that UCP2 and UCP3, like UCP1, have uncoupling activity. While UCP1 is known to play an important role in regulating heat production during cold exposure, the biological functions of UCP2 and UCP3 are unknown. Possible functions include 1) control of adaptive thermogenesis in response to cold exposure and diet, 2) control of reactive oxygen species production by mitochondria, 3) regulation of ATP synthesis, and 4) regulation of fatty acid oxidation. This article will survey present knowledge regarding UCP1, UCP2, and UCP3, and review proposed functions for the two new uncoupling proteins.

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