Metabolic control and regulation of mitochondrial proton leak: Effects of UCP1 deficiency and aging in mice.

The overall objective of this thesis was to examine various aspects of the metabolic significance and regulation of the mitochondrial proton leak. The research conducted specifically assesses the influence that leak has on age-associated changes in mitochondria, and the role that the leak plays in facultative energy expenditure of transgenic mice which lack uncoupling protein-1 (UCP1), a well known mediator of the proton leak. Proton leak in mitochondria has been studied for over ten years, but its exact mechanism has not yet been elucidated and only recently has it been realized that it might be mediated by uncoupling proteins (UCPs). UCPs may confer a mechanism for proton leakage and thus affect the efficiency of oxidative phosphorylation. Mice deficient in the gene for mitochondrial UCP1 (Ucp1-deficient mice) are cold-sensitive despite their abundant expression of genes for the isoforms (Ucp2 and Ucp3), and do not become more obese than controls when fed a high fat diet (Enerback et al. 1997) The objective of our work was to analyse the metabolic control and characteristics of proton leak in mitochondria from brown adipose tissue (BAT) of Ucp1-deficient mice and of heterozygote controls in order to establish the role of the UCPs in facultative thermogenesis. (Abstract shortened by UMI.