Deficiency in SLC25A1, Encoding the Mitochondrial Citrate Carrier, Causes Combined D-2- and L-2-Hydroxyglutaric Aciduria
Open accessAbstract
The Krebs cycle is of fundamental importance for the generation of the energetic and molecular needs of both prokaryotic and eukaryotic cells. Both enantiomers of metabolite 2-hydroxyglutarate are directly linked to this pivotal biochemical pathway and are found elevated not only in several cancers, but also in different variants of the neurometabolic disease 2-hydroxyglutaric aciduria. Recently we showed that cancer-associated IDH2 germline mutations cause one variant of 2-hydroxyglutaric aciduria. Complementary to these findings, we now report recessive mutations in SLC25A1, the mitochondrial citrate carrier, in 12 out of 12 individuals with combined D-2- and L-2-hydroxyglutaric aciduria. Impaired mitochondrial citrate efflux, demonstrated by stable isotope labeling experiments and the absence of SLC25A1 in fibroblasts harboring certain mutations, suggest that SLC25A1 deficiency is pathogenic. Our results identify defects in SLC25A1 as a cause of combined D-2- and L-2-hydroxyglutaric aciduria.
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D-2-HG accumulation under pathogenic conditions may contribute to tumorigenicity by stabilizing HIF-1α and impairing collagen biogenesis.
“the concentrations at which it accumulates under pathogenic conditions suggests HIF-1α stabilisation and impaired collagen biogenesis may contribute to tumorigenicity126-130.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [127]
HIF-1α stabilisation occurs in IDH1-mutant brain tissue.
“Indeed, D-2-HG accumulation in IDH-mutant glioma has been found to inhibit PHD hydroxylase and stabilise HIF-1α126 and HIF-1αstabilisation has been shown to occur in IDH1-mutant brain tissue127.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [127]
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- Authors
- Nota, B., Struys, E. A., Pop, A., Jansen, E. E., Fernandez Ojeda, M. R., Kanhai, W. A., Kranendijk, M., van Dooren, S. J. M., Bevova, M. R., Sistermans, E. A., Nieuwint, A. W. M., Barth, M., Ben-Omran, T., Hoffmann, G. F., de Lonlay, P., McDonald, M. T., Meberg, A., Muntau, A. C., Nuoffer, J.-M., Parini, R., Read, M.-H., Renneberg, A., Santer, R., Strahleck, T., van Schaftingen, E., van der Knaap, M. S., Jakobs, C., & Salomons, G. S.
- Affiliations
- Amsterdam Neuroscience (NL)
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- Centre Hospitalier Universitaire d'Angers (FR)
- University Hospital Heidelberg (DE)
- Duke University (US)
- Sykehuset i Vestfold (NO)
- Ludwig-Maximilians-Universität München (DE)
- University of Bern (CH)
- Azienda Ospedaliera San Gerardo (IT)
- Centre Hospitalier Universitaire de Caen Normandie (FR)
- Klinikum Bremerhaven-Reinkenheide (DE)
- Universität Hamburg (DE)
- Olgahospital (DE)
- Corresponding author
- Nota, Benjamin
- Salomons, Gajja S.
- ORCID
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2013-04
- Volume
- 92
- Issue
- 4
- Pages
- 627-631
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC3617390
- OpenAlex
- W2069775190
- Cited by
- 138
- References
- 30
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 8 · 2023: 14 · 2022: 12 · 2021: 13 · 2020: 12 · 2019: 15 · 2018: 8 · 2017: 15 · 2016: 12 · 2015: 5 · 2014: 14 · 2013: 2
- FWCI
- 7.33
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- VU Research Portal (publishedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- BORIS (University Library Bern) (submittedVersion)
- Digital Access to Libraries (Université catholique de Louvain (UCL), l'Université de Namur (UNamur) and the Université Saint-Louis (USL-B)) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- Vrije Universiteit Amsterdam
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- SLC25A1, mitochondrial citrate carrier, D-2-hydroxyglutaric aciduria, L-2-hydroxyglutaric aciduria, recessive mutations, TCA cycle, 2-hydroxyglutarate, neurometabolic disorders, stable isotope labeling
- MeSH terms
- Amino Acid Sequence, Cells, Cultured, Chromatography, Liquid, Female, Fibroblasts, Genes, Recessive, Glutarates, Humans, Male, Mitochondria, Molecular Sequence Data, Mutation, Phenotype, Retrospective Studies, Stereoisomerism, Biomarkers, Case-Control Studies, Sequence Homology, Amino Acid, Protein Structure, Tertiary, Citric Acid, Brain Diseases, Metabolic, Inborn, Mitochondrial Proteins, Anion Transport Proteins, Organic Anion Transporters, Tandem Mass Spectrometry, Exome
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