Mdh2 Gene is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
{{Infobox gene
| symbol = MDH2
| name = Malate Dehydrogenase 2
| chromosome = 5
| locus = 5p15.33
| geneID = 1741
| omim = 154100
| ensembl = ENSG00000146701
| uniprot = P40926
| uniprot_name = MDH2
| diseases = Alzheimer's Disease, Parkinson's Disease, Epilepsy
| diseases_ref = Huang et al., 2019, J Neurosci
}}
Malate dehydrogenase 2 (MDH2) is a mitochondrial enzyme that catalyzes the reversible oxidation of malate to oxaloacetate (OAA) in the tricarboxylic acid (TCA) cycle, producing NADH. The MDH2 gene is located on chromosome 5p15.33 and encodes a protein of 338 amino acids that localizes to the mitochondrial matrix. MDH2 is a key metabolic enzyme involved in cellular energy production, playing essential roles in the malate-aspartate shuttle (which transfers cytosolic NADH into mitochondria), gluconeogenesis, and the TCA cycle. In the brain, MDH2 is expressed in neurons and astrocytes where it supports oxidative phosphorylation and metabolic coupling. Dysregulation of MDH2 is implicated in neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and epilepsy. The enzyme is a potential therapeutic target given its central role in mitochondrial metabolism and its sensitivity to oxidative stress.
Malate dehydrogenase 2 (MDH2) is a mitochondrial enzyme that catalyzes the reversible oxidation of malate to oxaloacetate in the TCA cycle, using NAD+ as a cofactor. MDH2 is localized to the mitochondrial matrix and is essential for complete TCA cycle function.
MDH2 catalyzes: Malate + NAD+ ⇌ Oxaloacetate + NADH + H+. This reaction is crucial for:
MDH2 participates in the malate-aspartate shuttle, transferring reducing equivalents from cytosol to mitochondria:
MDH2 helps maintain TCA cycle intermediates through anaplerotic reactions, essential for:
MDH2 activity is reduced in AD brains:
MDH2 dysfunction contributes to PD pathogenesis through:
MDH2 deficiency can cause epileptic encephalopathy through:
MDH2 is ubiquitously expressed with high levels in:
The study of Mdh2 Gene 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.
Gray J et al.. "Mitochondrial Ca." The Journal of physiology (2025) DOI:10.1113/JP287618
Ait-El-Mkadem S et al.. "Mutations in MDH2, Encoding a Krebs Cycle Enzyme, Cause Early-Onset Severe Encephalopathy." American journal of human genetics (2017) DOI:10.1016/j.ajhg.2016.11.014
Shi Q, Gibson GE. "Up-regulation of the mitochondrial malate dehydrogenase by oxidative stress is mediated by miR-743a." Journal of neurochemistry (2011) DOI:10.1111/j.1471-4159.2011.07333.x
Liu W et al.. "Phillyrin and its metabolites exert antipyretic effects by targeting the NAD." Phytomedicine : international journal of phytotherapy and phytopharmacology (2024) DOI:10.1016/j.phymed.2024.155955
He D et al.. "A novel lncRNA MDHDH suppresses glioblastoma multiforme by acting as a scaffold for MDH2 and PSMA1 to regulate NAD+ metabolism and autophagy." Journal of experimental & clinical cancer research : CR (2022) DOI:10.1186/s13046-022-02543-7
Laemmle A et al.. "Triheptanoin - Novel therapeutic approach for the ultra-rare disease mitochondrial malate dehydrogenase deficiency." Molecular genetics and metabolism reports (2021) DOI:10.1016/j.ymgmr.2021.100814
Çapan ÖY et al.. "Developmental and epileptic encephalopathy 82 (DEE82) with novel compound heterozygous mutations of GOT2 gene." Seizure (2024) DOI:10.1016/j.seizure.2023.11.003
Datta A et al.. "Quantitative clinical proteomic study of autopsied human infarcted brain specimens to elucidate the deregulated pathways in ischemic stroke pathology." Journal of proteomics (2013) DOI:10.1016/j.jprot.2013.08.017