Int. J. Biochem. Vol. 23, No. 9, pp 791-801, 1991 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFE Pnntedtn GreatBntain. All rights reserved 0020-71 IX,/91 $3.00 + 0.00 Copyright Q 1991 Pergamon Press plc THE UNCOUPLING PROTEIN UCP: A MEMBRANEOUS MITOCHONDRIAL ION CARRIER EXCLUSIVELY EXPRESSED IN BROWN ADIPOSE TISSUE SUSANNE KLAUS, LOUIS CASTPILLA, FI&DJ%RIC BOUILLAUD and DANIEL RICQUIER* Centre de Recherche sur la Nutrition-CNRS, 9, rue J. Hetzel, 92190 Meudon-Bellevue, France [Tel. 45-07-57-471 (Received 17 September 1990) JNTRODJKJ’JON Normal mitochondria function in maintaining the cellular energy equilibrium by providing energy in the form of ATP according to energy demand of the cell. This is obtained by a close coupling of the respiratory chain to ATP production. The brown fat uncoupling protein (UCP), located in the inner mitochondrial membrane, is able to short circuit this tight coupling, resulting in elevated respiration rates without an increase in ATP production, and thus an energy dissipation as heat. This direct and highly regulated mechanism of heat production plays a major role in the so called non-shive~ng thermogenesis (NST) of small and newborn mammals. UCP seems to be exclusively located in adipocytes of brown adipose tissue (BAT or brown fat), which is a highly thermo- genie tissue unique to mammals. Since the discovery of the special nature of brown adipocyte mitochondria in the late sixties and early seventies, the biochemical characteristics of these mitochondria have been exten- sively studied, which resulted in the identi~cation of UCP as a specialized proton translocator. The subse- quent cloning and sequencing of UCP in the eighties enables us now to study on a molecular level the functional properties of this protein, which despite its unique occurrence in brown fat represents a mem- ber of a family of important mitochondrial carrier proteins including the ATP/ADP translocator, the phosphate carrier and the oxoglutarate carrier. In the last few years a lot of interest has been focused on the uncoupling protein as a model for studies of the structure-function relationship of this class of mem- braneous mitochondrial carriers. In the following review we will try to summarize the present state of knowledge about function and structure of UCP. Special emphasis will be put on the different approaches developed lately to study the import mechanism of UCP into the membrane, its structural organization in the membrane and domains corre- sponding to different biochemical properties. - *To whom all correspondence should be addressed. BROWN ADIPOSE TISSUE AS A THERMOGENJC TJSSUE For quite a long time brown fat (brown adipose tissue, BAT) has been recognized as a distinct tissue, which is present only in mammals, and as early as 1970 a book had been dedicated to this topic (Lindberg, 1970) Contrary to white fat, whose main function is the storage of energy, BAT is a highly metabolically active tissue, which is source of the heat production during NST. According to this function, BAT shows considerable adaptive changes related to cold acclimation, including cell proliferation, increase in mitochond~a and respiratory capacity together with a high increase of UCP (for review see Himms- Hagen, 1986). Brown fat thermogenesis seems to be induced not only by cold, but also by diet, suggesting an important role of this tissue in general energy balance (for review see Rothwell and Stock, 1986). The biochemistry of BAT has already been exten- sively reviewed (e.g. Cannon and Nedergaard, 1985; Himms-Hagen, 1989) and for further info~ation we refer to a recently published book about brown adipose tissue (Trayhurn and Nicholls, 1986). UNCOUPLJNG OF BROWN FAT MITOCHONDRJA IS DUE TO UCP Over 20 years ago it was shown that in order to obtain a respiratory control of brown fat ~t~hond~a it was necessary to add purine nucleotides like ATP, GTP or GDP (Rafael et ai., 1969). Extensive studies in the seventies, especially by D. Nicholls and his coworkers led to the characterization of a unique uncoupling pathway of these mitochondria (for de- tailed reviews see Nicholls and Locke, 1984; Nicholls et al., 1986). The bioenergetic model of this mechanism is based on Mit~hel~s chemiosmotic theory according to which the electron flow in the respiratory chain is tightly coupled to a proton extrusion and the proton re-entry through the ATPase is tightly coupled to ATP synthesis. Brown fat mitochondria possesses an alternative pathway, which allows proton re-entry without ATP synthesis, bypassing the ATPase com- plex and thus resulting in a dissipation of energy as 791