The mitochondrial uncoupling proteins

Abstract

The uncoupling proteins (UCPs) are transporters, present in the mitochondrial inner membrane, that mediate a regulated discharge of the proton gradient that is generated by the respiratory chain. This energy-dissipatory mechanism can serve functions such as thermogenesis, maintenance of the redox balance, or reduction in the production of reactive oxygen species. Some UCP homologs may not act as true uncouplers, however, and their activity has yet to be defined. The UCPs are integral membrane proteins, each with a molecular mass of 31-34 kDa and a tripartite structure in which a region of around 100 residues is repeated three times; each repeat codes for two transmembrane segments and a long hydrophilic loop. The functional carrier unit is a homodimer. So far, 45 genes encoding members of the UCP family have been described, and they can be grouped into six families. Most of the described genes are from mammals, but UCP genes have also been found in fish, birds and plants, and there is also functional evidence to suggest their presence in fungi and protozoa. UCPs are encoded in their mature form by nuclear genes and, unlike many nuclear-encoded mitochondrial proteins, they lack a cleavable mitochondrial import signal. The information for mitochondrial targeting resides in the first loop that protrudes into the mitochondrial matrix; the second matrix loop is essential for insertion of the protein into the inner mitochondrial membrane. UCPs are regulated at both the transcriptional level and by activation and inhibition in the mitochondrion.

Figure 1

An unrooted phylogenetic tree depicting the evolutionary relationships among the members of the UCP family. Colors illustrate the six major classes into which the proteins cluster. The key to nomenclature can be found in Table 1. Evolutionary distances were calculated from the sequence alignment applying the Jukes-Cantor correction method and the tree was constructed using the Neighbor-Joining method. The dotted lines indicate the more distant relationship of the UCP4 and BMCP1 proteins to the other UCPs.

Figure 2

The transmembrane arrangement of the UCPs. Six α-helical regions span the lipid bilayer, with the amino and carboxyl termini oriented to the cytosolic side of the membrane and the long hydrophilic loops on the matrix side. Dotted lines separate the three portions of the tripartite structure.

Figure 3

Sequence alignment of UCP1, UCP2 and UCP3 from human, dog, mouse and rat. Sequences are arranged to demonstrate the tripartite structure and lines between blocks help to identify amino acid residues strictly conserved in the three repeats. In the consensus sequence for each UCP homolog (consen), upper-case letters denote conservation and lower-case letters the existence of similarity.

Figure 4

Energy dissipation mediated by the uncoupling proteins. During respiration, protons are pumped by the respiratory chain complexes and a proton electrochemical potential gradient is generated. The energy of the proton gradient drives the synthesis of ATP by the F₀F₁-ATPase. UCPs catalyze a regulated re-entry of the protons into the matrix. The ADP/ATP carrier exports the newly synthesized ATP to the cytosol in exchange for ADP.

Figure 5

A phylogenetic tree of representative members of the mitochondrial transporter superfamily, which includes UCPs.