MDH1 — Malate Dehydrogenase 1

MDH1 — Malate Dehydrogenase 1

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2">MDH1</th></tr>
<tr><td>Full Name</td><td>Malate Dehydrogenase 1</td></tr>
<tr><td>Location</td><td>Chr 2p13.3</td></tr>
<tr><td>NCBI Gene ID</td><td><a href="https://www.ncbi.nlm.nih.gov/gene/4190" target="_blank">4190</a></td></tr>
<tr><td>OMIM</td><td><a href="https://www.omim.org/entry/154200" target="_blank">154200</a></td></tr>
<tr><td>Ensembl</td><td><a href="https://www.ensembl.org/Homo_sapiens/Gene/View?g=ENSG00000070785" target="_blank">ENSG00000070785</a></td></tr>
<tr><td>UniProt</td><td><a href="https://www.uniprot.org/uniprot/P40925" target="_blank">P40925</a></td></tr>
<tr><td>Associated Diseases</td><td>D-2-hydroxyglutaric aciduria, Cancer metabolism</td></tr>
</table>
</div>

Overview

MDH1 — Malate Dehydrogenase 1

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2">MDH1</th></tr>
<tr><td>Full Name</td><td>Malate Dehydrogenase 1</td></tr>
<tr><td>Location</td><td>Chr 2p13.3</td></tr>
<tr><td>NCBI Gene ID</td><td><a href="https://www.ncbi.nlm.nih.gov/gene/4190" target="_blank">4190</a></td></tr>
<tr><td>OMIM</td><td><a href="https://www.omim.org/entry/154200" target="_blank">154200</a></td></tr>
<tr><td>Ensembl</td><td><a href="https://www.ensembl.org/Homo_sapiens/Gene/View?g=ENSG00000070785" target="_blank">ENSG00000070785</a></td></tr>
<tr><td>UniProt</td><td><a href="https://www.uniprot.org/uniprot/P40925" target="_blank">P40925</a></td></tr>
<tr><td>Associated Diseases</td><td>D-2-hydroxyglutaric aciduria, Cancer metabolism</td></tr>
</table>
</div>

Overview

[MDH1](/genes/mdh1) (Malate Dehydrogenase 1) is a cytosolic enzyme that catalyzes the reversible conversion of malate to oxaloacetate using NAD+/NADH as cofactors["@minarik2002"]. MDH1 is a key component of the malate-aspartate shuttle, which transfers reducing equivalents from cytosolic NADH into mitochondria for oxidative phosphorylation["@borst1970"]. This enzyme is essential for maintaining cytosolic NAD+/NADH balance and supporting neuronal energy metabolism.

Gene and Protein Structure

The MDH1 gene is located on chromosome 2p13.3 and spans approximately 23 kb with 9 exons. Key features include:

• NAD⁺-binding domain: Rossmann fold for cofactor binding
• Dimerization domain: Forms active homodimer
• Active site: Contains catalytic residues for malate/oxaloacetate conversion
• Cytosolic localization: No mitochondrial targeting sequence

Function

Malate-Aspartate Shuttle

MDH1 is essential for the malate-aspartate shuttle, which:

• Transfers cytosolic NADH electrons to mitochondria: Bypasses the impermeable inner mitochondrial membrane
• Step 1: Cytosolic oxaloacetate + NADH → malate + NAD⁺ (MDH1)
• Step 2: Malate transported into mitochondria
• Step 3: Mitochondrial malate + NAD⁺ → oxaloacetate + NADH ([MDH2](/genes/mdh2))
• Net effect: Cytosolic reducing equivalents available for ATP production[@safer1975]

Gluconeogenesis Support

MDH1 supports gluconeogenesis in the cytosol:

• Converts oxaloacetate (gluconeogenic intermediate) to malate
• Enables transport of gluconeogenic precursors
• Maintains cytosolic NAD⁺/NADH balance for synthetic reactions[@jitrapakdee1999]

Redox Homeostasis

MDH1 contributes to cellular redox balance:

• Regulates cytosolic NAD⁺/NADH ratio
• Supports glycolysis by regenerating NAD⁺
• Links cytosolic metabolism to mitochondrial function

Metabolic Integration

MDH1 activity integrates multiple metabolic pathways:

• Glycolysis: Requires NAD⁺ regenerated by MDH1
• TCA cycle: Connected through malate-aspartate shuttle
• Amino acid metabolism: Aspartate/alanine interconversion
• Fatty acid synthesis: Provides cytosolic NADPH via malic enzyme[@mckenna2006]

Disease Associations

D-2-Hydroxyglutaric Aciduria

MDH1 variants have been associated with D-2-hydroxyglutaric aciduria (D2HGA) type II:

• Metabolic acidosis: Accumulation of D-2-hydroxyglutaric acid
• Developmental delay: Severe neurological impairment
• Seizures: Epileptic episodes
• Cardiomyopathy: Heart muscle dysfunction[@kranendijk2012]

Neurodegenerative Diseases

MDH1 dysfunction may contribute to neurodegeneration:

Alzheimer's Disease:

• Altered MDH1 expression in AD brains
• Impaired malate-aspartate shuttle function
• Energy metabolism dysregulation
• Oxidative stress sensitivity[@bubber2011]

• MDH1 activity changes in PD models
• Dopaminergic neuron vulnerability
• Energy failure in substantia nigra[@schapira1990]

Cancer Metabolism

MDH1 is frequently upregulated in cancer:

• Supports the Warburg effect
• Provides NAD⁺ for glycolysis
• Enables rapid proliferation
• Potential therapeutic target[@liu2021]

Expression

MDH1 is ubiquitously expressed in all tissues:

• Brain: High expression in [neurons](/entities/neurons) with active glycolysis
• Heart: Cardiomyocytes with continuous metabolism
• Liver: Hepatocytes with gluconeogenic function
• Pancreas: β-cells with active insulin secretion

Common Variants

| Variant | rsID | Effect | Significance |
|---------|------|--------|--------------|
| rs32425 | Coding (p.Thr125Ile) | Activity | Uncertain |
| rs3239 | 3' UTR | mRNA stability | eQTL |

Therapeutic Implications

MDH1 Enhancement Strategies

Potential approaches to support MDH1 function:

Metabolic Support

MDH1 function may be supported by:

• [Nicotinamide riboside](/therapeutics/nad-precursors-neurodegeneration): NAD⁺ precursor
• [Alpha-lipoic acid](/therapeutics/alpha-lipoic-acid-neurodegeneration): Cofactor and antioxidant
• Exercise: Enhances mitochondrial biogenesis and shuttle capacity

See Also

• [MDH2](/genes/mdh2) — Mitochondrial malate dehydrogenase
• [IDH2](/genes/idh2) — Isocitrate dehydrogenase 2
• [GOT2](/genes/got2) — Mitochondrial aspartate aminotransferase
• [TCA Cycle](/mechanisms/tca-cycle-dysfunction) — Central metabolic pathway
• [Mitochondrial Dysfunction](/mechanisms/mitochondrial-dysfunction) — Energy failure in neurodegeneration

External Links

• [GeneCards: MDH1](https://www.genecards.org/cgi-bin/carddisp.pl?gene=MDH1)
• [UniProt: P40925](https://www.uniprot.org/uniprot/P40925)
• [NCBI Gene: 4190](https://www.ncbi.nlm.nih.gov/gene/4190)

References

Pathway Diagram

The following diagram shows the key molecular relationships involving MDH1 — Malate Dehydrogenase 1 discovered through SciDEX knowledge graph analysis: