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J. Biol. Chem., Vol. 282, Issue 40, 29658-29666, October 5, 2007

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Evolutionarily Conserved Mammalian Adenine Nucleotide Translocase 4 Is Essential for Spermatogenesis^*

Jeffrey V. Brower¹, Nemanja Rodic¹, Tsugio Seki, Marda Jorgensen, Naime Fliess, Anthony T. Yachnis, John R. McCarrey^¶, S. Paul Oh, and Naohiro Terada²

From the Departments of Pathology and Physiology, University of Florida College of Medicine, Gainesville, Florida 32610 and the ^¶Department of Biology, University of Texas at San Antonio, San Antonio, Texas 78249

The adenine nucleotide translocases (Ant) facilitate the transport of ADP and ATP by an antiport mechanism across the inner mitochondrial membrane, thus playing an essential role in cellular energy metabolism. We recently identified a novel member of the Ant family in mouse, Ant4, of which gene configuration as well as amino acid homology is well conserved among mammals. The conservation of Ant4 in mammals, along with the absence of Ant4 in nonmammalian species, suggests a unique and indispensable role for this ADP/ATP carrier in mammalian development. Of interest, in contrast to its paralog Ant2, which is encoded by the X chromosome and ubiquitously expressed in somatic cells, Ant4 is encoded by an autosome and selectively expressed in testicular germ cells. Immunohistochemical examination as well as RNA expression analysis using separated spermatogenic cell types revealed that Ant4 expression was particularly high in spermatocytes. When we generated Ant4-deficient mice by targeted disruption, a significant reduction in testicular size was observed without any other distinguishable abnormalities in the mice. Histological examination as well as stage-specific gene expression analysis in adult and neonatal testes revealed a severe reduction of spermatocytes accompanied by increased apoptosis. Subsequently, the Ant4-deficient male mice were infertile. Taken together, these data elucidated the indispensable role of Ant4 in murine spermatogenesis. Considering the unique conservation and chromosomal location of the Ant family genes in mammals, the Ant4 gene may have arisen in mammalian ancestors and been conserved in mammals to serve as the sole and essential mitochondrial ADP/ATP carrier during spermatogenesis where the sex chromosome-linked Ant2 gene is inactivated.

Received for publication, May 29, 2007 , and in revised form, July 19, 2007.

^* This work was supported in part by National Institutes of Health Grants DK59699 and RR17001 (to N. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Pathology, University of Florida College of Medicine, P.O. Box 100275, Gainesville, FL 32610. Tel.: 352-392-2696; Fax: 352-392-6249; E-mail: terada{at}pathology.ufl.edu.

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