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Deficiency in SLC25A1, encoding the mitochondrial citrate carrier, causes combined D-2- and L-2-hydroxyglutaric aciduria.

ABSTRACT: 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.

SUBMITTER: Nota B

PROVIDER: S-EPMC3617390 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Deficiency in SLC25A1, encoding the mitochondrial citrate carrier, causes combined D-2- and L-2-hydroxyglutaric aciduria.

Nota Benjamin B Struys Eduard A EA Pop Ana A Jansen Erwin E EE Fernandez Ojeda Matilde R MR Kanhai Warsha A WA Kranendijk Martijn M van Dooren Silvy J M SJ Bevova Marianna R MR Sistermans Erik A EA Nieuwint Aggie W M AW Barth Magalie M Ben-Omran Tawfeg T Hoffmann Georg F GF de Lonlay Pascale P McDonald Marie T MT Meberg Alf A Muntau Ania C AC Nuoffer Jean-Marc JM Parini Rossella R Read Marie-Hélène MH Renneberg Axel A Santer René R Strahleck Thomas T van Schaftingen Emile E van der Knaap Marjo S MS Jakobs Cornelis C Salomons Gajja S GS

American journal of human genetics 20130401 4

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 acidu ...[more]

PMID: 23561848

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Project description:Pronounced resistance of lung cancer cells to radiotherapy and chemotherapy is a major barrier to successful treatment. Herein, both tumor hypoxia and the upregulation of the cellular antioxidant defense systems observed during malignant progression can contribute to radioresistance. We recently found that exposure to chronic cycling severe hypoxia/reoxygenation stress results in glutamine-dependent upregulation of cellular glutathione (GSH) levels and associated radiation resistance opening novel routes for tumor cell-specific radiosensitization. Here, we explored the role of the mitochondrial citrate carrier (SLC25A1) for the improved antioxidant defense of cancer cells with tolerance to acute and chronic severe hypoxia/reoxygenation stress and the use of pharmacologic SLC25A1 inhibition for tumor cell radiosensitization. Exposure to acute or chronic cycling severe hypoxia/reoxygenation stress triggered upregulated expression of SLC25A1 in lung cancer, prostate cancer, and glioblastoma cells in vitro. Interestingly, exposure to ionizing radiation (IR) further promoted SLC25A1 expression. Inhibition of SLC25A1 by 1,2,3-benzene-tricarboxylic acid (BTA) disturbed cellular and mitochondrial redox homeostasis, lowered mitochondrial metabolism, and reduced metabolic flexibility of cancer cells. Even more important, combining IR with BTA was able to overcome increased radioresistance induced by adaptation to chronic cycling severe hypoxia/reoxygenation stress. This radiosensitizing effect of BTA-treated cells was linked to increased reactive oxygen species and reduced DNA repair capacity. Of note, key findings could be reproduced when using the SLC25A1-inhibitor 4-Chloro-3-[[(3-nitrophenyl)amino]sulfonyl]-benzoic acid (CNASB). Moreover, in silico analysis of publically available databases applying the Kaplan-Meier plotter tool (kmplot.com) revealed that overexpression of SLC25A1 was associated with reduced survival of lung cancer patients suggesting a potential link to aggressive cancers. We show that SLC25A1 can contribute to the increased antioxidant defense of cancer cells allowing them to escape the cytotoxic effects of IR. Since upregulation of SLC25A1 is induced by adverse conditions in the tumor environment, exposure to IR, or both pharmacologic inhibition of SLC25A1 might be an effective strategy for radiosensitization of cancer cells particularly in chronically hypoxic tumor fractions.

Dataset Information

Deficiency in SLC25A1, encoding the mitochondrial citrate carrier, causes combined D-2- and L-2-hydroxyglutaric aciduria.

Publications

Deficiency in SLC25A1, encoding the mitochondrial citrate carrier, causes combined D-2- and L-2-hydroxyglutaric aciduria.

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