Calcium-binding mitochondrial carrier protein Aralar1 is a protein that in humans is encoded by the SLC25A12 gene.^[4][5][6][7] Aralar is an integral membrane protein located in the inner mitochondrial membrane. Its primary function as an antiporter is the transport of cytoplasmic glutamate with mitochondrial aspartate across the inner mitochondrial membrane, dependent on the binding of one calcium ion. Mutations in this gene cause early infantile epileptic encephalopathy 39 (EIEE39), symptomized by global hypomyelination of the central nervous system, refractory seizures, and neurodevelopmental impairment.^[8][9] This gene has connections to autism.^[10][11]

Quick Facts SLC25A12, Available structures ...

SLC25A12
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4P60, 4P5X,%%s4P5X, 4P60
Identifiers
Aliases	SLC25A12, AGC1, ARALAR, solute carrier family 25 member 12, EIEE39, DEE39
External IDs	OMIM: 603667; MGI: 1926080; HomoloGene: 48235; GeneCards: SLC25A12; OMA:SLC25A12 - orthologs
Gene location (Human) Chr. Chromosome 2 (human)[1] Band 2q31.1 Start 171,783,405 bp[1] End 171,999,859 bp[1]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in biceps brachii triceps brachii muscle vastus lateralis muscle gastrocnemius muscle thoracic diaphragm right ventricle deltoid muscle endothelial cell middle temporal gyrus body of tongue n/a More reference expression data BioGPS More reference expression data
Gene ontology Molecular function calcium ion binding metal ion binding L-aspartate transmembrane transporter activity L-glutamate transmembrane transporter activity acidic amino acid transmembrane transporter activity transmembrane transporter activity identical protein binding Cellular component membrane myelin sheath mitochondrion mitochondrial inner membrane integral component of membrane Biological process gluconeogenesis malate-aspartate shuttle response to calcium ion transmembrane transport aspartate transmembrane transport L-glutamate transmembrane transport transport glutamate biosynthetic process positive regulation of glucose metabolic process positive regulation of myelination L-aspartate transmembrane transport negative regulation of glucose catabolic process to lactate via pyruvate positive regulation of ATP biosynthetic process mitochondrial calcium ion transmembrane transport Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 8604 78830 Ensembl ENSG00000115840 n/a UniProt O75746 Q8BH59 RefSeq (mRNA) NM_003705 NM_172436 RefSeq (protein) NP_003696 NP_766024 Location (UCSC) Chr 2: 171.78 – 172 Mb n/a PubMed search [2] [3]
Wikidata
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The SLC25A12 gene is located on the q arm of chromosome 2 in position 31.1 and spans 110,902 base pairs.^[7] The gene produces a 74.8 kDa protein composed of 678 amino acids.^[12][13] The encoded protein, Aralar1, is a multi-pass membrane protein located in the inner mitochondrial membrane.^[8][9] The N-terminal half of this protein contains 2 imperfect EF-hand domains along with 3 canonical EF-hand calcium-binding domains; this part of the protein binds calcium in vitro. Aralar's C-terminal half shares 28-29% identity with other members of the mitochondrial solute carrier family, including SLC25A11, SLC25A5, SLC25A1, and has 6 putative transmembrane domains like the other members of mitochondrial solute carrier family.^[14][15]

The protein encoded by SLC25A12, Aralar1, is a mitochondrial calcium-binding carrier that facilitates the calcium-dependent exchange of cytoplasmic glutamate with mitochondrial aspartate across the mitochondrial inner membrane. Aralar binds to one calcium ion with high affinity. Upon calcium binding, the EF-hand-containing regulatory N-terminal domain binds to the C-terminal domain, opening a vestibule which allows the substrates to be translocated through the carrier domain. In the absence of calcium, the linker loop domain may close the vestibule, which may prevent substrates from entering the carrier domain.^[16] As a member of the malate-aspartate NADH shuttle, Aralar is also involved in the transfer of cytosolic reducing equivalents from the cytosol to the mitochondrial matrix.^[17] Aralar, along with the protein encoded by SLC25A13, are both calcium-binding aspartate/glutamate carriers which are substrates in the TIMM8A/TIMM13 complex.

Overexpression of Aralar1 augments mitochondrial metabolism and increases insulin secretion in pancreatic cells.^[18] Aralar is expressed as both a 3.2 kb and 2.9 kb mRNA transcript in heart and skeletal muscle cells, and in lesser amounts in brain and kidney cells.^[14][15]

Aralar has interactions with SCO1, ATF2, COX14, COA3, in addition to 36 other proteins.^[19]

• Solute carrier family