The α-ketoglutarate dehydrogenase complex in cancer metabolic plasticity

Vatrinet, Renaud; Leone, Giulia; Luise, Monica De; Girolimetti, Giulia; Vidone, Michele; Gasparre, Giuseppe; Porcelli, Anna Maria

doi:10.1186/s40170-017-0165-0

Cited by 83 publications

(64 citation statements)

References 136 publications

(157 reference statements)

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“…18,34 Any condition causing even a modest variation in the cytosolic levels of aKG might affect different pathways, promoting either oncogenic or tumor suppressive responses: an increase of fatty acid biosynthesis or promotion of aberrant mammalian target of rapamycin 1 (mTORC1) activation ( Figure S3). [35][36][37] In addition, DLST mutation causing the loss of OGDH-complex nuclear-translocation capacity might lead to altered overall gene expression ( Figure S3). 38 The increased aKG to fumarate ratio in p.Gly374Glumutated tumors suggests that this variant leads to a disruption of OGDH complex activity.…”

Section: Discussionmentioning

confidence: 99%

Recurrent Germline DLST Mutations in Individuals with Multiple Pheochromocytomas and Paragangliomas

Remacha

Pirman

Mahoney

et al. 2019

The American Journal of Human Genetics

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Pheochromocytomas and paragangliomas (PPGLs) provide some of the clearest genetic evidence for the critical role of metabolism in the tumorigenesis process. Approximately 40% of PPGLs are caused by driver germline mutations in 16 known susceptibility genes, and approximately half of these genes encode members of the tricarboxylic acid (TCA) cycle. Taking as a starting point the involvement of the TCA cycle in PPGL development, we aimed to identify unreported mutations that occurred in genes involved in this key metabolic pathway and that could explain the phenotypes of additional individuals who lack mutations in known susceptibility genes. To accomplish this, we applied a targeted sequencing of 37 TCA-cycle-related genes to DNA from 104 PPGL-affected individuals with no mutations in the major known predisposing genes. We also performed omics-based analyses, TCA-related metabolite determination, and 13 C 5 -glutamate labeling assays. We identified five germline variants affecting DLST in eight unrelated individuals ($7%); all except one were diagnosed with multiple PPGLs. A recurrent variant, c.1121G>A (p.Gly374Glu), found in four of the eight individuals triggered accumulation of 2-hydroxyglutarate, both in tumors and in a heterologous cell-based assay designed to functionally evaluate DLST variants. p.Gly374Glu-DLST tumors exhibited loss of heterozygosity, and their methylation and expression profiles are similar to those of EPAS1-mutated PPGLs; this similarity suggests a link between DLST disruption and pseudohypoxia. Moreover, we found positive DLST immunostaining exclusively in tumors carrying TCA-cycle or EPAS1 mutations. In summary, this study reveals DLST as a PPGL-susceptibility gene and further strengthens the relevance of the TCA cycle in PPGL development.

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Section: Discussionmentioning

confidence: 99%

Recurrent Germline DLST Mutations in Individuals with Multiple Pheochromocytomas and Paragangliomas

Remacha

Pirman

Mahoney

et al. 2019

The American Journal of Human Genetics

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“…1–5 Tumor-derived mutant forms of IDH catalyze the NAD-dependent dehydrogenation of α-ketoglutarate (αKG) to D-2-hydroxyglutarate (D-2HG), a function that supplants the physiological activity of IDH, which entails reductive decarboxylation of isocitrate to αKG (Figure 1b). 6–13 L-2HG, the stereoisomer of D-2HG, has been identified as an oncometabolite with elevated concentrations in renal cell carcinoma 9,10 neurodegenerative disorders, 14,15 and in tissues under oxygen limitation or hypoxic conditions. 11,12 The elevation of L-2HG under such conditions is key from either loss of expression of L-2HG dehydrogenase or promiscuous substrate utilization by lactate dehydrogenase A and malate dehydrogenases 1 and 2.…”

Section: Introductionmentioning

confidence: 99%

Oncometabolites d- and l-2-Hydroxyglutarate Inhibit the AlkB Family DNA Repair Enzymes under Physiological Conditions

Chen

Bian

Tang

et al. 2017

Chem. Res. Toxicol.

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Cancer-associated mutations often lead to perturbed cellular energy metabolism and accumulation of potentially harmful oncometabolites. One example is the chiral molecule 2-hydroxyglutarate (2HG); its two stereoisomers (D- and L-2HG) have been found with abnormally high concentrations in tumors featuring anomalous metabolic pathways. 2HG has been demonstrated to competitively inhibit several α-ketoglutarate (αKG)- and non-heme iron-dependent dioxygenases, including some of the AlkB family DNA repair enzymes, such as ALKBH2 and ALKBH3. However, previous studies have only provided the IC50 values of D-2HG on the enzymes and the results have not been correlated to physiologically relevant concentrations of 2HG and αKG in cancer cells. In this work, we carried out detailed kinetic analyses of DNA repair reactions catalyzed by ALKBH2, ALKBH3 and the bacterial AlkB in the presence of D- and L-2HG in both double and single stranded DNA contexts. We determined kinetic parameters of inhibition, including kcat, KM, and Ki. We also correlated the relative concentrations of 2HG and αKG previously measured in tumor cells with the inhibitory effect of 2HG on the AlkB family enzymes. Both D- and L-2HG significantly inhibited the human DNA repair enzymes ALKBH2 and ALKBH3 under pathologically relevant concentrations (73–88% for D-2HG and 31–58% for L-2HG inhibition). This work provides a new perspective that the elevation of either D- or L-2HG in cancer cells may contribute to an increased mutation rate by inhibiting the DNA repair carried out by the AlkB family enzymes and thus exacerbate the genesis and progression of tumors.

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“…However, the accumulation of α-KG and NADPH may activate cancerrelated proteins including mammalian target of rapamycin 1, thereby promoting tumorigenesis (30). Regulation of α-KG levels is also essential in modulating the epigenetic landscape of cancer cells (13). In our study, the levels of α-KG and NADPH were increased in the IDH KO cells transfected with plasmids containing WT IDH1.…”

Section: Discussionmentioning

confidence: 47%

“…Isocitrate dehydrogenase 1 (IDH1) is an enzyme encoded by IDH1, which is responsible for catalyzing isocitrate to produce α-ketoglutarate (α-KG) and generating nicotinamide adenine dinucleotide phosphate (NADPH) (11,12). α-KG and NADPH are components of the tricarboxylic acid (TCA) cycle, which are thought to detoxify against oxidative stress (12,13). Therefore, IDH1 indirectly regulates oxidative damage.…”

Section: Introductionmentioning

confidence: 99%

Mutation of Isocitrate Dehydrogenase 1 in Cholangiocarcinoma Impairs Tumor Progression by Inhibiting Isocitrate Metabolism

Zhang

Zheng

et al. 2020

Front. Endocrinol.

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Aim: Isocitrate dehydrogenase 1 (IDH1) is key enzyme involved in cellular metabolism and DNA repair. Mutations in IDH1 occur in up to 25% of cholangiocarcinomas. The present study aimed to explore the features of cellosaurus REB cells with mutant and wide-type IDH1.Methods: To compare the features of IDH1 knockout and mutation in cholangiocarcinoma, we firstly constructed the IDH1 knockout and IDH1 mutation cell lines. We then evaluated the viability of these cell lines using the cell count assay and MTT assay. Next, we determined cell migration and invasion using the Transwell assay. Additionally, to evaluate the effects of IDH1 on cellular metabolism, the levels of α-ketoglutarate (α-KG) and nicotinamide adenine dinucleotide phosphate (NADPH) were determined using enzyme-linked immunosorbent assay. We then applied ChIPbase dataset to explore the genes that were regulated by IDH1.Results: High frequency of mutated IDH1 was observed in the cholangiocarcinoma and IDH1 R132C was presented in more than 80% of mutations. The results showed that IDH1 knockout decreased cell proliferation, migration and invasion, whereas the overexpression of IDH1 in IDH1 knockout cell line recovered its proliferation, migration and invasion capacities. Additionally, IDH1 mutation reduced the levels of NADPH and α-KG. Furthermore, investigation into the underlying mechanisms revealed that IDH1 overexpression induced the expression of aldehyde dehydrogenase 1 thereby promoting cell proliferation, migration and invasion.Conclusion: IDH1 plays an important role in cholangiocarcinoma and its mutation impairs tumor progression in part by inhibition of isocitrate metabolism.

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The α-ketoglutarate dehydrogenase complex in cancer metabolic plasticity

Cited by 83 publications

References 136 publications

Recurrent Germline DLST Mutations in Individuals with Multiple Pheochromocytomas and Paragangliomas

Recurrent Germline DLST Mutations in Individuals with Multiple Pheochromocytomas and Paragangliomas

Oncometabolites d- and l-2-Hydroxyglutarate Inhibit the AlkB Family DNA Repair Enzymes under Physiological Conditions

Mutation of Isocitrate Dehydrogenase 1 in Cholangiocarcinoma Impairs Tumor Progression by Inhibiting Isocitrate Metabolism

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