Mitochondrial uncoupling proteins: from mitochondria to the regulation of energy balance

Abstract

The coupling of oxygen consumption to ADP phosphorylation is incomplete, as is particularly evident in brown adipocyte mitochondria which use a regulated uncoupling mechanism to dissipate heat produced by substrate oxidation. In brown adipose tissue, uncoupling is effected by a specific protein in the inner mitochondrial membrane referred to as uncoupling protein-1 (UCP1). UCP1 gene disruption in mice has confirmed UCP1's role in cold-induced thermogenesis. Genetic analysis of human cohorts has suggested that UCP1 plays a minor role in the control of fat content and body weight. The recent cloning of UCP2 and UCP3, two homologues of UCP1, has boosted research on the importance of respiration control in metabolic processes, metabolic diseases and energy balance. UCP2 is widely expressed in different organs whereas UCP3 is mainly present in skeletal muscle. The chromosomal localization of UCP2 as well as UCP2 mRNA induction by a lipid-rich diet in obesity-resistant mice suggested that UCP2 is involved in diet-induced thermogenesis. A strong linkage between markers in the vicinity of human UCP2 and UCP3 (which are adjacent genes) and resting metabolic rate was calculated. UCPs are known or supposed to participate in basal and regulatory thermogenesis, but their exact biochemical and physiological functions have yet to be elucidated. UCPs may constitute novel targets in the development of drugs designed to modulate substrate oxidation. However, very recent data suggest an important role for the UCPs in the control of production of free radicals by mitochondria, and in response to oxidants.

Figure 1. Schematic representation of mechanisms linking respiration to ATP synthesis and thermogenesis in mitochondria

Only the inner membrane of mitochondria is schematised. Vox identifies the respiratory chain. The respiratory chain works as a proton pump which generates a proton gradient and a membrane potential (ΔΨ). The proton gradient is used by ATP-synthase to phosphorylate ADP. During this process, the proton gradient is decreased and this activates the respiration. The UCPs function as a proton translocator; they decrease the proton gradient and activate coenzyme reoxidation.

Figure 2. Schematic mechanism of proton transport by the UCPs: direct proton translocation, or proton release associated with cycling of fatty acid

The inner mitochondrial membrane is shown as the two outer stippled rectangles. The matricial side is below the membrane. The UCP is represented as the two inner striped grey rectangles and ovals corresponding to membranous domain and gating domain, respectively. The right-hand side part of the figure shows a direct transport of proton by UCP; the proton is provided by the carboxyl group of either amino acid residues or fatty acid. The left-hand side of the figure illustrates the free diffusion of protonated fatty acid through the membrane followed by release of proton on the matricial side. Then, UCP returns the anionic form of fatty acid through the membrane.