Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate transporters in mitochondria

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 Ca(2+)-binding motifs in their N-terminal domains. Both protei...

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Bibliographic Details
Published in:The EMBO journal 2001-09, Vol.20 (18), p.5060-5069
Main Authors: Palmieri, L, Pardo, B, Lasorsa, F M, del Arco, A, Kobayashi, K, Iijima, M, Runswick, M J, Walker, J E, Saheki, T, Satrústegui, J, Palmieri, F
Format: Article
Language:English
Subjects:
Amino Acid Transport Systems, Acidic
Antiporters
Calcium - pharmacology
Calcium-Binding Proteins - genetics
Calcium-Binding Proteins - physiology
Carrier Proteins - genetics
Carrier Proteins - physiology
Cell Line
Citrullinemia - etiology
Escherichia coli - genetics
Humans
Kinetics
Membrane Transport Proteins
Mitochondria - metabolism
Mitochondrial Membrane Transport Proteins
Mitochondrial Proteins
Models, Chemical
Organic Anion Transporters
Proteolipids - metabolism
Transfection
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Summary: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 Ca(2+)-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 Ca(2+) on the external side of the inner mitochondrial membrane, where the Ca(2+)-binding domains of these proteins are localized. These results show that the aspartate/glutamate carrier is regulated by Ca(2+) through a mechanism independent of Ca(2+) entry into mitochondria, and suggest a novel mechanism of Ca(2+) regulation of the aspartate/malate shuttle.
ISSN:0261-4189