Increased mitochondrial proton leak in skeletal muscle mitochondria of UCP1-deficient mice

Mice having targeted inactivation of uncoupling protein 1 (UCP1) are cold s ensitive but not obese (Enerback S, Jacobsson A, Simpson EM, Guerra C, Yama shita H, Harper M-E, and Kozak LP. Nature 387: 90-94, 1997). Recently, we h ave shown that proton leak in brown adipose tissue (BAT) mitochondria from UCP1-deficient mice is insensitive to guanosine diphosphate (GDP), a well k nown inhibitor of UCP1 activity (Monemdjou S, Kozak LP, and Harper M-E. Am J Physiol Endocrinol Metab 276: E1073-E1082, 1999). Moreover, despite a fiv efold increase of UCP2 mRNA in BAT of UCP1-deficient mice, we found no diff erences in the overall kinetics of this GDP-insensitive proton leak between UCP1-deficient mice and controls. Based on these findings, which show no a daptive increase in UCP1-independent leak in BAT, we hypothesized that adap tive thermogenesis may be occurring in other tissues of the UCP1-deficient mouse (e.g., skeletal muscle), thus allowing them to maintain their normal resting metabolic rate, feed efficiency, and adiposity. Here, we report on the overall kinetics of the mitochondrial proton leak, respiratory chain, a nd ATP turnover in skeletal muscle mitochondria from UCP1-deficient and het erozygous control mice. Over a range of mitochondrial protonmotive force (D elta p) values, leak-dependent oxygen consumption is higher in UCP1-deficie nt mice compared with controls. State 4 (maximal leak-dependent) respiratio n rates are also significantly higher in the mitochondria of mice deficient in UCP1, whereas state 4 Delta p is significantly lower. No significant di fferences in state 3 respiration rates or Delta p values were detected betw een the two groups. Thus the altered kinetics of the mitochondrial proton l eak in skeletal muscle of UCP1-deficient mice indicate a thermogenic mechan ism favoring the lean phenotype of the UCP1-deficient mouse.