The Mitochondrial Uncoupling Proteins : UCP

In the internal mitochondrial membranes, there are plenty of transporters that ensure the entry and exit of substrates that are crucial to the oxidative and energetic metabolism of mitochondria. Among these transporters, the uncoupling mitochondrial proteins (UCPs) have very distinguished functions.

By assisting the comeback of protons in the mitochondrial matrix, UCP1 uncouples the respiratory chain process of ATP synthesis. The energy outcoming from substrates oxidation is no longer converted in ATP but dissipated in the form of heat. The recent discovery of brown adipose tissue in adult humans make UCP1 a target gene for the increase of the energy expenditure and the fight against obesity.

UCP2, discovered in the laboratory of Daniel Ricquier in 1997, plays a role in the use of the energetic substrates (glucose, fatty acids) and the production of reactive oxygen species ROS. The phenotypes of mice invalidated for the gene UCP2 as well as genetical studies have brought out the important role of UCP2 in the inflammation. As such, UCP2 could become a target gene for the treatment of chronic inflammatory diseases such as atherosclerosis, type I diabetes or multiple sclerosis.

From a biochemical and structural point of view, the UCPs are not very well known. We have no clue on how the proton transport by UCP1 is done, or if the mechanism of action of UCP2 on ROS is explained simply by electron transport or through other anionic substrates of the mitochondrial metabolism. The determination of the molecular structure of the ADP/ATP carrier (AAC), close to UPCs, does not answer any of these questions. Thus, we think that identification of the binding site of activating fatty acids as well as obtaining one or more crystallographic structures of UCPs should shed more light into the mechanisms of actions and regulation of this mitochondrial carriers family.

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