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Obviously, in this condition, the potential energy of the proton gradient is not used for phosphorylation of ADP, indicating that there is proton transfer across the inner mitochondrial membrane that is not coupled to phosphory- lation of ADP (referred to as proton leak or mitochondrial uncoupling). This process, called state 4 respiration (Figure 1), indicates that uncoupling of mitochondria is an existing phenomenon that occurs in mitochondria derived from nu- merous tissues [e.g., brown adipose tissue (BAT), skeletal muscle, and hepatocytes]. For most tissues, the physiolog- ical significance of uncoupling is still unknown, but much is learned from the mitochondrial uncoupling that occurs in BAT. This tissue plays a recognized role in adaptive ther- mogenesis, when the energy generated in the electron trans- fer chain is released as heat rather than used for phosphor- ylation of ADP, thereby allowing adaptation to cold. Conversely, during hibernation, when preservation of en- ergy is essential, BAT mitochondria become more tightly coupled, attenuating energy expenditure and saving energy stores. Moreover, only in BAT has the protein responsible for mitochondrial uncoupling been identified and named thermogenin [now called uncoupling protein-1 (UCP1)] (2). Thus, this protein is responsible for adaptive thermogenesis and, therefore, the regulation of energy balance in rodents. should be noted, however, that computations have been made indicating that in vivo proton leak in liver and skeletal muscle mitochondria may account for contracting skeletal muscle, proton leak makes up 15% of basal metabolic rate (4). Whereas these studies clearly un- derscore the impact of proton leak on basal metabolic rate, the protein(s) responsible for the proton leak had not been identified. Not surprisingly, the discovery of the UCP1 homologs UCP2 (5) and UCP3 (6) in 1997 was warmly welcomed. "true" (7) uncoupling protein UCP1 made UCP2 and UCP3 attractive targets for interventions aimed at manipulating energy expenditure. Extensive research toward the regula- tion and the putative functions of these novel uncoupling proteins has resulted in a vast amount of publications in the last 6 years. Notwithstanding the overwhelming number of studies published, there seems to be no consensus on a possible role for these novel uncoupling proteins in the regulation of energy expenditure and obesity. In fact, the primary function of UCP2 and UCP3 is still under debate. Because UCP3 is expressed almost exclusively in skeletal muscle, which makes up metabolic rate, the pioneering studies focused mainly on ATP hydrolysis blocked, mitochondria start respiring at a relatively high rate (state 3 respiration). Under state 3 conditions, oxygen is consumed and coupled to phosphorylation of ADP to ATP, which is driven by the energy liberated in the electron transfer chain (coupled respiration). On depletion of ADP (because all ADP has been phosphorylated and ATP hydrolysis is blocked), mitochondria continue respiration at a much lower rate, referred to as state 4 respiration. Because the energy generated in the electron transfer cannot be coupled to oxidative phosphorylation (because ADP is depleted), this is uncoupled respiration. If uncoupling agents like dinitrophenol (DNP) or p-trifluoromethoxy carbonyl cyanide phenyl hydrazone (FCCP) are added to the medium, the rate of uncoupled respiration is increased (fully uncoupled respiration), as indicated by the rapid depletion of oxygen from the medium (dotted line). Note that uncoupled respiration is an intrinsic trait of mitochondria (also of "normal healthy" mitochondria). |
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