Reduced N-acetylaspartate levels in mice lacking aralar, a brain- and muscle-type mitochondrial aspartate-glutamate carrier.
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.
Department of Molecular Metabolism and Biochemical Genetics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan.
Md Abdul
MA
Jalil
Laila
L
Begum
Laura
L
Contreras
Beatriz
B
Pardo
Mikio
M
Iijima
Meng Xian
MX
Li
Milagros
M
Ramos
Patricia
P
Marmol
Masahisa
M
Horiuchi
Kyoko
K
Shimotsu
Shiro
S
Nakagawa
Akiko
A
Okubo
Munefumi
M
Sameshima
Yasushi
Y
Isashiki
Araceli
A
Del Arco
Keiko
K
Kobayashi
Jorgina
J
Satrústegui
Takeyori
T
Saheki
D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism*; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D001923:Brain Chemistry; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D019069:Cell Respiration / Q000502:physiology; D008055:Lipids / Q000032:analysis; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*
D002135:Calcium-Binding Proteins; D008055:Lipids; D026901:Membrane Transport Proteins; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; C491956:Slc25a12 protein, mouse; D001224:Aspartic Acid; C000179:N-acetylaspartate