Reduced N-acetylaspartate levels in mice lacking Aralar, a brain-and muscle-type mitochondrial aspartate-glutamate carrier

doi:10.1074/jbc.M505286200

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Papers In Press, published online ahead of print June 29, 2005
J. Biol. Chem, 10.1074/jbc.M505286200
Submitted on May 13, 2005
Revised on June 27, 2005
Accepted on June 29, 2005

Reduced N-acetylaspartate levels in mice lacking Aralar, a brain-and muscle-type mitochondrial aspartate-glutamate carrier

Md. Abdul Jalil, Laila Begum, Laura Contreras, Beatriz Pardo, Mikio Iijima, Meng Xian Li, Milagros Ramos, Patricia Marmol, Masahisa Horiuchi, Kyoko Shimotsu, Shiro Nakagawa, Akiko Okubo, Munefumi Sameshima, Yasushi Isashiki, Araceli del Arco, Keiko Kobayashi, Jorgina Satrustegui, and Takeyori Saheki

Department of Molecular Metabolism and Biochemical Genetics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Kagoshima 890-8544

Corresponding Author: takesah{at}m.kufm.kagoshima-u.ac.jp

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.

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