Discovering The Developmental Origins of Obesity

The Polish Academy of Sciences in Olsztyn, Poland

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

Rea P. Anunciado-Koza1, Jingying Zhang, Jozef Ukropec2, Sudip Bajpeyi, Robert A. Koza, Richard C. Rogers, William T. Cefalu, Randall L. Mynatt, and Leslie P. Kozak3

From the Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808

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 Ca2+-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.

JOURNAL OF BIOLOGICAL CHEMISTRY APRIL 1, 2011 VOLUME 286 NUMBER 13

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Thisworkwas supported, inwhole or in part, byNational Institutes ofHealth
Grants R01-HD008431 (to L. P. K.) and 1P30 DK07246.
1 Present address: Taconic Farms, One Hudson City Center, Hudson, NY 12534.
2 Present address: Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovak Republic.
3 Present address: Polish Academy of Sciences in Olsztyn, ul. Tuwima 10, 10-747 Olsztyn, Poland. To whom correspondence should be addressed. Tel.: 48-89-523-46-86; Fax: 48-524-01-24; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it. .

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