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J. Biol. Chem., Vol. 282, Issue 10, 7098-7106, March 9, 2007

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Ca²⁺ Activation Kinetics of the Two Aspartate-Glutamate Mitochondrial Carriers, Aralar and Citrin

ROLE IN THE HEART MALATE-ASPARTATE NADH SHUTTLE^*

Laura Contreras¹, Paulino Gomez-Puertas, Mikio Iijima^¶, Keiko Kobayashi^¶, Takeyori Saheki^¶, and Jorgina Satrústegui²

From the Departamento de Biología Molecular and the Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid, C.S.I.C., 28049 Madrid, Spain and the ^¶Department of Molecular Metabolism and Biochemical Genetics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan

Ca²⁺ regulation of the Ca²⁺ binding mitochondrial carriers for aspartate/glutamate (AGCs) is provided by their N-terminal extensions, which face the intermembrane space. The two mammalian AGCs, aralar and citrin, are members of the malate-aspartate NADH shuttle. We report that their N-terminal extensions contain up to four pairs of EF-hand motifs plus a single vestigial EF-hand, and have no known homolog. Aralar and citrin contain one fully canonical EF-hand pair and aralar two additional half-pairs, in which a single EF-hand is predicted to bind Ca²⁺. Shuttle activity in brain or skeletal muscle mitochondria, which contain aralar as the major AGC, is activated by Ca²⁺ with S_0.5 values of 280–350 nM; higher than those obtained in liver mitochondria (100–150 nM) that contain citrin as the major AGC. We have used aralar- and citrin-deficient mice to study the role of the two isoforms in heart, which expresses both AGCs. The S_0.5 for Ca²⁺ activation of the shuttle in heart mitochondria is about 300 nM, and it remains essentially unchanged in citrin-deficient mice, although it undergoes a drastic reduction to about 100 nM in aralar-deficient mice. Therefore, aralar and citrin, when expressed as single isoforms in heart, confer differences in Ca²⁺ activation of shuttle activity, probably associated with their structural differences. In addition, the results reveal that the two AGCs fully account for shuttle activity in mouse heart mitochondria and that no other glutamate transporter can replace the AGCs in this pathway.

Received for publication, November 10, 2006 , and in revised form, January 8, 2007.

^* This work was supported in part by grants from the Ministerio de Educación y Ciencia (BFU2005-C02-01, GEN2003-20235-C05-03/NAC), Instituto de Salud Carlos III del Ministerio de Sanidad (PI042457), European Union (LSHM-CT-2006-518153) (to J. S.), by Grant SAF2004-06843-C03 from the Ministerio de Educación y Ciencia (to P. G.-P.), by an institutional grant from the Fundación Ramón Areces to the CBMSO, and by Grants-in-Aid for Scientific Research (16390100) from the Japan Society for the Promotion of Science (to K. K.). 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.

¹ Recipient of Comunidad de Madrid and IP3-CSIC fellowships.

² To whom correspondence should be addressed: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain. Tel.: 34-91-497-4872; Fax: 34-91-497-4799; E-mail: jsatrustegui{at}cbm.uam.es.

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