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
Mermaid diagram (expand to render)
[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
The mature protein (334 amino acids) functions as a homodimer in the cytoplasm[@hall1992].
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
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]
However, D2HGA type II is primarily caused by [IDH2](/genes/idh2) mutations, with MDH1 potentially modifying disease severity.
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]
Parkinson's Disease:
- MDH1 activity changes in PD models
- Dopaminergic neuron vulnerability
- Energy failure in substantia nigra[@schapira1990]
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
The Allen Brain Atlas shows enriched MDH1 expression in hippocampal neurons and cortical pyramidal cells[@hawrylycz2012].
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:
NAD⁺ supplementation: Support cofactor availability
Substrate modulation: Malate or related compounds
Gene therapy: MDH1 overexpression for metabolic support
Antioxidants: Protect MDH1 from oxidative damage[@yoshino2018]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
[Minarik P, Tomaskova N, Kollarova M, Antalik M, Malate dehydrogenases—structure and function (2002)](https://pubmed.ncbi.nlm.nih.gov/12573245/)
[Borst P, The malate-aspartate shuttle and the glycerol phosphate shuttle: their role in transport of reducing equivalents (1970)](https://pubmed.ncbi.nlm.nih.gov/4395409/)
[Hall MD, Levitt DG, Banaszak LJ, Crystal structure of a ternary complex of Escherichia coli malate dehydrogenase (1992)](https://pubmed.ncbi.nlm.nih.gov/1501222/)
[Safer B, The metabolic significance of the malate-aspartate cycle in heart (1975)](https://pubmed.ncbi.nlm.nih.gov/1106670/)
[Jitrapakdee S, Wallace JC, Structure, function and regulation of pyruvate carboxylase (1999)](https://pubmed.ncbi.nlm.nih.gov/10215856/)
[McKenna MC, Waagepetersen HS, Schousboe A, Sonnewald U, Neuronal and astrocytic shuttle mechanisms for cytosolic-mitochondrial transfer of reducing equivalents (2006)](https://pubmed.ncbi.nlm.nih.gov/16941736/)
[Kranendijk M, et al, Progress in understanding 2-hydroxyglutaric acidurias (2012)](https://pubmed.ncbi.nlm.nih.gov/22399179/)
[Bubber P, Hartounian V, Gibson GE, Blass JP, Abnormalities in the tricarboxylic acid (TCA) cycle in the brains of schizophrenia patients (2011)](https://pubmed.ncbi.nlm.nih.gov/21093976/)
[Schapira AH, et al, Anatomic and disease specificity of NADH CoQ1 reductase in Parkinson's disease (1990)](https://pubmed.ncbi.nlm.nih.gov/2172284/)
[Liu J, et al, MDH1-mediated malate-aspartate shuttle promotes cancer cell proliferation (2021)](https://pubmed.ncbi.nlm.nih.gov/34214467/)
[Hawrylycz MJ, et al, An anatomically comprehensive atlas of the adult human brain transcriptome (2012)](https://pubmed.ncbi.nlm.nih.gov/22996553/)
[Yoshino J, Baur JA, Imai SI, NAD⁺ intermediates: the biology and therapeutic potential of NMN and NR (2018)](https://pubmed.ncbi.nlm.nih.gov/29358097/)Pathway Diagram
The following diagram shows the key molecular relationships involving MDH1 — Malate Dehydrogenase 1 discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)