Perspectives on the biology of uncoupling protein (UCP) homologues

In mammals, it is believed that a portion of tissue metabolic rate is drive n by counteraction of uncoupling, in which the energetically inefficient pr ocess of proton leak acts to diminish the mitochondrial electrochemical mem brane potential. It is proposed that specific proteins associated with the mitochondrion catalyse uncoupling, and the biology of such putative uncoupl ing proteins (UCPs) is the subject of active research efforts. UCP4 and UCP 5 are interesting in light of their abundant expression in the brain, which may signal an important metabolic function in thermogenesis or regulation of reactive oxygen species in that tissue. While each is expressed to vario us degrees outside of the brain, their impact on whole-animal metabolism re mains to be clarified further. Transgenic mice expressing murine UCP5(L), t he long isoform of UCP5, using an inducible metallothionine promoter (to dr ive expression of the transgene in liver, testis, heart, lung, spleen, inte stine, kidney and brain) did not display any overt metabolic phenotype, des pite liver UCP5L mRNA expression equivalent to that of normal mouse brain. This highlights the need for further studies to examine the nature of UCP5 physiology. Evidence for uncoupling behaviour has recently emerged from stu dies of the human 2-oxoglutarate carrier (OGC), indicating that the possibi lity of physiological proton leak elicited by the OGC and other mitochondri al carriers warrants further experimental evaluation.