Uncoupling proteins: current status and therapeutic prospects.

Introduction In a springtime Madrid, under the auspices of the Juan March Foundation, some 50 scientists who work on uncoupling proteins convened to debate the mode of action of these mitochondrial membrane carriers, the control of their expression, their physiological roles and their therapeutic potential. In bioenergetics, ‘uncoupling’ refers to any process through which energy released from the combustion of substrate (food) in the mitochondria is not conserved. The final steps in the oxidation of substrate are the transfer of electrons to oxygen, forming water, by the respiratory chain. The energy released is used by the respiratory chain to pump protons out of the mitochondria, as seen in Fig 1A. In most mitochondria, the majority of these protons re-enter through the ATP synthase, and the energy is used to synthesize ATP. However, if the protons re-enter by any other means, the mitochondria are considered to be uncoupled. To some degree this happens in all mitochondria, in ways not understood at present. There is also at least one protein whose function is to allow protons to re-enter the mitochondria without using the energy for any purpose (Fig 1A). Under these conditions, the energy is released as heat. The undisputed uncoupling protein, UCP1, performs this task in brown adipose tissue. Mammals, including newborn humans, use the released heat to protect themselves against cold; this process is referred to as nonshivering thermogenesis. As energy in this process is transferred to heat and not stored as fat in the body, the activity of the uncoupling protein(s) can be viewed as an anti-obesity mechanism—a possibility that has attracted much attention, as both pharmaceutical companies and the general public are looking for easy ‘slimming’ agents. It would be expected that the congregation of scientists assembled in Madrid would be united at least in the definition of an uncoupling protein. However, given the intense and animated discussions that characterized the meeting, it is clear that an accord has not even been reached on this basic subject, a fact that underlines the timeliness of this lively meeting. The reasons for this plurality of definitions are mostly historical. They reflect the development of the field, from a time when only one uncoupling protein was known (UCP1), to the present day when a steadily increasing number of proteins are being advocated as functional uncoupling proteins. The discussions in this respect centred on whether uncoupling proteins should be identified on the basis of their structural similarity to UCP1 or on their functional properties. The advantage of a structural similarity definition is that there is a formal solution to the problem—only proteins with high sequence similarity are included in the UCP family. The disadvantage is that some