The function of the original uncoupling protein, UCP1. (A) In isolated brown-adipose mitochondria, UCP1 is spontaneously active. Protons pumped out by the respiratory chain leak back through UCP1 and heat is generated. (B) Within the unstimulated brown adipocyte, UCP1 is inherently inactive because of constant inhibition by purine nucleotides, particularly ATP. Protons from the respiratory chain can now re-enter the mitochondria, through the ATP synthase—although the activity of this is low in brown adipose tissue. The inhibition of UCP1 can be overcome by fatty acids, which, physiologically, are released from triglycerides in the cell when it is stimulated with norepinephrine. (C) If UCP1, or any other UCP, is wrongly inserted into the mitochondrion in transfected cells, it may convey a constantly uncoupled state that cannot be inhibited by ATP.

Pathological consequences and therapeutic effects of altered expression/activity of the different uncoupling proteins.

The Meeting on Uncoupling Proteins took place at the Instituto Juan March de Estudios e Investigaciones in Madrid, Spain, between 4 and 6 April 2005, and was organized by E. Rial, D. Ricquier and J.-P. Giacobino.

The suggested function of uncoupling proteins 2 and 3 as protectors against the formation of reactive oxygen species. This figure is based on the hypothesis of M. Brand (Cambridge, UK), which was critically debated during the meeting. (A) In conditions under which electrons build up in the respiratory chain, for example when ATP synthesis is not ongoing, electrons might interact with oxygen to form superoxide, leading to oxidative damage. However, superoxide could activate UCPs through the formation of hydroxynonenal (HNE) from phospholipid acyl chains (PLs). (B) Activated UCP could dissipate some of the proton motive force, so that fewer electrons accumulate, leading to less superoxide production.

Jan Nedergaard, Leslie P. Kozak and Daniel Ricquier, photographed on Plaza Mayor in Madrid during a break in the meeting.