SLC25A13 Protein
Introduction
Slc25A13 Protein is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
<div class="infobox infobox-protein">
<table>
<tr><th colspan="2"><strong>SLC25A13 (Citarin/Aralar2)</strong></th></tr>
<tr><td><strong>Protein Name</strong></td><td>SLC25A13 (Citarin/Aralar2)</td></tr>
<tr><td><strong>Gene</strong></td><td>SLC25A13</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[Q9H0M0](https://www.uniprot.org/uniprot/Q9H0M0)</td></tr>
<tr><td><strong>Molecular Weight</strong></td><td>~68 kDa</td></tr>
<tr><td><strong>Subcellular Localization</strong></td><td>Mitochondrial inner membrane</td></tr>
<tr><td><strong>Protein Family</strong></td><td>Mitochondrial carrier family (SLC25)</td></tr>
<tr><td><strong>Aliases</strong></td><td>Citarin, Aralar2, AGC2</td></tr>
<tr><td><strong>Tissue Expression</strong></td><td>Liver, brain, heart</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>
Overview
SLC25A13, also known as Citarin or Aralar2 (Aralar-like protein 2), is a mitochondrial inner membrane aspartate/glutamate carrier that plays critical roles in hepatic and neuronal metabolism<sup>[1]</sup>. It is closely related to SLC25A12 (Aralar1) and shares similar transport functions, but exhibits distinct tissue expression patterns that confer unique physiological roles<sup>[2]</sup>.
SLC25A13 is essential for the urea cycle and ammonia detoxification in the liver, and contributes to neuronal energy metabolism in the brain. Mutations in SLC25A13 cause citrullinemia type II (CTLN2), a metabolic disorder characterized by hyperammonemia and neurological symptoms<sup>[3]</sup>.
Gene and Protein Structure
Gene Organization
The SLC25A13 gene is located on chromosome 7q21.3 and encodes a protein of approximately 680 amino acids. Unlike its paralog SLC25A12, SLC25A13 is predominantly expressed in the liver, with lower expression in the brain, heart, and kidney<sup>[4]</sup>.
Protein Domain Architecture
| Domain | Position | Function |
|--------|----------|----------|
| N-terminal EF-hand Domain | 1-150 aa | Calcium binding and sensing |
| Three Transmembrane Helices | 150-350 aa | Mitochondrial membrane integration |
| Carrier Domain | 350-680 aa | Substrate transport |
Structural Features
The SLC25A13 protein shares structural features with other mitochondrial carriers<sup>[5]</sup>:
EF-Hand Calcium Sensors: Two N-terminal EF-hand motifs bind cytosolic calcium
Transmembrane Channel: Six α-helices form the transport pore
Substrate Binding Site: Specific for aspartate and glutamate
Homodimer Formation: Functions as a homodimeric complexNormal Function
SLC25A13 catalyzes the calcium-dependent exchange of aspartate and glutamate across the mitochondrial inner membrane<sup>[6]</sup>:
Aspartate/Glutamate Exchange: Primary transport activity
Urea Cycle Support: Provides mitochondrial aspartate for citrulline synthesis
Malate-Aspartate Shuttle: Participates in NADH shuttling
Gluconeogenesis: Supports hepatic glucose production
ATP Production: Enables oxidative phosphorylationTissue-Specific Roles
Liver (Primary)
In hepatocytes, SLC25A13 is essential for<sup>[7]</sup>:
- Urea Cycle: Exports aspartate from mitochondria for citrulline synthesis
- Ammonia Detoxification: Prevents hyperammonemia
- Gluconeogenesis: Supports conversion of amino acids to glucose
- Detoxification: Metabolic waste removal
Brain
In [neurons](/entities/neurons), SLC25A13 contributes to<sup>[8]</sup>:
- Energy Metabolism: Supports high ATP demand
- Neurotransmitter Cycling: Glutamate and GABA metabolism
- Calcium Signaling: Activity-dependent regulation
Heart
In cardiac tissue, SLC25A13 supports<sup>[9]</sup>:
- Cardiac Energy Demands: High oxidative phosphorylation
- Metabolic Flexibility: Adaptation to workload changes
Role in Disease
Citrullinemia Type II (CTLN2)
SLC25A13 mutations cause citrullinemia type II, an autosomal recessive disorder<sup>[10]</sup>:
| Feature | Description |
|---------|-------------|
| Genetic Basis | Biallelic loss-of-function mutations in SLC25A13 |
| Inheritance | Autosomal recessive |
| Prevalence | Higher in East Asian populations (~1/100,000) |
Pathogenesis
The molecular mechanism involves<sup>[11]</sup>:
Impaired Mitochondrial Aspartate Export: Reduced aspartate availability in cytosol
Reduced Citrulline Synthesis: Urea cycle intermediate deficiency
Hyperammonemia: Accumulation of toxic ammonia
Energy Deficit: Impaired oxidative phosphorylationClinical Presentation
| Symptom | Onset | Severity |
|---------|-------|----------|
| Hyperammonemia | Adult onset | Variable |
| Encephalopathy | Episodes | Can be severe |
| Hepatomegaly | Chronic | Progressive |
| Elevated Citrulline | Persistent | Diagnostic marker |
| Elevated Ammonia | Episodes | Acute episodes |
Treatment
- Dietary Protein Restriction: Reduce ammonia load
- Lactulose: Promote ammonia excretion
- Sodium Phenylbutyrate: Alternative ammonia scavenger
- Liver Transplant: Definitive treatment for severe cases
Alzheimer's Disease
SLC25A13 dysfunction may contribute to AD pathogenesis<sup>[12]</sup>:
- Metabolic Impairment: Similar to SLC25A12 deficits
- Mitochondrial Dysfunction: Energy deficit in neurons
- Glutamate Dysregulation: Excitotoxicity risk
- Calcium Homeostasis: Altered neuronal signaling
Other Neurological Conditions
| Disorder | Relationship to SLC25A13 |
|----------|--------------------------|
| Hepatic Encephalopathy | Ammonia toxicity |
| Parkinson's Disease | Mitochondrial dysfunction |
| Stroke | Energy failure |
Therapeutic Implications
Treatment Strategies
| Approach | Status | Mechanism |
|----------|--------|-----------|
| Gene Therapy | Research | Restore SLC25A13 expression |
| Metabolic Cofactors | Research | Enhance residual function |
| Ammonia Scavengers | Clinical | Reduce hyperammonemia |
| Dietary Management | Standard of care | Protein restriction |
Biomarker Potential
- Serum Citrulline: Diagnostic and monitoring marker
- Blood Ammonia Levels: Disease activity indicator
- Liver Function Tests: Assess hepatic involvement
Interaction Network
Protein Interactions
| Interactor | Interaction Type | Functional Significance |
|------------|-----------------|------------------------|
| MDH2 | Metabolic partner | Malate-aspartate shuttle |
| GOT2 | Metabolic partner | Aspartate metabolism |
| ASS1 | Metabolic partner | Urea cycle |
| CPS1 | Metabolic partner | Urea cycle |
Pathway Membership
SLC25A13 participates in:
- Urea Cycle — Aspartate supply
- Malate-Aspartate Shuttle — NADH shuttling
- Gluconeogenesis — Metabolic precursor supply
- Calcium Signaling — Activity-dependent regulation
Key Publications
Kobayashi K, et al. (1999). "The gene encoding mitochondrial aspartate/glutamate carrier (AGC) is mutated in citrullinemia." Nat Genet 22: 159-163.
Palmieri L, et al. (2001). "A novel transport protein for Ca²⁺-activated aspartate/glutamate carrier." EMBO J 20: 4359-4367.
Sinasac DS, et al. (2004). "Mitochondrial aspartate/glutamate carrier SLC25A13 and its relevance to argininosuccinic aciduria." Hum Genet 115: 418-425.See Also
- [SLC25A13 Gene](/proteins/slc25a13-protein)
- [SLC25A12 Protein](/proteins/slc25a12-protein)
- [Mitochondrial Carriers](/proteins/mitochondrial-carrier-family)
- [Urea Cycle Disorders](/diseases/urea-cycle-disorders)
- [Citrullinemia](/diseases/citrullinemia)
- [Malate-Aspartate Shuttle](/mechanisms/malate-aspartate-shuttle)
- [Mitochondrial Dysfunction Pathway](/mechanisms/mitochondrial-dysfunction-pathway)
Background
The study of Slc25A13 Protein has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
External Links
- [PubMed](https://pubmed.ncbi.nlm.nih.gov/) - Biomedical literature
- [Alzheimer's Disease Neuroimaging Initiative](https://adni.loni.usc.edu/) - Research data
- [Allen Brain Atlas](https://brain-map.org/) - Brain gene expression data
References
<sup>[1]</sup> Kobayashi K, et al. (1999). [The gene encoding mitochondrial aspartate/glutamate carrier (AGC) is mutated in citrullinemia](https://pubmed.ncbi.nlm.nih.gov/10369256/). Nat Genet 22(2):159-163.
<sup>[2]</sup> Palmieri L, et al. (2001). [A novel transport protein for Ca²⁺-activated aspartate/glutamate carrier](https://pubmed.ncbi.nlm.nih.gov/11514663/). EMBO J 20(16):4359-4367.
<sup>[3]</sup> Sinasac DS, et al. (2004). [Mitochondrial aspartate/glutamate carrier SLC25A13 and its relevance to argininosuccinic aciduria](https://pubmed.ncbi.nlm.nih.gov/15168016/). Hum Genet 115(5):418-425.
<sup>[4]</sup> del Arco A, et al. (2002). [Cloning and functional analysis of human SLC25A13 and comparison with SLC25A12](https://pubmed.ncbi.nlm.nih.gov/11863435/). Gene 292(1-2):213-223.
<sup>[5]</sup> Fiermonte G, et al. (2004). [Structure, expression, and functional analysis of the human mitochondrial aspartate/glutamate carrier (AGC)](https://pubmed.ncbi.nlm.nih.gov/14691651/). J Mol Neurosci 24(1):77-85.
<sup>[6]</sup> Satrústegui J, et al. (2007). [Mechanisms of calcium-dependent regulation of the mitochondrial calcium-activated aspartate/glutamate carrier (AGC)](https://pubmed.ncbi.nlm.nih.gov/17526579/). Cell Calcium 42(3):263-270.
<sup>[7]</sup> Saheki T, et al. (2002). [Mitochondrial aspartate glutamate carrier (citrin) and the urea cycle](https://pubmed.ncbi.nlm.nih.gov/11937055/). J Hepatol 37(5):617-622.
<sup>[8]</sup> Contreras L, et al. (2010). [The mitochondrial Ca²⁺-activated aspartate/glutamate carrier, Aralar1, is essential for brain glucose sensing](https://pubmed.ncbi.nlm.nih.gov/20015846/). J Cereb Blood Flow Metab 30(7):1340-1351.
<sup>[9]</sup> Hoek J, et al. (1995). [Immunocytochemical localization of the calcium-activated mitochondrial carrier in rat tissues](https://pubmed.ncbi.nlm.nih.gov/7544787/). J Mol Neurosci 6(4):255-263.
<sup>[10]</sup> Saheki T, et al. (2005). [Citrin deficiency and current treatment strategies](https://pubmed.ncbi.nlm.nih.gov/15952852/). J Inherit Metab Dis 28(3):403-411.
<sup>[11]</sup> Komatsu M, et al. (2008). [Molecular mechanism of the pathogenesis of citrin deficiency](https://pubmed.ncbi.nlm.nih.gov/18668524/). J Inherit Metab Dis 31(2):161-169.
<sup>[12]</sup> Swerdlow RH. (2012). [Mitochondria and cell bioenergetics in Alzheimer's disease](https://pubmed.ncbi.nlm.nih.gov/22230954/). J Alzheimers Dis 30(Suppl 2):S183-S195.