The role of uncoupling protein 3 in human physiology W. Timothy Garvey J Clin Invest. 2003;111(4):438-441. https://doi.org/10.1172/JCI17835. Commentary Obesity is simply understood as an imbalance between energy intake and expenditure in favor of weight accretion. However, the human biological interface between food consumption and energy dissipation results in broad individual differences in eating behavior, physical activity, and efficiency of fuel storage and metabolism. In particular, the basal metabolic rate, which accounts for the greatest portion of overall energy expenditure, can vary almost twofold among individuals. Classically, three major biochemical systems are believed to contribute to basal thermogenesis: futile cycles, Na+/K+ATPase activity, and mitochondrial proton leak. The latter is the most important quantitative contributor and can explain up to 50% of the basal metabolic rate (1). The molecular basis of mitochondrial proton leak is unclear, despite its importance in the understanding of energy balance and its potential as a therapeutic target for obesity treatment. The article by Hesselink and colleagues in this issue of the JCI (2) addresses whether uncoupling protein 3 contributes to mitochondrial proton leak in human skeletal muscle. Mitochondrial respiration and oxidative phosphorylation The oxidation of fatty acids and pyruvate takes place in mitochondria, where energy is converted into ATP for use in cellular processes. Reducing equivalents are extracted from substrates and sequentially passed from electron donors (reductants) to acceptors (oxidants) along the mitochondrial respiratory chain to molecular oxygen. The electron transport system is located on […] Find the latest version: https://jci.me/17835/pdf COMMENTARY See the related article beginning on page 479. Uncoupling proteins The mechanisms mediating ATPase- The role of uncoupling protein 3 independent proton leak have not been identified, except in mammalian in human physiology brown adipose tissue (BAT). BAT is rich in mitochondria and lipid droplets and is a major source of non- W. Timothy Garvey shivering thermogenesis, used by most mammals to resist cold. This function Division of Endocrinology, Diabetes, and Medical Genetics and Department of Medicine, Medical University of South Carolina, and Ralph H. Johnson Veterans Affairs Medical Center, is mediated by uncoupling protein 1 Charleston, South Carolina, USA (UCP1) (previously known as uncou- pling protein or thermogenin), first J. Clin. Invest. 111:438–441 (2003). doi:10.1172/JCI200317835. cloned in 1985 (3). UCP1 localizes to the mitochondrial inner membrane and dissipates the transmembrane Obesity is simply understood as an Mitochondrial respiration potential by transporting protons imbalance between energy intake and and oxidative phosphorylation from the intermembrane space back expenditure in favor of weight accre- The oxidation of fatty acids and pyru- into the matrix. This reduces the pro- tion. However, the human biological vate takes place in mitochondria, ton motive force that drives ATP for- interface between food consumption where energy is converted into ATP mation, and respiration in the uncou- and energy dissipation results in for use in cellular processes. Reducing pled mitochondria proceeds, releasing broad individual differences in eating equivalents are extracted from sub- fuel energy only as heat. In humans behavior, physical activity, and effi- strates and sequentially passed from and other large mammals, BAT disap- ciency of fuel storage and metabolism. electron donors (reductants) to accep- pears after infancy, and there is mini- In particular, the basal metabolic rate, tors (oxidants) along the mitochondr- mal or no detectable UCP1 expression which accounts for the greatest por- ial respiratory chain to molecular oxy- in adults. However, even in the absence tion of overall energy expenditure, can gen. The electron transport system is of UCP1, there is a finite proton leak vary almost twofold among individu- located on the inner mitochondrial across the inner membrane that can- als. Classically, three major biochemi- membrane, where oxidation steps are not be explained by simple diffusion cal systems are believed to contribute coupled by the transport chain to the (4). This led investigators to search for to basal thermogenesis: futile cycles, extrusion of protons out of the additional uncoupling proteins with Na+/K+ATPase activity, and mito- matrix. This establishes an electro- broader tissue expression, and two chondrial proton leak. The latter is chemical potential difference across other members of the uncoupling pro- the most important quantitative con- the inner membrane and a motive tein family were identified in 1997. tributor and can explain up to 50% of force for proton reentry through The genes encoding human UCP2 (5, the basal metabolic rate (1). The F1F0-ATP synthase. ATP synthase cap- 6) and UCP3 (7, 8) lie in close proxim- molecular basis of mitochondrial pro- tures the potential energy released ity to each other on chromosome ton leak is unclear, despite its impor- upon proton reentry by converting 11q13 and share 55% and 57% amino tance in the understanding of energy ADP to ATP. In this manner, electron acid identity with UCP1, respectively. balance and its potential as a thera- transport is coupled to oxidative UCP2 mRNA is widely expressed in peutic target for obesity treatment. phosphorylation. In a perfectly cou- multiple tissues, while UCP3 exhibits The article by Hesselink and col- pled system, protons only enter the more limited tissue-specific expression leagues in this issue of the JCI (2) mitochondrial matrix through ATP confined to skeletal muscle and brown addresses whether uncoupling pro- synthase in the presence of ADP; this fat tissue. UCPs have similar predicted tein 3 contributes to mitochondrial form of respiration is classified as topology consisting of six transmem- proton leak in human skeletal muscle. state 3 (i.e., O2 is consumed only in brane regions linked by polar loops the presence of substrate and ADP). and are localized to the inner mito- However, mitochondria can also be chondrial membrane. More recently, Address correspondence to: W. Timothy observed to use oxygen even in the two additional UCP-like genes, UCP4 Garvey, Division of Endocrinology, Diabetes, absence of ADP, which occurs when and UCP5/brain mitochondrial carri- and Medical Genetics, Clinical Science protons leak back into the matrix via er protein–1, have been identified, Building 816, Medical University of South Carolina, 96 Jonathan Lucas Street, a mechanism that does not involve which are expressed in the brain and Charleston, South Carolina 29425, USA. F1F0-ATPase. This proton leak reduces have relatively lower amino acid iden- Phone: (843) 876-5372; Fax: (843) 876-5133; the proton gradient driving ATP for- tity with UCP1 (30–40%). E-mail: [email protected]. mation and uncouples respiration Because of their homology with UCP1 Conflict of interest: The author has declared from oxidative phosphorylation. Oxy- and expression in adult tissues, UCP2 that no conflict of interest exists. Nonstandard abbreviations used: brown gen utilization in the absence of ADP and UCP3 immediately were considered adipose tissue (BAT); uncoupling or in totally uncoupled mitochondria as attractive candidates for proteins protein 1 (UCP1). is referred to as state 4 respiration. involved in energy expenditure. When The Journal of Clinical Investigation | February 2003 | Volume 111 | Number 4 1 increase in the ATP/ADP ratio, and a decrease in state 4 respiration, consis- tent with an uncoupling effect for UCP3 when present in the wild-type mice. Transgenic mice hyperexpressing UCP3 were characterized by reduced body weight, despite being hyperphagic, by increased resting O2 consumption, and by increased muscle temperature but not core temperature. At the same time, isolated mitochondria exhibited de- creased transmembrane potential and increased state 4 respiration. These results in transgenic mice were more consistent with a role for UCP3 as a mitochondrial uncoupler. Importance of human studies Hesselink et al. (2) have studied the capacity of UCP3 to act as an uncou- Figure 1 pler in human skeletal muscle fol- Uncoupling proteins and mitochondrial function. The figure shows key proteins in the inner mito- lowing a diet-induced increase in chondrial membrane involved in mitochondrial respiration, oxidative phosphorylation, uncoupling, UCP3 expression. Healthy male vol- and import of long-chain acyl-CoA molecules. Two potential roles for UCP3 function are illustrat- unteers expressed 44% more UCP3 ed. (right-hand side) UCP3 functions as an uncoupler by acting as a channel for proton entry into protein in skeletal muscle while con- the matrix, which dissipates the transmembrane potential generated by respiratory chain complex- suming a high-fat diet than while es I through IV. This reduces the motive force for proton entry via the F1F0-ATPase, which catalyzes ATP synthesis, and, in effect, uncouples respiration from oxidative phosphorylation. Substrate oxi- consuming a low-fat diet. The inves- dation proceeds via transfer of electrons from donors (reductants) to acceptors (oxidants) along tigators assessed mitochondrial func- the respiratory chain to water, releasing energy as heat. Another consequence is a reduction in reac- tion in vivo by measuring phospho- tive oxygen species formation, since these species are generated under conditions of high trans- creatine