Inactivation of the Mitochondrial Carrier SLC25A25 (ATP-Mg2+/Pi Transporter) Reduces Physical Endurance and Metabolic Efficiency in Mice

Abstract

An ATP-Mg 2؉/ P i inner mitochondrial membrane solute transporter (SLC25A25), which is induced during adaptation to cold stress in the skeletal muscle of mice with defective UCP1/ brown adipose tissue thermogenesis, has been evaluated for its role in metabolic efficiency. SLC25A25 is thought to control ATP homeostasis by functioning as a Ca 2؉ -regulated shuttle of ATP-Mg 2؉ and P i across the inner mitochondrial membrane. Mice with an inactivated Slc25a25 gene have reduced metabolic efficiency as evidenced by enhanced resistance to diet-induced obesity and impaired exercise performance on a treadmill. Obesity and its associated co-morbidities develop from a prolonged energy imbalance that occurs when food intake exceeds energy expenditure. Although considerable progress has been made in our understanding of the food intake side of the energy balance equation (1), much less is known of mechanisms of energy expenditure that can be utilized to reduce a positive energy balance. Two major thermogenic systems are known that can be activated voluntarily to increase energy expenditure. One is brown adipose tissue that functions to regulate body temperature and will be activated or not depending in part on whether a person chooses to become exposed to and to tolerate a reduced ambient temperature. The other is skeletal muscle, which functions primarily for motility, but is a major site for caloric expenditure and can be recruited to reduce excessive caloric stores. Although either exposure to reduced ambient temperature or physical activity can increase energy expenditure to maintain energy balance (2, 3), the modern lifestyle of many individuals does not support these natural antiobesity solutions. Mouse embryo fibroblasts fromGiven that skeletal muscle comprises up to 40% of total body weight and is able to consume 90% of the whole body oxygen uptake during maximal physical activity (4), the positive energy balance of obese individuals could be determined by variations in the efficiency of muscle energy metabolism (5). Mutations to several genes encoding and/or regulating the sarcoendoplasmic reticulum Ca 2ϩ -ATPases (SERCAs) 4 show deleterious phenotypes caused by defective Ca 2ϩ cycling, energy metabolism, and muscle function (6 -8); however, very few of these mutations have been analyzed for their impact on susceptibility to obesity and type 2 diabetes. Although the suppression of oxidative phosphorylation by reducing the number of mitochondria has been proposed to provide the conditions for the development of obesity and type 2 diabetes (5), in fact such suppression, as occurs with a skeletal muscle-specific inactivation of PGC-1␣, leads to mice with a lean body composition and resistance to diet-induced obesity (9). Therefore PGC-1␣-deficient mice are similar to UCP1-deficient mice in that a reduction in the capacity for energy expenditure and reduced mitochondrial function paradoxically reduces susceptibility to environmental obesity (10).It is generally observed that the inactivation of genes of energy metaboli...

Brown and beige fat: development, function and therapeutic potential

“…Notably, previous studies in rats housed at thermoneutrality failed to find any substantial contribution of BAT activity to diet-induced thermogenesis 58 . Moreover, Anunciado-Koza et al 55 did not observe changes in adiposity in their studies of Ucp1 knockout mice when the mice were housed under varying temperature conditions. In addition, increases in BAT or Ucp1 activity in response to high-fat feeding are not consistently observed 59 .…”

“…At room temperature (20-22 °C), mice are cold and must therefore expend extra energy to defend their body temperature. Ucp1-deficient mice, which cannot use BAT, activate alternative thermogenic mechanisms 55,56 . This is thought to conceal the effect of brown fat and Ucp1 on energy balance.…”

Uncoupling Protein 1 and Sarcolipin Are Required to Maintain Optimal Thermogenesis, and Loss of Both Systems Compromises Survival of Mice under Cold Stress

“…Although BAT is unequivocally a dominant thermogenic mechanism in rodents, several studies have suggested other mechanisms of heat production. Indeed, published studies on cold-adapted UCP1-KO mice have implicated that Ca 2ϩ cycling in skeletal muscle, thermogenesis from white adipose tissue (UCP1-independent), and substrate cycling in skeletal muscle could be recruited to produce heat, but none of these mechanisms were found to be dominant (15)(16)(17)(18).…”

Loss of the RNA polymerase III repressor MAF1 confers obesity resistance

“…These approaches stimulate facultative thermogenic responses that uncouple substrate oxidation from ATP synthesis, dissipate the mitochondrial proton gradient, and release chemical energy as heat. Other possibilities to enhance energy expenditure by decreasing the metabolic efficiency of obligatory cellular processes remain largely unexplored (Alekseev et al 2010;Anunciado-Koza et al 2011;Oie et al 2014).…”