SLC25A10 Gene

SLC25A10 — Solute Carrier Family 25 Member 10 (Malate Carrier)

Historical Discovery

The mitochondrial carrier family was first characterized in the 1960s-1970s with the identification of specific transport systems for metabolites across the inner mitochondrial membrane. The malate carrier (then termed the dicarboxylate carrier or Pi-exchanger) was one of the first to be characterized biochemically. The molecular identification came later with the cloning and sequencing of SLC25A10 in the 1990s, which revealed homology to other mitochondrial carriers and established the now-extensive SLC25 gene family.

SLC25A10 encodes a mitochondrial carrier protein that transports malate and other dicarboxylates across the inner mitochondrial membrane. This protein plays a crucial role in the malate-aspartate shuttle, which transfers reducing equivalents across the mitochondrial membrane for oxidative phosphorylation. In neurons, proper function of this shuttle is essential for maintaining NADH/NAD+ ratios and supporting high energy demands of synaptic activity. Dysfunction has been implicated in various neurodegenerative diseases, including Alzheimer's and Parkinson's disease [@agrimi2014].

SLC25A10 — Solute Carrier Family 25 Member 10 (Malate Carrier)

Historical Discovery

The mitochondrial carrier family was first characterized in the 1960s-1970s with the identification of specific transport systems for metabolites across the inner mitochondrial membrane. The malate carrier (then termed the dicarboxylate carrier or Pi-exchanger) was one of the first to be characterized biochemically. The molecular identification came later with the cloning and sequencing of SLC25A10 in the 1990s, which revealed homology to other mitochondrial carriers and established the now-extensive SLC25 gene family.

SLC25A10 encodes a mitochondrial carrier protein that transports malate and other dicarboxylates across the inner mitochondrial membrane. This protein plays a crucial role in the malate-aspartate shuttle, which transfers reducing equivalents across the mitochondrial membrane for oxidative phosphorylation. In neurons, proper function of this shuttle is essential for maintaining NADH/NAD+ ratios and supporting high energy demands of synaptic activity. Dysfunction has been implicated in various neurodegenerative diseases, including Alzheimer's and Parkinson's disease [@agrimi2014].

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">Solute Carrier Family 25 Member 10</th></tr>
<tr><td><strong>Gene Symbol</strong></td><td>SLC25A10</td></tr>
<tr><td><strong>Full Name</strong></td><td>Malate Carrier (dicarboxylate carrier)</td></tr>
<tr><td><strong>Chromosome</strong></td><td>17q11.2</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>[51175](https://www.ncbi.nlm.nih.gov/gene/51175)</td></tr>
<tr><td><strong>OMIM</strong></td><td>609521</td></tr>
<tr><td><strong>Ensembl ID</strong></td><td>ENSG00000183048</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[Q9NS28](https://www.uniprot.org/uniprot/Q9NS28)</td></tr>
<tr><td><strong>Associated Diseases</strong></td><td>[Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease), Metabolic Disorders</td></tr>
</table>
</div>

Mitochondrial Carrier Family

The SLC25 family (mitochondrial carrier proteins, MCPs) comprises over 50 members in humans, each transporting specific metabolites across the inner mitochondrial membrane. These carriers are essential for cellular metabolism, connecting cytosolic and mitochondrial pools of metabolites, nucleotides, and cofactors.

SLC25 Family Members

Key mitochondrial carriers include:

• SLC25A10 (malate carrier, CiP): Dicarboxylate carrier
• SLC25A11 (OGC): Oxoglutarate carrier
• SLC25A1 (CIC): Citrate carrier
• SLC25A12 (AGC1): Arginine carrier
• SLC25A13 (AGC2): Citrulline carrier
• SLC25A20 (CACT): Carnitine/acylcarnitine carrier

Gene Structure and Protein

SLC25A10 is located on chromosome 17q11.2 and encodes a 303 amino acid protein. The protein adopts the typical mitochondrial carrier fold with six transmembrane alpha-helices and three internal repeat motifs. Each repeat contains a conserved sequence motif that forms the substrate binding site and translocation pathway.

Molecular Function

Transport Mechanism

SLC25A10 catalyzes the strict counterexchange of dicarboxylates:

• Substrates: Malate, succinate, phosphate, sulfate
• Antiport: One substrate transported in, one transported out per transport cycle
• Energy coupling: Driven by the mitochondrial membrane potential

Role in Malate-Apartate Shuttle

The malate-aspartate shuttle is the primary means of transferring reducing equivalents (NADH) from the cytosol to the mitochondria in many tissues, including brain:

Cytosol:
OAA + NADH → Malate + NAD+ (MDH1)
↓ SLC25A10
Mitochondria:
Malate + NAD+ → OAA + NADH + H+ (MDH2)
↓ ETC
NADH → NAD+ + e- → ATP

This shuttle is essential for [neuronal](/cell-types/neurons) energy metabolism, particularly in regions with high oxidative phosphorylation demand.

Expression Pattern

SLC25A10 is expressed throughout the body with highest levels in tissues with high metabolic activity:

• Brain: Particularly in cortex, hippocampus, and substantia nigra
• Heart: High cardiac energy demands
• Liver: Central metabolic organ
• Kidney: Metabolic processing
• Skeletal muscle: High ATP demand

Disease Associations

Alzheimer's Disease

Mitochondrial dysfunction is an early hallmark of AD:

• Energy metabolism: Reduced glucose metabolism in AD brain correlates with shuttle dysfunction
• Amyloid-beta effects: Aβ impairs mitochondrial carrier function
• Tau pathology: Neurofibrillary tangles affect mitochondrial distribution
• Therapeutic targeting: enhancing shuttle function may improve neuronal bioenergetics [@rutherford2015]

Parkinson's Disease

In PD, mitochondrial dysfunction is well-established:

• Complex I deficiency: Related to shuttle activity
• Substantia nigra: High energy demand makes neurons vulnerable
• Genetic forms: PINK1, parkin, and DJ-1 affect mitochondrial quality
• Malate-aspartate shuttle: Implicated in dopaminergic neuron survival [@monell2018]

Metabolic Disorders

• Diabetes: Altered mitochondrial carrier function
• Fatty liver disease: Metabolic inflexibility
• Inborn errors: Some carrier mutations cause metabolic disease

Therapeutic Implications

Drug Development

Strategies targeting mitochondrial carriers:

• Activators: Enhance carrier function to improve bioenergetics
• Substrate supplementation: Provide metabolic intermediates
• Gene therapy: Deliver functional carrier proteins
• Combination approaches: Target multiple aspects of mitochondrial function

Research Directions

• Developing brain-penetrant metabolic modifiers
• Understanding isoform-specific functions
• Combination therapies for neurodegenerative diseases

See Also

• [Mitochondrial Function](/mechanisms/mitochondrial-dysfunction)
• [Malate-Apartate Shuttle](/mechanisms/malate-aspartate-shuttle)
• [Oxidative Phosphorylation](/mechanisms/oxidative-phosphorylation)
• [Cellular Bioenergetics](/mechanisms/cellular-bioenergetics)
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [SLC25A11](/genes/slc25a11)
• [SLC25A12](/genes/slc25a12)

External Links

• [NCBI Gene: SLC25A10](https://www.ncbi.nlm.nih.gov/gene/51175)
• [OMIM: SLC25A10](https://www.omim.org/entry/609521)
• [Ensembl: SLC25A10](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000183048)
• [UniProt: SLC25A10](https://www.uniprot.org/uniprot/Q9NS28)
• [GeneCards: SLC25A10](https://www.genecards.org/cgi-bin/carddisp.pl?gene=SLC25A10)

References