ArticleAmerican journal of human genetics2017
Mutations in MDH2, Encoding a Krebs Cycle Enzyme, Cause Early-Onset Severe Encephalopathy.
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Article in American journal of human genetics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.
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53citing papers in PubMed
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53 citing papers in PubMed, 90 citations in OpenAlex.
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- 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 · 2026Article
- Citric Acid Cycle Genes and Nutrigenetics.International journal of molecular sciences · 2026Review
- Modifier variants in metabolic pathways are associated with an increased penetrance of Leber's Hereditary Optic Neuropathy.European journal of human genetics : EJHG · 2026Article
- Comprehensive genotypic, phenotypic, and biochemical characterization of GOT2 deficiency: A progressive neurodevelopmental disorder with epilepsy and abnormal movements.Genetics in medicine : official journal of the American College of Medical Genetics · 2025Article
- Mitochondrial dysfunction-mediated metabolic remodeling of TCA cycle promotes Parkinson's disease through inhibition of H3K4me3 demethylation.Cell death discovery · 2025Article
- Are Hippocampal Hypoperfusion and ATP Depletion Prime Movers in the Genesis of Alzheimer's Disease? A Review of Recent Pertinent Observations from Molecular Biology.International journal of molecular sciences · 2025Review
- Prenatal diagnosis using next-generation sequencing in genetic counseling: Novel mutations in three large Iranian families: A case series.International journal of reproductive biomedicine · 2025Article
- Lacc1-engineered extracellular vesicles reprogram mitochondrial metabolism to alleviate inflammation and cartilage degeneration in TMJ osteoarthritis.Journal of nanobiotechnology · 2025Article
- Metabolic crosstalk between the mitochondrion and the nucleus is essential for Toxoplasma gondii infection.Communications biology · 2025Article
- Targeting Mitochondrial Dysfunction in Cerebral Ischemia: Advances in Pharmacological Interventions.Antioxidants (Basel, Switzerland) · 2025Review
- Moonlighting Proteins: Unveiling Their Multifunctionality in Metabolic Regulation and Drug Discovery.Current drug metabolism · 2025Review
- Intra- and extracellular real-time analysis of perfused fibroblasts using an NMR bioreactor: A pilot study.Journal of inherited metabolic disease · 2025Article
- A high-resolution two-step evolution experiment in yeast reveals a shift from pleiotropic to modular adaptation.PLoS biology · 2024Article
- MDH2 regulates the sensitivity of clear cell renal cell carcinoma to ferroptosis through its interaction with FSP1.Cell death discovery · 2024Article
- Cytosolic RNA binding of the mitochondrial TCA cycle enzyme malate dehydrogenase.RNA (New York, N.Y.) · 2024Article
- Induced pluripotent stem cell-derived hepatocytes reveal TCA cycle disruption and the potential basis for triheptanoin treatment for malate dehydrogenase 2 deficiency.Molecular genetics and metabolism reports · 2024Article
- Metabolomics in paraganglioma: applications and perspectives from genetics to therapy.Endocrine-related cancer · 2023Article
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Authors and funding
36 authors at 15 institutions in 5 countries.
Samira Ait-El-MkademDepartment of Medical Genetics, National Centre for Mitochondrial Diseases, Nice Teaching Hospital, 06202 Nice, France; Nice Sophia-Antipolis University, CNRS UMR 7284, INSERM U1081, Institute for Research on Cancer and Aging, Nice, 06107 Nice, France.
Manal Dayem-QuereDepartment of Medical Genetics, National Centre for Mitochondrial Diseases, Nice Teaching Hospital, 06202 Nice, France; Nice Sophia-Antipolis University, CNRS UMR 7284, INSERM U1081, Institute for Research on Cancer and Aging, Nice, 06107 Nice, France.
Mirjana GusicInstitute of Human Genetics, Technical University of Munich, 81675 München, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Annabelle ChaussenotDepartment of Medical Genetics, National Centre for Mitochondrial Diseases, Nice Teaching Hospital, 06202 Nice, France; Nice Sophia-Antipolis University, CNRS UMR 7284, INSERM U1081, Institute for Research on Cancer and Aging, Nice, 06107 Nice, France.
Sylvie BannwarthDepartment of Medical Genetics, National Centre for Mitochondrial Diseases, Nice Teaching Hospital, 06202 Nice, France; Nice Sophia-Antipolis University, CNRS UMR 7284, INSERM U1081, Institute for Research on Cancer and Aging, Nice, 06107 Nice, France.
Bérengère FrançoisNice Sophia-Antipolis University, CNRS UMR 7284, INSERM U1081, Institute for Research on Cancer and Aging, Nice, 06107 Nice, France.
Emmanuelle C GeninNice Sophia-Antipolis University, CNRS UMR 7284, INSERM U1081, Institute for Research on Cancer and Aging, Nice, 06107 Nice, France.
Konstantina FragakiDepartment of Medical Genetics, National Centre for Mitochondrial Diseases, Nice Teaching Hospital, 06202 Nice, France; Nice Sophia-Antipolis University, CNRS UMR 7284, INSERM U1081, Institute for Research on Cancer and Aging, Nice, 06107 Nice, France.
Catharina L M Volker-TouwDepartment of Genetics, University Medical Center Utrecht, 3584 Utrecht, the Netherlands.
Christelle VasnierInstitute for Integrative Biology of the Cell (I2BC), Commissariat à l'Énergie Atomique et aux Énergies Alternatives, CNRS, Université Paris-Sud, Université Paris-Saclay, 91198 Gif-sur-Yvette Cedex, France.
Valérie SerreCNRS UMR 7592, Jacques Monod Institute, Paris Diderot University, 75205 Paris, France.
Koen L I van GassenDepartment of Genetics, University Medical Center Utrecht, 3584 Utrecht, the Netherlands.
Françoise LespinasseNice Sophia-Antipolis University, CNRS UMR 7284, INSERM U1081, Institute for Research on Cancer and Aging, Nice, 06107 Nice, France.
Susan RichterInstitute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307 Dresden, Germany.
Graeme EisenhoferInstitute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307 Dresden, Germany.
Cécile RouzierDepartment of Medical Genetics, National Centre for Mitochondrial Diseases, Nice Teaching Hospital, 06202 Nice, France; Nice Sophia-Antipolis University, CNRS UMR 7284, INSERM U1081, Institute for Research on Cancer and Aging, Nice, 06107 Nice, France.
Fanny MochelINSERM U1127, CNRS UMR 7225, Sorbonne Universités, l'Université Pierre et Marie Curie (Paris 06) UMR S1127, Institut du Cerveau et de la Moelle Épinière Department of Genetics, Pitié-Salpêtrière University Hospital, 75013 Paris, France.
Anne De Saint-MartinService de Neurologie Pédiatrique, Centre de Référence pour les Épilepsies Rares, Centre Hospitalier Universitaire de Strasbourg, 67098 Strasbourg, France.
Marie-Thérèse Abi WardeService de Neurologie Pédiatrique, Centre de Référence pour les Épilepsies Rares, Centre Hospitalier Universitaire de Strasbourg, 67098 Strasbourg, France.
Monique G M de Sain-van der VeldeLaboratory of Metabolic Diseases, University Medical Center Utrecht, 3584 Utrecht, the Netherlands.
Judith J M JansLaboratory of Metabolic Diseases, University Medical Center Utrecht, 3584 Utrecht, the Netherlands.
Jeanne AmielDepartment of Genetics, Hôpital Necker-Enfants Malades, 75015 Paris, France.
Ziga AvsecDepartment of Informatics, Technical University of Munich, 85748 Garching, Germany.
Christian MertesDepartment of Informatics, Technical University of Munich, 85748 Garching, Germany.
Tobias B HaackInstitute of Human Genetics, Technical University of Munich, 81675 München, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Tim StromInstitute of Human Genetics, Technical University of Munich, 81675 München, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Thomas MeitingerInstitute of Human Genetics, Technical University of Munich, 81675 München, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Penelope E BonnenDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Robert W TaylorWellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, NE2 4HH Newcastle upon Tyne, UK.
Julien GagneurDepartment of Informatics, Technical University of Munich, 85748 Garching, Germany.
Peter M van HasseltDepartment of Metabolic Diseases, University Medical Center Utrecht, 3584 Utrecht, the Netherlands.
Agnès RötigINSERM U1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France.
Agnès DelahoddeInstitute for Integrative Biology of the Cell (I2BC), Commissariat à l'Énergie Atomique et aux Énergies Alternatives, CNRS, Université Paris-Sud, Université Paris-Saclay, 91198 Gif-sur-Yvette Cedex, France.
Holger ProkischInstitute of Human Genetics, Technical University of Munich, 81675 München, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Sabine A FuchsLaboratory of Metabolic Diseases, University Medical Center Utrecht, 3584 Utrecht, the Netherlands.
Véronique Paquis-FlucklingerDepartment of Medical Genetics, National Centre for Mitochondrial Diseases, Nice Teaching Hospital, 06202 Nice, France; Nice Sophia-Antipolis University, CNRS UMR 7284, INSERM U1081, Institute for Research on Cancer and Aging, Nice, 06107 Nice, France. Electronic address: paquis@hermes.unice.fr.
Technical University of Munich · DEUniversity Medical Center Utrecht · NLCentre National de la Recherche Scientifique · FRCentre Hospitalier Universitaire de Nice · FRHôpitaux Universitaires de Strasbourg · FRInserm · FRTU Dresden · DEBaylor College of Medicine · USCommissariat à l'Énergie Atomique et aux Énergies Alternatives · FRDélégation Paris 5 · FRHelmholtz Zentrum München · DEHôpital Necker-Enfants Malades · FRInstitut de Recherche sur le Cancer et le Vieillissement de Nice · FRSorbonne Université · FRWellcome Centre for Mitochondrial Research · GB
Funding
Personalized Functional Genomics for Mitochondrial Encephalopathy Gene DiscoveryR01NS083726 · NINDS · BAYLOR COLLEGE OF MEDICINE · PI BONNEN, PENELOPE E · 2014 to 2025
$6.1MNINDS NIH HHS R01 NS083726Wellcome Trust
Abstract
MDH2 encodes mitochondrial malate dehydrogenase (MDH), which is essential for the conversion of malate to oxaloacetate as part of the proper functioning of the Krebs cycle. We report bi-allelic pathogenic mutations in MDH2 in three unrelated subjects presenting with early-onset generalized hypotonia, psychomotor delay, refractory epilepsy, and elevated lactate in the blood and cerebrospinal fluid. Functional studies in fibroblasts from affected subjects showed both an apparently complete loss of MDH2 levels and MDH2 enzymatic activity close to null. Metabolomics analyses demonstrated a significant concomitant accumulation of the MDH substrate, malate, and fumarate, its immediate precursor in the Krebs cycle, in affected subjects' fibroblasts. Lentiviral complementation with wild-type MDH2 cDNA restored MDH2 levels and mitochondrial MDH activity. Additionally, introduction of the three missense mutations from the affected subjects into Saccharomyces cerevisiae provided functional evidence to support their pathogenicity. Disruption of the Krebs cycle is a hallmark of cancer, and MDH2 has been recently identified as a novel pheochromocytoma and paraganglioma susceptibility gene. We show that loss-of-function mutations in MDH2 are also associated with severe neurological clinical presentations in children.
Indexed as
Citric Acid CycleMutationAge of OnsetAllelesAmino Acid SequenceBrain DiseasesChildChild, PreschoolFibroblastsFumaratesGenetic Complementation TestHumansInfantInfant, NewbornMalate DehydrogenaseMalatesFumaratesfumaric acidMalate DehydrogenaseMalatesmalic acidMDH2 protein, human
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