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INVITED EDITORIALS
Yale Medical School
New Haven, Connecticut
e-mail: gary.cline{at}yale.edu
In rodents, the challenge of maintaining core body temperature in a cold environment is partially met by increased activity of mitochondrial uncoupling protein (UCP) 1 in brown adipose tissue (BAT) (1). The energy that would normally be preserved by coupling ATP synthesis with the translocation of protons across the inner mitochondrial membrane is instead converted to heat when protons "leak" across the membrane through UCP1. The production of heat by mitochondrial proton leak is commonly referred to as nonshivering thermogenesis (NST). Several homologs of UCP1 are also found in the mitochondria of other tissues throughout the body, with UCP3 restricted primarily to skeletal muscle and BAT (11). Although the high sequence homology of the various UCPs leads to the quite reasonable expectation that all UCPs may have a similar physiological function, the study by Barger et al. (1) in this issue of the Journal of Applied Physiology clearly resolves a long-standing debate as to whether UCP3 contributes toward cold-induced thermogenesis when it is most needed (2).
The authors assessed the regulation of cold-induced expression and protein levels of UCP1 in BAT and UCP3 in skeletal muscle at ambient temperatures above (5°C) and below freezing (–10°C) in awake (fed and fasted) and in hibernating artic ground squirrels (1). Expression levels and protein concentrations of UCP1 and UCP3 were reciprocal. UCP1 levels increased as the temperature decreased, whereas there was little change in UCP3 levels when temperatures were further lowered from 5 to –10°C. Fasting-induced changes in UCP1 and UCP3 were radically different: fasting decreased UCP1 levels, whereas UCP3 levels increased. Functionally, in the extreme of hibernation at –10°C, UCP1 activity maintained tissue temperatures in the BAT and proximal tissue significantly higher than both the environment and compared with more distal non-BAT tissue. Any contribution of UCP3 to NST was probably negligible and was more likely due to perfusion of blood warmed indirectly by BAT. These observations argue against any significant temperature-responsive contribution of UCP3 toward thermogenesis in the muscle produced by mitochondrial uncoupling. Supporting this conclusion are results from mice with UCP1 ablation in BAT (8). Mitochondria isolated from these mice had normal basal metabolic rates but were refractory to adrenergically induced thermogenesis despite high ectopic expression of UCP2 and UCP3. Thus thermogenesis seems to be a proprietary characteristic of UCP1.
The current study (1) adds to the growing body of evidence arguing against corresponding changes in uncoupling activity in the face of changes in UCP3 concentrations, and it begs the question of does UCP3 actually possess thermogenic uncoupling activity that is physiologically relevant. Direct measurement of the basal mitochondrial oxidative phosphorylation (P/O) ratio in the skeletal hindlimb muscle of mice was 
93% of the theoretical P/O ratio, suggesting that oxidative phosphorylation in skeletal muscle is highly coupled, at least at rest (9). However, no data were presented with regard to temperature- or adrenergically inducible changes of mitochondrial coupling. In earlier studies of UCP3 knockout (UCP3KO) mice, oxidative phosphorylation was shown to be more tightly coupled compared with their wild-type littermates both in vitro and in vivo (4, 12). Interestingly, in UCP3KO mice, tighter coupling was accompanied by increased rates of ATP synthesis with minimal changes in tricarboxycylic acid cycle rates, suggesting that maintaining the correct redox state has higher priority over ATP synthesis in setting basal rates of mitochondrial respiration. The converse experiment of overexpressing UCP3 led to increased mitochondrial uncoupling and higher basal metabolic rate in these mice (3). The validity of extrapolating the magnitude of UCP3-mediated proton leak in mitochondria with supraphysiological levels of UCP3 to normal physiology is questionable; however, the discovery that reactive oxygen species (ROS) can upregulate UCP3 activity to levels seen in the UCP3-overexpressing mice leaves open the possibility of UCP3-mediated thermogenesis (6). Hibernation represents an extreme condition where NST is critical to survival, and if there were ever a time for UCP3 to help keep an animal warm, this is it. The cooling of the extremities of the hibernating animals measured by Barger et al. (1) would argue against any physiological stimulation of UCP3 for heat production in skeletal muscle.
This is not to say that increases in UCP3 are without effect on mitochondrial metabolism. A paradox of UCP3 is the observation of others, as well as of Barger et al. (1), that UCP3 expression and protein levels increase under fasting conditions where one would expect uncoupling to be minimized and oxidative-phosphorylation efficiency maximized. The logical implication is that UCP3 may serve as a mitochondrial mediator of fatty acid metabolism in the muscle. Proposed mechanisms for the direct involvement of UCP3 in fatty acid metabolism are still subject to active debate (2). Common to the models though is UCP3-mediated export of fatty acid anions from the mitochondrial matrix in response to increased flux of either acyl-CoA or protonated free fatty acids. Export tied to hydrolysis of acyl-CoA provides a means to maintain an adequate supply of CoA, whereas the latter model represents a form of nonthermogenic uncoupling. Alternatively, and as an added bonus of protection from potentially damaging modification of membrane lipids by ROS, UCP3 may serve to transport lipid peroxides out of the mitochondria (2). Indeed, although a doubling of UCP3 concentration in myotubes had no effect on mitochondrial uncoupling, as assessed by oxygen consumption and membrane potential, fatty acid oxidation was significantly increased, whereas the production of ROS was suppressed (7). In vivo, UCP3KO mice had increased rates of ROS production, lending credence to the hypothesis that UCP3 moderates the generation of ROS (12). Thus another primary and critical function of UCP3 may be to moderate ROS generation, thereby protecting the mitochondrial from the detrimental effects of ROS and its by-products. This protective role of UCP3 is especially germane to an aging population, since the decline in aerobic performance is directly proportional to decreased oxidative capacity in skeletal muscle (5). Recent NMR measurements of mitochondrial metabolism in the muscle of insulin resistant and healthy control subjects implicate mitochondrial dysfunction as the primary event leading to increased intracellular lipids and the development of insulin resistance in elderly patients (10). UCP3 may not be the fountain of youth, but it may go along way toward making for an active and enjoyable retirement.
REFERENCES
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