Affinage

MDH2

Malate dehydrogenase, mitochondrial · UniProt P40926

Length
338 aa
Mass
35.5 kDa
Annotated
2026-06-10
50 papers in source corpus 25 papers cited in narrative 25 extracted findings
Cross-family judge faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MDH2 is a malate dehydrogenase that catalyzes the reversible NAD+-dependent oxidation of malate to oxaloacetate, a core step of the TCA cycle whose loss in human cells and patient fibroblasts causes accumulation of malate and fumarate and collapse of mitochondrial MDH activity (PMID:25766404, PMID:27989324). Bi-allelic loss-of-function mutations abolishing MDH2 protein and enzyme activity cause a Mendelian mitochondrial encephalopathy, with phenotype rescue by WT complementation (PMID:27989324). The malate/oxaloacetate reaction places MDH2 at a control point for respiratory NADH supply: its oxaloacetate product feedback-inhibits complex II to favor NADH oxidation through complex I (PMID:35063410), and its activity governs NADH/NAD+ and NADPH balance that determines mitochondrial membrane potential, ATP output, and cellular energy state (PMID:36527092, PMID:41496511). MDH2 activity is tuned by an extensive layer of post-translational modifications: ZDHHC18-mediated palmitoylation at C138 (PMID:35366151), KAT8-deposited lactylation at K239 (reversed by SIRT3) (PMID:40769364), and S246 phosphorylation (PMID:41496511) each activate the enzyme, whereas SIRT5-dependent desuccinylation at K314, downstream of STING, controls its activity and links MDH2 dysfunction to mtDNA damage and cGAS-STING signaling (PMID:41856470). Enzyme abundance is set by a ubiquitin-proteasome axis in which USP5 stabilizes MDH2 while the lncRNA MDHDH scaffolds MDH2 to the proteasome subunit PSMA1 to drive its degradation (PMID:38973363, PMID:36527092). Beyond catalysis, MDH2 acts as a moonlighting protein: it binds the SCN1A 3' UTR as an RNA-binding protein to destabilize that transcript under oxidative conditions (PMID:28433711), modulates ferroptosis sensitivity through interaction with FSP1 and stabilization of GPX4 (PMID:39519171, PMID:39138167), and undergoes acetylation-dependent nuclear translocation to drive CTR2 transcription (PMID:42161958). In yeast, MDH2 is a cytosolic/peroxisomal isozyme required for gluconeogenic growth on non-fermentable carbon sources and is subject to glucose-induced phosphorylation and N-terminal-signal-dependent degradation (PMID:1986231, PMID:1324938, PMID:7986072, PMID:33177075).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1991 High

    Established the core metabolic identity of MDH2 by showing the yeast cytosolic isozyme is essential for gluconeogenic carbon metabolism.

    Evidence Chromosomal disruption, enzyme assays, and growth tests on acetate/ethanol in S. cerevisiae

    PMID:1986231

    Open questions at the time
    • Does not address the human mitochondrial isozyme
    • Cytosolic localization specific to yeast
  2. 1994 High

    Separated MDH2 enzymatic inactivation from its degradation, showing phosphorylation and an N-terminal signal, not catalysis, drive glucose-induced turnover.

    Evidence Site-directed mutants (S12A/S12D, H214L) with phosphorylation, activity, and turnover assays in yeast

    PMID:1324938 PMID:7986072

    Open questions at the time
    • Kinase responsible not identified
    • Mechanism may be yeast-specific
  3. 2015 High

    Defined the TCA-cycle enzymatic role of human MDH2 by showing knockdown causes malate/fumarate accumulation rescued by WT cDNA.

    Evidence shRNA knockdown and rescue in HeLa cells with metabolite measurement

    PMID:25766404

    Open questions at the time
    • Does not address moonlighting or regulatory functions
  4. 2016 High

    Established MDH2 as a Mendelian disease gene, with bi-allelic loss-of-function abolishing enzyme activity and causing metabolite accumulation reversible by complementation.

    Evidence Patient fibroblast immunoblot, enzyme assay, metabolomics, lentiviral complementation, yeast missense validation

    PMID:27989324

    Open questions at the time
    • Genotype-phenotype spectrum not fully mapped
  5. 2022 High

    Revealed that MDH2 activity is post-translationally activated by ZDHHC18 palmitoylation at C138, required for respiration and tumor growth.

    Evidence C138S mutagenesis, in vitro palmitoylation and enzyme assays, ZDHHC18 co-IP, xenografts

    PMID:35366151

    Open questions at the time
    • Depalmitoylase not identified
    • Stoichiometry in normal tissue unknown
  6. 2022 Medium

    Positioned MDH2's oxaloacetate product as a regulator of respiratory chain fuelling via feedback inhibition of complex II.

    Evidence Substrate competition and OAA titration in heart/liver mitochondria with respiratory measurements

    PMID:35063410

    Open questions at the time
    • Single-lab biochemistry
    • Physiological OAA concentrations in vivo unclear
  7. 2022 Medium

    Identified a lncRNA-driven degradation route, with MDHDH scaffolding MDH2 to PSMA1 to accelerate its proteasomal turnover and lower mitochondrial potential.

    Evidence RNA pulldown/MS, RIP, MDH2-PSMA1 co-IP, ubiquitination and membrane potential assays

    PMID:36527092

    Open questions at the time
    • E3 ligase not defined
    • Single lab
  8. 2017 Medium

    Uncovered a moonlighting RNA-binding function: MDH2 binds the SCN1A 3' UTR to destabilize it in an oxidation-sensitive manner.

    Evidence RIP, 3' UTR reporter, knockdown/overexpression, mRNA stability, H2O2 treatment in HEK293 and mouse hippocampus

    PMID:28433711

    Open questions at the time
    • RNA-binding interface not mapped
    • Relationship to catalytic function unclear
  9. 2023 Medium

    Linked MDH2 acetylation status to mitochondrial dynamics, with SIRT3 deacetylation promoting fusion via JNK-FIS1 inhibition.

    Evidence Proteomics, SIRT3 manipulation, co-IP, mitochondrial imaging in adipocytes and HFD mice

    PMID:36815302

    Open questions at the time
    • Acetylation site not defined
    • JNK-FIS1 link not reconstituted
  10. 2024 Medium

    Defined a stability axis where USP5 deubiquitinates and stabilizes MDH2 to drive drug resistance, with ZDHHC18 palmitoylation also blocking ubiquitination.

    Evidence Ubiquitinome sequencing, co-IP/MS (TRIM21-USP5, USP5-MDH2), resistance assays in GIST

    PMID:38973363

    Open questions at the time
    • Ubiquitination sites not mapped
    • Single lab
  11. 2024 Medium

    Established MDH2 as a ferroptosis modulator acting through GPX4 stabilization and FSP1 destabilization in distinct cancers.

    Evidence Knockdown/knockout, MDH2-FSP1 co-IP, GPX4 levels, RSL3 ferroptosis assays with rescue

    PMID:39138167 PMID:39519171

    Open questions at the time
    • Direct mechanism of GPX4 stabilization unresolved
    • Whether catalytic activity is required is unclear
  12. 2024 Medium

    Identified lactylation as a regulatory modification linking MDH2 to mitochondrial dysfunction and cardiomyocyte ferroptosis under ischemia-reperfusion.

    Evidence Lactylation proteomics, MIRI models, NR3C1/PDK4 blots, metabolomics

    PMID:39467114

    Open questions at the time
    • Lactylation site not specified
    • Writer/eraser in this context unknown
  13. 2024 Medium

    Demonstrated druggability by showing phillygenin reversibly engages the NAD+ binding domain to inhibit MDH2 and lower NADH.

    Evidence Chemical proteomics, DARTS, enzymatic inhibition, metabolomics

    PMID:39191169

    Open questions at the time
    • Binding mode not structurally resolved
    • Selectivity over MDH1 untested
  14. 2025 High

    Resolved an activating lactylation cycle: KAT8 deposits and SIRT3 removes K239 lactylation, boosting MDH2 activity and SLC25A1-coupled NADPH production for oxidative stress resistance.

    Evidence Lactylome profiling, K239 mutants, KAT8/SIRT3 co-IP, NADH/NADPH assays, SLC25A1 co-IP in RCC

    PMID:40769364

    Open questions at the time
    • Reconciliation with cardiomyocyte lactylation (different effect) unresolved
  15. 2025 Medium

    Connected MDH2 activity to epigenetic control of senescence via methionine cycle flux and H3K27me3.

    Evidence Knockdown/overexpression, glibenclamide ABPP inhibition, metabolomics, histone methylation, liver-specific KD in aged mice

    PMID:39962087

    Open questions at the time
    • Direct mechanism linking malate metabolism to methionine cycle not detailed
  16. 2025 Medium

    Placed MDH2 under transcriptional control of the FSH/CREB axis governing osteoclast NAD+ and energy metabolism.

    Evidence FSHR conditional KO, CREB ChIP, luciferase, OCR/NAD+ measurement, bone histomorphometry

    PMID:39880362

    Open questions at the time
    • Single lab
    • Direct CREB occupancy in vivo across tissues not assessed
  17. 2026 High

    Defined the STING-SIRT5 axis that desuccinylates MDH2 at K314 to impair its activity, triggering mtDNA damage and cGAS-STING-dependent cisplatin sensitivity.

    Evidence Succinylation proteomics, K314 mutants, SIRT5 co-IP/MS, TRIM21-SIRT5 ubiquitination, enzyme and mtDNA assays, in vivo cisplatin models

    PMID:41856470

    Open questions at the time
    • Succinyl-transferase not identified
    • Generalization beyond cisplatin context untested
  18. 2026 Medium

    Extended MDH2 moonlighting to the nucleus, where acetylation-dependent translocation drives CTR2 transcription and cuproptosis during infection.

    Evidence Subcellular fractionation/imaging, acetylation detection, CTR2 promoter reporter, knockdown/overexpression, in vivo infection model

    PMID:42161958

    Open questions at the time
    • Nuclear import mechanism unknown
    • DNA-binding mode of MDH2 unresolved
  19. 2026 Medium

    Confirmed S246 phosphorylation as an activating modification controlling mitochondrial energetics and biogenesis under hypoxia/reoxygenation.

    Evidence S246A mutant, enzyme assay, metabolomics, membrane potential/ATP, PGC1a/OPA1 blots

    PMID:41496511

    Open questions at the time
    • Responsible kinase not identified
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the dense layer of competing PTMs and moonlighting functions is integrated and prioritized within a single cell remains unresolved.
  • No structural basis for how distinct modifications coordinately tune activity
  • Mechanism partitioning catalytic vs RNA-binding vs nuclear pools undefined
  • Crosstalk among palmitoylation, lactylation, succinylation, phosphorylation, and acetylation not mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 8 GO:0003723 RNA binding 1 GO:0140110 transcription regulator activity 1
Localization
GO:0005739 mitochondrion 4 GO:0005829 cytosol 3 GO:0005634 nucleus 1 GO:0005777 peroxisome 1
Pathway
R-HSA-1430728 Metabolism 5 R-HSA-5357801 Programmed Cell Death 4 R-HSA-8953854 Metabolism of RNA 1
Partners
FSP1KAT8PSMA1SIRT3SIRT5SLC25A1USP5ZDHHC18

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 MDH2 encodes a Krebs cycle enzyme that catalyzes a step in the malate-oxaloacetate conversion; knockdown of MDH2 in HeLa cells causes accumulation of malate and fumarate, which is reversed by reintroduction of wild-type MDH2 cDNA, establishing its enzymatic role in the TCA cycle. shRNA knockdown in HeLa cells with metabolite measurement; rescue by transient WT MDH2 cDNA expression Journal of the National Cancer Institute High 25766404
2016 Bi-allelic loss-of-function mutations in MDH2 result in complete loss of MDH2 protein and near-null mitochondrial malate dehydrogenase enzymatic activity in patient fibroblasts, with concomitant accumulation of malate and fumarate; lentiviral complementation with WT MDH2 restores MDH2 protein levels and mitochondrial MDH activity. Functional studies in patient-derived fibroblasts: immunoblot for protein levels, enzymatic activity assay, metabolomics; lentiviral WT complementation; yeast missense mutant functional validation American journal of human genetics High 27989324
2022 MDH2 is palmitoylated at cysteine 138 (C138) by the palmitoyltransferase ZDHHC18, and this modification increases MDH2 enzymatic activity. A palmitoylation-deficient C138S mutant fails to sustain mitochondrial respiration or restore ovarian cancer cell growth, demonstrating that palmitoylation is required for full MDH2 function. Site-directed mutagenesis (C138S), in vitro palmitoylation assay, enzymatic activity assay, co-immunoprecipitation of ZDHHC18-MDH2, cell proliferation and mitochondrial respiration assays in vitro and in vivo xenograft Science China. Life sciences High 35366151
2022 MDH2-produced oxaloacetate (OAA) inhibits complex II (succinate dehydrogenase) via product feedback, thereby rewiring respiratory chain fuelling to favour NADH oxidation through complex I and redirecting TCA cycle anaplerosis to oxidize cytosolic malate rather than produce malate from succinate. Characterization of heart and liver mitochondria with substrate competition assays, OAA addition/titration experiments, respiratory chain activity measurements Biochimica et biophysica acta. Bioenergetics Medium 35063410
2010 Drosophila Mdh2, which localizes to mitochondria and encodes malate dehydrogenase, is required for larval salivary gland programmed cell death downstream of ecdysone signaling; Mdh2 mutants show reduced ATP levels, accumulation of late-stage TCA cycle intermediates, and failure of caspase cleavage. Genetic loss-of-function mutations in Drosophila, subcellular localization (mitochondria), ATP measurement, metabolite profiling, caspase cleavage assay Developmental dynamics Medium 20063412
1991 MDH2 in S. cerevisiae encodes the major nonmitochondrial (cytosolic) isozyme of malate dehydrogenase (~42 kDa subunit); disruption of MDH2 prevents growth on acetate or ethanol as sole carbon source, establishing its essential role in gluconeogenic carbon metabolism. Gene disruption (chromosomal deletion), enzyme activity assays, immunological detection, growth phenotype analysis on diagnostic carbon sources Molecular and cellular biology High 1986231
1992 The N-terminal 12 amino acids of yeast MDH2 are required for glucose-induced proteolytic degradation; a truncated MDH2 lacking residues 1-12 is fully enzymatically active but is resistant to glucose-induced turnover, demonstrating a selective degradation signal at the N-terminus. N-terminal truncation mutagenesis, enzyme activity measurement, turnover rate measurement after carbon source shift, growth rate analysis The Journal of biological chemistry High 1324938
1994 Yeast MDH2 is phosphorylated during glucose-induced degradation, and phosphorylation depends on the N-terminal region. The S12D substitution causes phosphorylation and inactivation without rapid degradation, demonstrating that inactivation and degradation are separable events; the H214L (active-site) mutation shows that catalytic activity is not required for degradation. Site-directed mutagenesis (S12A, S12D, H214L), phosphorylation detection, enzyme activity measurement, turnover assay after glucose shift Archives of biochemistry and biophysics High 7986072
1997 Overexpression of cytosolic MDH2 in yeast leads to 6–16-fold increase in MDH activity and up to 3.7-fold increase in L-malate accumulation; the high apparent Km of MDH2 for L-malate (11.8 mM) contrasts with the mitochondrial MDH1 (0.28 mM), consistent with its cytosolic function in gluconeogenesis. MDH2 overexpression under inducible and constitutive promoters, enzyme activity assay, substrate kinetics (Km determination), organic acid measurement Applied microbiology and biotechnology Medium 9299784
2001 Transcription of yeast MDH2 is activated by zinc cluster proteins Cat8 and Sip4 through three carbon-source-responsive elements (CSREs) in its promoter; Cat8 and Sip4 DNA-binding domains interact with CSRE motifs in vitro, and deregulated Cat8/Sip4 variants relieve glucose repression of MDH2. Promoter mutagenesis, in vitro DNA binding assays with recombinant proteins, yeast two-hybrid and protein extracts, reporter gene assays Yeast Medium 11169757
2020 Yeast Mdh2 is dually localized to the cytosol and peroxisomes; peroxisomal targeting is achieved via a piggybacking mechanism dependent on its association with Mdh3 and the peroxisomal import receptor Pex5, rather than a canonical peroxisome-targeting signal on Mdh2 itself. Fluorescence microscopy (subcellular localization), co-immunoprecipitation of Mdh2-Mdh3 and Pex5, genetic deletion of Mdh3 and Pex5 with localization rescue experiments Journal of cell science High 33177075
2017 MDH2 functions as an RNA-binding protein that binds conserved regions in the 3′ UTR of SCN1A mRNA; MDH2 knockdown or inactivation increases SCN1A reporter expression, while MDH2 overexpression decreases SCN1A mRNA stability. Oxidative conditions (H2O2) enhance MDH2 binding to SCN1A mRNA, and reducing agents decrease it, linking seizure-induced oxidation to posttranscriptional SCN1A repression. RNA immunoprecipitation (RIP), reporter gene assays with SCN1A 3′ UTR, siRNA knockdown, overexpression, mRNA stability assay, H2O2/β-mercaptoethanol treatment in HEK-293 cells and mouse hippocampus Biochimica et biophysica acta. Molecular basis of disease Medium 28433711
2023 Sirt3 deacetylates MDH2 in adipocytes, and this deacetylation promotes mitochondrial fusion by inhibiting the JNK-FIS1 pathway; intermittent fasting upregulates Sirt3 expression, leading to MDH2 deacetylation and improved mitochondrial function in high-fat diet mice. Proteomic sequencing, Sirt3 overexpression/knockdown in adipocytes, co-IP, mitochondrial morphology imaging, JNK-FIS1 pathway analysis The British journal of nutrition Medium 36815302
2024 MDH2 lactylation (at an unspecified site) impairs mitochondrial function and induces ferroptosis in cardiomyocytes; dexmedetomidine reduces MDH2 lactylation by upregulating NR3C1 phosphorylation, downregulating PDK4, and reducing lactate production, thereby alleviating myocardial ischemia-reperfusion injury. Lactylation proteomics, in vivo and in vitro MIRI models, cardiac function measurement, NR3C1/PDK4 western blotting, metabolomics Advanced science Medium 39467114
2024 USP5 deubiquitinates MDH2, increasing its protein stability and promoting ripretinib resistance in GIST; TRIM21 regulates USP5 via ubiquitination. Additionally, ZDHHC18 palmitoylates MDH2, preventing its ubiquitination and further stabilizing the protein. Proteome-ubiquitinome sequencing, co-IP/MS to validate TRIM21-USP5 and USP5-MDH2 interactions, mass spectrometry validation, cell-based resistance assays Advanced science Medium 38973363
2024 MDH2 promotes ferroptosis resistance in hepatocellular carcinoma by stabilizing GPX4 protein; MDH2 knockdown reduces GPX4 levels, increases RSL3-induced lipid peroxidation and ROS, and promotes ferroptotic death that is rescued by ferroptosis blockade. MDH2 knockdown, GPX4 protein co-expression analysis, RSL3-induced ferroptosis assay, ROS/lipid peroxide/free iron measurement, rescue with ferrostatin-1 and deferiprone International journal of molecular sciences Medium 39519171
2024 MDH2 regulates ferroptosis sensitivity in clear cell renal cell carcinoma through protein-protein interaction with FSP1, promoting FSP1 ubiquitination and degradation; MDH2 knockout enhances FSP1 levels and reduces lipid peroxidation sensitivity. MDH2 knockout (CRISPR or siRNA), co-immunoprecipitation of MDH2-FSP1, ubiquitination assay, lipid peroxidation measurement, proliferation assays Cell death discovery Medium 39138167
2025 MDH2 inhibition (knockdown or pharmacological by glibenclamide) disrupts central carbon metabolism, enhances methionine cycle flux, and promotes H3K27 trimethylation, thereby delaying cellular senescence; liver-specific Mdh2 knockdown in aged mice reduces p16INK4a expression and hepatic fibrosis. MDH2 knockdown/overexpression in fibroblasts, glibenclamide enzymatic inhibition (activity-based protein profiling), metabolomics, histone methylation assay (H3K27me3), in vivo liver-specific KD in aged mice Signal transduction and targeted therapy Medium 39962087
2025 FSH regulates osteoclast NAD+ levels and energy metabolism via the CREB/MDH2 axis; ChIP assays showed CREB binds the MDH2 promoter, and FSHR-deficient osteoclasts display reduced NAD+, impaired energy metabolism, and reduced bone resorption. Lyz2-Cre-Flox FSHR conditional knockout, ChIP assay, dual-luciferase reporter, oxygen consumption rate, NAD+ measurement, bone histomorphometry Metabolism: clinical and experimental Medium 39880362
2026 STING stabilizes the mitochondrial desuccinylase SIRT5 by reducing TRIM21-mediated SIRT5 ubiquitination; SIRT5 then desuccinylates MDH2 at lysine 314, impairing MDH2 enzymatic activity and causing mitochondrial respiratory dysfunction and mtDNA damage that activates cGAS-STING signaling to restore cisplatin sensitivity. Modification omics (succinylation proteomics), site-specific MDH2 mutants (K314 succinylation-mimetic and desuccinylation), co-IP/MS for SIRT5 identification, TRIM21-SIRT5 ubiquitination assay, MDH2 enzymatic activity assay, mtDNA damage assay, in vitro and in vivo cisplatin resistance experiments Journal of advanced research High 41856470
2025 MDH2 is lactylated at K239 by KAT8 and deacylated by SIRT3; K239 lactylation increases MDH2 enzymatic activity, elevates NADH/NAD+ ratio and NADPH production, and strengthens MDH2 interaction with the citrate transporter SLC25A1 to facilitate citrate efflux and IDH1-dependent NADPH production, promoting oxidative stress resistance in renal cancer cells. Lactylome profiling, site-specific K239 mutants, KAT8/SIRT3 co-IP, enzymatic activity assay, NADH/NAD+/NADPH measurement, SLC25A1 co-IP, in vitro and in vivo RCC experiments International journal of biological macromolecules High 40769364
2026 During pathogenic E. coli infection, MDH2 undergoes acetylation-dependent nuclear translocation and functions as a transcriptional regulator to drive CTR2 (copper transporter) expression and metabolic reprogramming, triggering cuproptosis. Subcellular fractionation and imaging showing nuclear MDH2, acetylation detection, CTR2 promoter luciferase reporter, MDH2 knockdown/overexpression with CTR2 expression readout, in vivo infection model Nature communications Medium 42161958
2022 The lncRNA MDHDH acts as a molecular scaffold that simultaneously binds MDH2 and the proteasome subunit PSMA1, accelerating MDH2 ubiquitin-dependent proteasomal degradation; MDH2 degradation by MDHDH decreases mitochondrial membrane potential and NAD+/NADH ratio. RNA pulldown/mass spectrometry, RNA immunoprecipitation, co-immunoprecipitation of MDH2-PSMA1, ubiquitination assay, mitochondrial membrane potential assay, NAD+/NADH measurement Journal of experimental & clinical cancer research Medium 36527092
2026 Phosphorylation of MDH2 at serine 246 (S246) is required for full MDH2 enzymatic activity; the S246A phosphomutation decreases MDH2 activity, increases acetate and lactate accumulation, lowers mitochondrial membrane potential and ATP production, and under hypoxia/reoxygenation reduces mitochondrial biogenesis and fusion proteins PGC1α and OPA1. S246A phosphomutation, MDH2 enzymatic activity assay, metabolomics (acetate/lactate), mitochondrial membrane potential assay, ATP measurement, PGC1α/OPA1 western blot under H/R conditions The Korean journal of physiology & pharmacology Medium 41496511
2024 Phillygenin (metabolite of phillyrin) reversibly targets the NAD+ binding domain of MDH2 and inhibits its enzymatic activity, leading to decreased NADH production and reduced cellular energy supply. Chemical proteomics with alkynylated probe, DARTS assay, enzymatic inhibition assay, cellular metabolomics, mitochondrial stress testing Phytomedicine Medium 39191169

Source papers

Stage 0 corpus · 50 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 Whole-exome sequencing identifies MDH2 as a new familial paraganglioma gene. Journal of the National Cancer Institute 149 25766404
2024 Dexmedetomidine Ameliorates Myocardial Ischemia-Reperfusion Injury by Inhibiting MDH2 Lactylation via Regulating Metabolic Reprogramming. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 87 39467114
1991 Isolation, nucleotide sequence analysis, and disruption of the MDH2 gene from Saccharomyces cerevisiae: evidence for three isozymes of yeast malate dehydrogenase. Molecular and cellular biology 83 1986231
2016 Mutations in MDH2, Encoding a Krebs Cycle Enzyme, Cause Early-Onset Severe Encephalopathy. American journal of human genetics 73 27989324
2022 Palmitoylation of MDH2 by ZDHHC18 activates mitochondrial respiration and accelerates ovarian cancer growth. Science China. Life sciences 72 35366151
2018 Role of MDH2 pathogenic variant in pheochromocytoma and paraganglioma patients. Genetics in medicine : official journal of the American College of Medical Genetics 55 30008476
2015 Mitochondrial proteomics with siRNA knockdown to reveal ACAT1 and MDH2 in the development of doxorubicin-resistant uterine cancer. Journal of cellular and molecular medicine 45 25639359
2022 MDH2 produced OAA is a metabolic switch rewiring the fuelling of respiratory chain and TCA cycle. Biochimica et biophysica acta. Bioenergetics 42 35063410
1992 Glucose-induced degradation of the MDH2 isozyme of malate dehydrogenase in yeast. The Journal of biological chemistry 41 1324938
1997 Overexpression of cytosolic malate dehydrogenase (MDH2) causes overproduction of specific organic acids in Saccharomyces cerevisiae. Applied microbiology and biotechnology 39 9299784
2010 Med24 and Mdh2 are required for Drosophila larval salivary gland cell death. Developmental dynamics : an official publication of the American Association of Anatomists 31 20063412
2022 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 29 36527092
1994 Glucose-induced phosphorylation of the MDH2 isozyme of malate dehydrogenase in Saccharomyces cerevisiae. Archives of biochemistry and biophysics 26 7986072
2007 Localization of the single copy gene Mdh2 on Xenopus tropicalis chromosomes by FISH-TSA. Cytogenetic and genome research 25 17268187
2020 A piggybacking mechanism enables peroxisomal localization of the glyoxylate cycle enzyme Mdh2 in yeast. Journal of cell science 24 33177075
1981 Density- and frequency-dependent selection at the Mdh-2 locus in Drosophila pseudoobscura. Genetics 23 7297852
2017 MDH2 Stimulated by Estrogen-GPR30 Pathway Down-Regulated PTEN Expression Promoting the Proliferation and Invasion of Cells in Endometrial Cancer. Translational oncology 20 28189066
2001 Cat8 and Sip4 mediate regulated transcriptional activation of the yeast malate dehydrogenase gene MDH2 by three carbon source-responsive promoter elements. Yeast (Chichester, England) 20 11169757
2012 Differential expression analysis of porcine MDH1, MDH2 and ME1 genes in adipose tissues. Genetics and molecular research : GMR 19 22614353
2024 USP5 Promotes Ripretinib Resistance in Gastrointestinal Stromal Tumors by MDH2 Deubiquition. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 18 38973363
2017 MDH2 is an RNA binding protein involved in downregulation of sodium channel Scn1a expression under seizure condition. Biochimica et biophysica acta. Molecular basis of disease 18 28433711
2024 MDH2 regulates the sensitivity of clear cell renal cell carcinoma to ferroptosis through its interaction with FSP1. Cell death discovery 17 39138167
2023 Intermittent fasting promotes adipocyte mitochondrial fusion through Sirt3-mediated deacetylation of Mdh2. The British journal of nutrition 17 36815302
2025 FSH exacerbates bone loss by promoting osteoclast energy metabolism through the CREB-MDH2-NAD+ axis. Metabolism: clinical and experimental 16 39880362
2024 Phillyrin and its metabolites exert antipyretic effects by targeting the NAD+ binding domain of GAPDH, MDH2 and IDH2. Phytomedicine : international journal of phytotherapy and phytopharmacology 11 39191169
2025 Glibenclamide targets MDH2 to relieve aging phenotypes through metabolism-regulated epigenetic modification. Signal transduction and targeted therapy 10 39962087
2025 KAT8-mediated MDH2 lactylation promotes renal cancer progression by enhancing mitochondrial function and stress resistance. International journal of biological macromolecules 9 40769364
2024 MDH2 Promotes Hepatocellular Carcinoma Growth Through Ferroptosis Evasion via Stabilizing GPX4. International journal of molecular sciences 9 39519171
2021 Synthesis, biological evaluation and molecular docking studies of indeno [1, 2-c] pyrazol derivatives as inhibitors of mitochondrial malate dehydrogenase 2 (MDH2). Bioorganic chemistry 8 33689977
2021 Bi-allelic variants in MDH2: Expanding the clinical phenotype. Clinical genetics 8 34766628
2024 An fusaric acid-based CRISPR library screen identifies MDH2 as a broad-spectrum regulator of Fusarium toxin-induced cell death. Journal of hazardous materials 7 39342847
2022 MDH1 and MDH2 Promote Cell Viability of Primary AT2 Cells by Increasing Glucose Uptake. Computational and mathematical methods in medicine 7 36158123
2024 Transcription Factor STAT3-Activated LDHB Promotes Tumor Properties of Endometrial Cancer Cells by Inducing MDH2 Expression. Molecular biotechnology 6 38381377
2019 Recognition of gluconeogenic enzymes; Icl1, Fbp1, and Mdh2 by Gid4 ligase: A molecular docking study. Journal of molecular recognition : JMR 6 31863529
2019 Gene Encoding a Novel Enzyme of LDH2/MDH2 Family is Lost in Plant and Animal Genomes During Transition to Land. Journal of molecular evolution 5 30607448
1986 Functional hemizygosity for the MDH2 locus in Chinese hamster ovary cells. Somatic cell and molecular genetics 5 3457474
2018 Validation of a yeast malate dehydrogenase 2 (Mdh2) antibody tested for use in western blots. F1000Research 4 29568493
2023 A Rare Variant in MDH2 (rs111879470) Is Associated with Predisposition to Recurrent Breast Cancer in an Extended High-Risk Pedigree. Cancers 3 38136396
2021 Analysis of Hsp90 allosteric modulators interactome reveals a potential dual action mode involving mitochondrial MDH2. Bioorganic chemistry 3 34392176
2025 Xinmailong injection ameliorates Doxorubicin‑induced cardiotoxicity via the MDH2/OAA pathway. Phytomedicine : international journal of phytotherapy and phytopharmacology 2 40561861
2025 Multi-Omics Insights into the Impact of MDH2 on Breast Cancer Progression: A Promising Druggable Target. Oncology research 2 41179294
2022 Integrated genomic, transcriptomic and metabolomic analysis reveals MDH2 mutation-induced metabolic disorder in recurrent focal segmental glomerulosclerosis. Frontiers in immunology 2 36159820
2025 Presentation of a missense MDH2 variant in a Greek patient with pheochromocytoma. Hormones (Athens, Greece) 1 41085877
2023 Complex I, V, and MDH2 deficient human skin fibroblasts reveal distinct metabolic signatures by 1 H HR-MAS NMR. Journal of inherited metabolic disease 1 38084664
2026 MDH2 S246 phosphorylation protects mitochondria against hypoxia/reoxygenation injury due to acetate/lactate metabolism. The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology 0 41496511
2026 Discovery of Novel MDH2 Inhibitor 28i by Secondary Development of Glibenclamide with Potent Antiaging Activities. Journal of medicinal chemistry 0 41572571
2026 STING-driven mitochondrial metabolism reverses cisplatin resistance via MDH2 desuccinylation in non-small cell lung cancer. Journal of advanced research 0 41856470
2026 Curcumin inhibits colorectal cancer progression by regulating MDH2-mediated glycolysis and NAD+ metabolism. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 0 41903769
2026 Acetylated mitochondrial MDH2 regulates CTR2 transcription to induce cuproptosis during Escherichia coli infection. Nature communications 0 42161958
2023 Retracted: MDH1 and MDH2 Promote Cell Viability of Primary AT2 Cells by Increasing Glucose Uptake. Computational and mathematical methods in medicine 0 38094447

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