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J. Biol. Chem., Vol. 281, Issue 2, 1039-1047, January 13, 2006

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Essential Role of Aralar in the Transduction of Small Ca⁺ Signals to Neuronal Mitochondria^*

Beatriz Pardo12, Laura Contreras13, Antonio Serrano, Milagros Ramos, Keiko Kobayashi¶, Mikio Iijima¶, Takeyori Saheki¶, and Jorgina Satrústegui4

From the Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa and Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, 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

Aralar, the neuronal Ca²⁺-binding mitochondrial aspartate-glutamate carrier, has Ca²⁺ binding domains facing the extramitochondrial space and functions in the malate-aspartate NADH shuttle (MAS). Here we showed that MAS activity in brain mitochondria is stimulated by extramitochondrial Ca²⁺ with an S_0.5 of 324 nM. By employing primary neuronal cultures from control and aralar-deficient mice and NAD(P)H imaging with two-photon excitation microscopy, we showed that lactate utilization involves a substantial transfer of NAD(P)H to mitochondria in control but not aralar-deficient neurons, in agreement with the lack of MAS activity associated with aralar deficiency. The increase in mitochondrial NAD(P)H was greatly potentiated by large [Ca²⁺]_i signals both in control and aralar-deficient neurons, showing that these large signals activate the Ca²⁺ uniporter and mitochondrial dehydrogenases but not MAS activity. On the other hand, small [Ca²⁺]_i signals potentiate the increase in mitochondrial NAD(P)H only in control but not in aralar-deficient neurons. We concluded that neuronal MAS activity is selectively activated by small Ca²⁺ signals that fall below the activation range of the Ca²⁺ uniporter and plays an essential role in mitochondrial Ca²⁺ signaling.

Received for publication, July 5, 2005 , and in revised form, October 26, 2005.

^* This work was supported in part by Dirección General de Investigación del Ministerio de Ciencia y Tecnología Grant BMC2002-02072, Comunidad de Madrid Grant 08.5/0024/2003, Fondo de Investigaciones Sanitarias del Ministerio de Sanidad y Consumo 01/0395 (to J. S.), an institutional grant from the Fundación Ramón Areces to the Centro de Biología Molecular `Severo Ochoa,' and by a Grant-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 Both authors contributed equally to this work.

² Recipient of a postdoctoral contract from the Comunidad de Madrid.

³ Recipient of a fellowship from the Comunidad de Madrid.

⁴ To whom correspondence should be addressed: Dept. de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Facultad de Ciencias, Universidad Autónoma, 28049 Cantoblanco, Madrid, Spain. Tel.: 34-91-397-4872; Fax: 34-91-397-4799; E-mail: jsatrustegui{at}cbm.uam.es.

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