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| The EMBO Journal
(2001) 20, 5060–5069, doi:10.1093/emboj/20.18.5060 |
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| Citrin and aralar1 are Ca2+-stimulated aspartate/glutamate transporters in mitochondria |
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| L. Palmieri1, B. Pardo2, F.M. Lasorsa1, A. del Arco2, 3, K. Kobayashi4, M. Iijima4, M.J. Runswick5, J.E. Walker5, T. Saheki4, J. Satrústegui2 and F. Palmieri1 |
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1 Department of Pharmaco-Biology, University of Bari, Via Orabona 4, 70125 Bari, Italy 2 Departamento de Biologia Molecular, Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid, 28049 Madrid Spain 3 Facultad de Ciencias del Medio Ambiente, Universidad de Castilla La Mancha, Toledo, Spain 4 Department of Biochemistry, Faculty of Medicine, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan 5 The Medical Research Council, Dunn Human Nutrition Unit, Hills Road, Cambridge CB2 2XY, UK To whom correspondence should be addressed F. Palmieri, fpalm@farmbiol.uniba.it Received 16 May 2001; Revised 27 June 2001; Accepted 27 July 2001. |
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| Abstract |
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| The mitochondrial aspartate/glutamate carrier catalyzes an important step in both the urea cycle and the aspartate/malate NADH shuttle. Citrin and aralar1 are homologous proteins belonging to the mitochondrial carrier family with EF-hand Ca2+-binding motifs in their N-terminal domains. Both proteins and their C-terminal domains were overexpressed in Escherichia coli, reconstituted into liposomes and shown to catalyze the electrogenic exchange of aspartate for glutamate and a H+. Overexpression of the carriers in transfected human cells increased the activity of the malate/aspartate NADH shuttle. These results demonstrate that citrin and aralar1 are isoforms of the hitherto unidentified aspartate/glutamate carrier and explain why mutations in citrin cause type II citrullinemia in humans. The activity of citrin and aralar1 as aspartate/glutamate exchangers was stimulated by Ca2+ on the external side of the inner mitochondrial membrane, where the Ca2+-binding domains of these proteins are localized. These results show that the aspartate/glutamate carrier is regulated by Ca2+ through a mechanism independent of Ca2+ entry into mitochondria, and suggest a novel mechanism of Ca2+ regulation of the aspartate/malate shuttle. |
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| Keywords: aralar1, aspartate, glutamate carrier, calcium, citrin, mitochondria |
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