Inactivation of the mitochondrial carrier SLC25A25 (ATP-Mg2+/Pi transporter) reduces physical endurance and metabolic efficiency in mice

Abstract

An ATP-Mg2+/Pi 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-Mg2+ and Pi 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. Mouse embryo fibroblasts from Slc25a25-/- mice have reduced Ca2+ flux across the endoplasmic reticulum, basal mitochondrial respiration, and ATP content. Although Slc25a25-/-mice are metabolically inefficient, the source of the inefficiency is not from a primary function in thermogenesis, because Slc25a25-/- mice maintain body temperature upon acute exposure to the cold (4 °C). Rather, the role of SLC25A25 in metabolic efficiency is most likely linked to muscle function as evidenced from the physical endurance test of mutant mice on a treadmill. Consequently, in the absence of SLC25A25 the efficiency ofATPproduction required for skeletal muscle function is diminished with secondary effects on adiposity. However, in the absence of UCP1-based thermogenesis, induction of Slc25a25 in mice with an intact genemaycontribute to an alternative thermogenic pathway for the maintenance of body temperature during cold stress. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.