Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate transporters in mitochondria.
Palmieri L,
Pardo B,
Lasorsa FM,
del Arco A,
Kobayashi K,
Iijima M,
Runswick MJ,
Walker JE,
Saheki T,
Satrústegui J,
Palmieri F.
Department of Pharmaco-Biology, University of Bari, Via Orabona 4, 70125 Bari, Italy.
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.
PMID: 11566871 [PubMed - indexed for MEDLINE]
PMCID: PMC125626