| MDH1 | |
|---|---|
| Full Name | Malate Dehydrogenase 1 |
| Location | Chr 2p13.3 |
| NCBI Gene ID | 4190 |
| OMIM | 154200 |
| Ensembl | ENSG00000070785 |
| UniProt | P40925 |
| Associated Diseases | D-2-hydroxyglutaric aciduria, Cancer metabolism |
MDH1 (Malate Dehydrogenase 1) is a cytosolic enzyme that catalyzes the reversible conversion of malate to oxaloacetate using NAD⁺/NADH as cofactors[1]. MDH1 is a key component of the malate-aspartate shuttle, which transfers reducing equivalents from cytosolic NADH into mitochondria for oxidative phosphorylation[2]. This enzyme is essential for maintaining cytosolic NAD⁺/NADH balance and supporting neuronal energy metabolism.
The MDH1 gene is located on chromosome 2p13.3 and spans approximately 23 kb with 9 exons. Key features include:
The mature protein (334 amino acids) functions as a homodimer in the cytoplasm[3].
MDH1 is essential for the malate-aspartate shuttle, which:
MDH1 supports gluconeogenesis in the cytosol:
MDH1 contributes to cellular redox balance:
MDH1 activity integrates multiple metabolic pathways:
MDH1 variants have been associated with D-2-hydroxyglutaric aciduria (D2HGA) type II:
However, D2HGA type II is primarily caused by IDH2 mutations, with MDH1 potentially modifying disease severity.
MDH1 dysfunction may contribute to neurodegeneration:
MDH1 is frequently upregulated in cancer:
MDH1 is ubiquitously expressed in all tissues:
The Allen Brain Atlas shows enriched MDH1 expression in hippocampal neurons and cortical pyramidal cells[11].
| Variant | rsID | Effect | Significance |
|---|---|---|---|
| rs32425 | Coding (p.Thr125Ile) | Activity | Uncertain |
| rs3239 | 3' UTR | mRNA stability | eQTL |
Potential approaches to support MDH1 function:
MDH1 function may be supported by:
Minarik P, Tomaskova N, Kollarova M, Antalik M. Malate dehydrogenases—structure and function. General Physiology and Biophysics. 2002. ↩︎
Borst P. The malate-aspartate shuttle and the glycerol phosphate shuttle: their role in transport of reducing equivalents. Biochemical Society Symposia. 1970. ↩︎
Hall MD, Levitt DG, Banaszak LJ. Crystal structure of a ternary complex of Escherichia coli malate dehydrogenase. Journal of Molecular Biology. 1992. ↩︎
Safer B. The metabolic significance of the malate-aspartate cycle in heart. Circulation Research. 1975. ↩︎
Jitrapakdee S, Wallace JC. Structure, function and regulation of pyruvate carboxylase. Biochemical Journal. 1999. ↩︎
McKenna MC, Waagepetersen HS, Schousboe A, Sonnewald U. Neuronal and astrocytic shuttle mechanisms for cytosolic-mitochondrial transfer of reducing equivalents. Journal of Neuroscience Research. 2006. ↩︎
Kranendijk M, et al. Progress in understanding 2-hydroxyglutaric acidurias. Journal of Inherited Metabolic Disease. 2012. ↩︎
Bubber P, Hartounian V, Gibson GE, Blass JP. Abnormalities in the tricarboxylic acid (TCA) cycle in the brains of schizophrenia patients. European Neuropsychopharmacology. 2011. ↩︎
Schapira AH, et al. Anatomic and disease specificity of NADH CoQ1 reductase in Parkinson's disease. Journal of Neurochemistry. 1990. ↩︎
Liu J, et al. MDH1-mediated malate-aspartate shuttle promotes cancer cell proliferation. Cell Metabolism. 2021. ↩︎
Hawrylycz MJ, et al. An anatomically comprehensive atlas of the adult human brain transcriptome. Nature. 2012. ↩︎
Yoshino J, Baur JA, Imai SI. NAD⁺ intermediates: the biology and therapeutic potential of NMN and NR. Cell Metabolism. 2018. ↩︎