1. Reduced N-acetylaspartate levels in mice lacking aralar, a brain- and muscle-type mitochondrial aspartate-glutamate carrier.
- Author
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Jalil MA, Begum L, Contreras L, Pardo B, Iijima M, Li MX, Ramos M, Marmol P, Horiuchi M, Shimotsu K, Nakagawa S, Okubo A, Sameshima M, Isashiki Y, Del Arco A, Kobayashi K, Satrústegui J, and Saheki T
- Subjects
- Animals, Aspartic Acid genetics, Behavior, Animal physiology, Brain cytology, Brain Chemistry, Calcium-Binding Proteins genetics, Calcium-Binding Proteins metabolism, Cell Respiration physiology, Lipids analysis, Membrane Transport Proteins genetics, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitochondrial Membrane Transport Proteins, Mitochondrial Proteins genetics, Muscle, Skeletal cytology, Aspartic Acid analogs & derivatives, Aspartic Acid metabolism, Brain metabolism, Membrane Transport Proteins metabolism, Mitochondria metabolism, Mitochondrial Proteins metabolism, Muscle, Skeletal metabolism
- Abstract
Aralar is a mitochondrial calcium-regulated aspartate-glutamate carrier mainly distributed in brain and skeletal muscle, involved in the transport of aspartate from mitochondria to cytosol, and in the transfer of cytosolic reducing equivalents into mitochondria as a member of the malate-aspartate NADH shuttle. In the present study, we describe the characteristics of aralar-deficient (Aralar-/-) mice, generated by a gene-trap method, showing no aralar mRNA and protein, and no detectable malate-aspartate shuttle activity in skeletal muscle and brain mitochondria. Aralar-/- mice were growth-retarded, exhibited generalized tremoring, and had pronounced motor coordination defects along with an impaired myelination in the central nervous system. Analysis of lipid components showed a marked decrease in the myelin lipid galactosyl cerebroside. The content of the myelin lipid precursor, N-acetylaspartate, and that of aspartate are drastically decreased in the brain of Aralar-/- mice. The defect in N-acetylaspartate production was also observed in cell extracts from primary neuronal cultures derived from Aralar-/- mouse embryos. These results show that aralar plays an important role in myelin formation by providing aspartate for the synthesis of N-acetylaspartate in neuronal cells.
- Published
- 2005
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