MDH2 Gene

Name	malate dehydrogenase 2, NAD (mitochondrial)
Description	Malate dehydrogenase catalyzes the reversible oxidation of malate to oxaloacetate, utilizing the NAD/NADH cofactor system in the citric acid cycle. The protein encoded by this gene is localized to the mitochondria and may play pivotal roles in the malate-aspartate shuttle that operates in the metabolic coordination between cytosol and mitochondria. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2013]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMDH2 encodes mitochondrial malate dehydrogenase, an enzyme that catalyzes the reversible conversion of malate to oxaloacetate and thus plays a central role in the Krebs cycle. Its normal activity is essential not only for energy metabolism but also for “metabolite repair,” since even a low‐level side activity—for example, the reduction of α‐ketoglutarate to L‑2‑hydroxyglutarate—is buffered by dedicated “house‐cleaning” enzymes. High‐resolution structural studies have further shown that binding of ligands such as phosphate induces conformational changes in the active loop of MDH2, thereby securing its substrate and cofactor to facilitate its enzymatic function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nLoss‐of‐function mutations or reduced expression of MDH2 have been linked to several inherited disorders. Germline and biallelic mutations lead to substantial decreases in enzyme activity and protein levels, resulting in the accumulation of malate and its precursor fumarate—a disruption associated with severe neurological presentations, encephalocardiopathy, and drug‐responsive epilepsy. Furthermore, monoallelic defects in MDH2 have been implicated as a novel susceptibility gene for pheochromocytoma and paraganglioma, and emerging studies suggest that MDH2 alterations may contribute to familial metabolic and endocrine disorders."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}, {"type": "fg_fs", "start_ref": "5", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its canonical metabolic role, MDH2 is also emerging as an important player in cancer biology. In uterine cancer cells, altered expression of MDH2 has been associated with the development of doxorubicin resistance, likely by promoting cell survival and reducing apoptosis during treatment. In addition, elevated levels of MDH2 found in urine have been proposed as a promising noninvasive biomarker for the early detection of non‐small‐cell lung cancer, consistent with evidence that MDH2 supports the proliferation of lung cancer cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIntriguingly, MDH2 also fulfills noncanonical functions. It can act as an RNA-binding protein, where under oxidative stress conditions the enzyme binds to conserved elements in the 3′ untranslated region of the SCN1A gene, thereby destabilizing its transcript and contributing to reduced expression of the brain’s voltage‐gated sodium channel NaV1.1—a mechanism potentially relevant in seizure conditions. Moreover, recent studies have linked specific MDH2 variants with recurrent focal segmental glomerulosclerosis after kidney transplantation, suggesting that MDH2 dysfunction may promote progressive podocyte injury in renal disease."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "R Rzem, M-F Vincent, E Van Schaftingen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "L-2-hydroxyglutaric aciduria, a defect of metabolite repair."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Inherit Metab Dis (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10545-007-0487-0"}], "href": "https://doi.org/10.1007/s10545-007-0487-0"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17603759"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17603759"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Alberto Cascón, Iñaki Comino-Méndez, María Currás-Freixes, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Whole-exome sequencing identifies MDH2 as a new familial paraganglioma gene."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Natl Cancer Inst (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/jnci/djv053"}], "href": "https://doi.org/10.1093/jnci/djv053"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25766404"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25766404"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Samira Ait-El-Mkadem, Manal Dayem-Quere, Mirjana Gusic, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations in MDH2, Encoding a Krebs Cycle Enzyme, Cause Early-Onset Severe Encephalopathy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajhg.2016.11.014"}], "href": "https://doi.org/10.1016/j.ajhg.2016.11.014"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27989324"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27989324"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Yumi Eo, Men Thi Hoai Duong, Hee-Chul Ahn "}, {"type": "b", "children": [{"type": "t", "text": "Structural Comparison of hMDH2 Complexed with Natural Substrates and Cofactors: The Importance of Phosphate Binding for Active Conformation and Catalysis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biomolecules (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/biom12091175"}], "href": "https://doi.org/10.3390/biom12091175"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36139014"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36139014"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Bruna Calsina, Maria Currás-Freixes, Alexandre Buffet, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Role of MDH2 pathogenic variant in pheochromocytoma and paraganglioma patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genet Med (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41436-018-0068-7"}], "href": "https://doi.org/10.1038/s41436-018-0068-7"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30008476"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30008476"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Prapaporn Jungtrakoon Thamtarana, Antonella Marucci, Luca Pannone, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Gain of Function of Malate Dehydrogenase 2 and Familial Hyperglycemia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Endocrinol Metab (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/clinem/dgab790"}], "href": "https://doi.org/10.1210/clinem/dgab790"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34718610"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34718610"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Chiara Ticci, Claudia Nesti, Anna Rubegni, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Bi-allelic variants in MDH2: Expanding the clinical phenotype."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Genet (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/cge.14088"}], "href": "https://doi.org/10.1111/cge.14088"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34766628"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34766628"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Yi-Wen Lo, Szu-Ting Lin, Shing-Jyh Chang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mitochondrial proteomics with siRNA knockdown to reveal ACAT1 and MDH2 in the development of doxorubicin-resistant uterine cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Mol Med (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/jcmm.12388"}], "href": "https://doi.org/10.1111/jcmm.12388"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25639359"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25639359"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Yu-Chen Ma, Peng-Fei Tian, Zhi-Peng Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Urinary malate dehydrogenase 2 is a new biomarker for early detection of non-small-cell lung cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Sci (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/cas.14845"}], "href": "https://doi.org/10.1111/cas.14845"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33565687"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33565687"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Yong-Hong Chen, Shu-Jing Liu, Mei-Mei Gao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MDH2 is an RNA binding protein involved in downregulation of sodium channel Scn1a expression under seizure condition."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochim Biophys Acta Mol Basis Dis (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbadis.2017.04.018"}], "href": "https://doi.org/10.1016/j.bbadis.2017.04.018"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28433711"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28433711"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Qixia Shen, Lisha Teng, Yucheng Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Integrated genomic, transcriptomic and metabolomic analysis reveals MDH2 mutation-induced metabolic disorder in recurrent focal segmental glomerulosclerosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Front Immunol (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3389/fimmu.2022.962986"}], "href": "https://doi.org/10.3389/fimmu.2022.962986"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36159820"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36159820"}]}]}]}
Synonyms	MOR1, M-MDH, MDH, MGC:3559, EIEE51
Proteins	MDHM_HUMAN
NCBI Gene ID	4191
API
Download Associations
Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

MDH2 has 9,839 functional associations with biological entities spanning 9 categories (molecular profile, organism, chemical, disease, phenotype or trait, functional term, phrase or reference, structural feature, cell line, cell type or tissue, gene, protein or microRNA, sequence feature) extracted from 130 datasets.

Click the + buttons to view associations for MDH2 from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

MDH2 Gene

Functional Associations

Please acknowledge the Harmonizome in your publications by citing the following reference(s):

	Dataset	Summary
	Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of MDH2 gene relative to other tissues from the Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles	tissue samples with high or low expression of MDH2 gene relative to other tissue samples from the Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray	tissue samples with high or low expression of MDH2 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq	tissue samples with high or low expression of MDH2 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq dataset.
	Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of MDH2 gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset.
	BioGPS Cell Line Gene Expression Profiles	cell lines with high or low expression of MDH2 gene relative to other cell lines from the BioGPS Cell Line Gene Expression Profiles dataset.
	BioGPS Human Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of MDH2 gene relative to other cell types and tissues from the BioGPS Human Cell Type and Tissue Gene Expression Profiles dataset.
	BioGPS Mouse Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of MDH2 gene relative to other cell types and tissues from the BioGPS Mouse Cell Type and Tissue Gene Expression Profiles dataset.
	Carcinogenome Chemical Perturbation Carcinogenicity Signatures	small molecule perturbations changing expression of MDH2 gene from the Carcinogenome Chemical Perturbation Carcinogenicity Signatures dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of MDH2 gene relative to other cell lines from the CCLE Cell Line Gene CNV Profiles dataset.
	CCLE Cell Line Gene Expression Profiles	cell lines with high or low expression of MDH2 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Proteomics	Cell lines associated with MDH2 protein from the CCLE Cell Line Proteomics dataset.
	CellMarker Gene-Cell Type Associations	cell types associated with MDH2 gene from the CellMarker Gene-Cell Type Associations dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of MDH2 gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of MDH2 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets dataset.
	ChEA Transcription Factor Targets 2022	transcription factors binding the promoter of MDH2 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	ClinVar Gene-Phenotype Associations 2025	phenotypes associated with MDH2 gene from the curated ClinVar Gene-Phenotype Associations 2025 dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of MDH2 gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing MDH2 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores 2025	cellular components containing MDH2 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores	cellular components containing MDH2 protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores 2025	cellular components containing MDH2 protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with MDH2 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025	cellular components co-occuring with MDH2 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	COSMIC Cell Line Gene CNV Profiles	cell lines with high or low copy number of MDH2 gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with MDH2 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with MDH2 gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with MDH2 gene/protein from the curated CTD Gene-Disease Associations dataset.
	DeepCoverMOA Drug Mechanisms of Action	small molecule perturbations with high or low expression of MDH2 protein relative to other small molecule perturbations from the DeepCoverMOA Drug Mechanisms of Action dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by MDH2 gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DISEASES Curated Gene-Disease Association Evidence Scores 2025	diseases involving MDH2 gene from the DISEASES Curated Gene-Disease Association Evidence Scores 2025 dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores	diseases co-occuring with MDH2 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores 2025	diseases co-occuring with MDH2 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores 2025 dataset.
	DisGeNET Gene-Disease Associations	diseases associated with MDH2 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with MDH2 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Phenoptype Associations dataset.
	DrugBank Drug Targets	interacting drugs for MDH2 protein from the curated DrugBank Drug Targets dataset.
	ENCODE Histone Modification Site Profiles	histone modification site profiles with high histone modification abundance at MDH2 gene from the ENCODE Histone Modification Site Profiles dataset.
	ENCODE Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of MDH2 gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of MDH2 gene in ChIP-seq datasets from the ENCODE Transcription Factor Targets dataset.
	ESCAPE Omics Signatures of Genes and Proteins for Stem Cells	PubMedIDs of publications reporting gene signatures containing MDH2 from the ESCAPE Omics Signatures of Genes and Proteins for Stem Cells dataset.