The Role of Mitochondrial NADPH-Dependent Isocitrate Dehydrogenase in Cancer Cells
Isocitrate dehydrogenase 2 (IDH2) is located in the mitochondrial matrix. IDH2 acts in the forward Krebs cycle as an NADP+-consuming enzyme, providing NADPH for maintenance of the reduced glutathione and peroxiredoxin systems and for self-maintenance by reactivation of cystine-inactivated IDH2 by gl...
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Wiley
2012-01-01
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| Series: | International Journal of Cell Biology |
| Online Access: | http://dx.doi.org/10.1155/2012/273947 |
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| author | Katarína Smolková Petr Ježek |
| author_facet | Katarína Smolková Petr Ježek |
| author_sort | Katarína Smolková |
| collection | DOAJ |
| description | Isocitrate dehydrogenase 2 (IDH2) is located in the mitochondrial matrix. IDH2 acts in the forward Krebs cycle as an NADP+-consuming enzyme, providing NADPH for maintenance of the reduced glutathione and peroxiredoxin systems and for self-maintenance by reactivation of cystine-inactivated IDH2 by glutaredoxin 2. In highly respiring cells, the resulting NAD+ accumulation then induces sirtuin-3-mediated activating IDH2 deacetylation, thus increasing its protective function. Reductive carboxylation of 2-oxoglutarate by IDH2 (in the reverse Krebs cycle direction), which consumes NADPH, may follow glutaminolysis of glutamine to 2-oxoglutarate in cancer cells. When the reverse aconitase reaction and citrate efflux are added, this overall “anoxic” glutaminolysis mode may help highly malignant tumors survive aglycemia during hypoxia. Intermittent glycolysis would hypothetically be required to provide ATP. When oxidative phosphorylation is dormant, this mode causes substantial oxidative stress. Arg172 mutants of human IDH2—frequently found with similar mutants of cytosolic IDH1 in grade 2 and 3 gliomas, secondary glioblastomas, and acute myeloid leukemia—catalyze reductive carboxylation of 2-oxoglutarate and reduction to D-2-hydroxyglutarate, which strengthens the neoplastic phenotype by competitive inhibition of histone demethylation and 5-methylcytosine hydroxylation, leading to genome-wide histone and DNA methylation alternations. D-2-hydroxyglutarate also interferes with proline hydroxylation and thus may stabilize hypoxia-induced factor α. |
| format | Article |
| id | doaj-art-e5765ce857d6438dae282e10ebb3d95a |
| institution | Kabale University |
| issn | 1687-8876 1687-8884 |
| language | English |
| publishDate | 2012-01-01 |
| publisher | Wiley |
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| series | International Journal of Cell Biology |
| spelling | doaj-art-e5765ce857d6438dae282e10ebb3d95a2025-02-03T06:13:51ZengWileyInternational Journal of Cell Biology1687-88761687-88842012-01-01201210.1155/2012/273947273947The Role of Mitochondrial NADPH-Dependent Isocitrate Dehydrogenase in Cancer CellsKatarína Smolková0Petr Ježek1Department of Membrane Transport Biophysics (No. 75), Institute of Physiology v.v.i., Academy of Sciences of the Czech Republic, Vídeňská 1083, CZ-14220 Prague, Czech RepublicDepartment of Membrane Transport Biophysics (No. 75), Institute of Physiology v.v.i., Academy of Sciences of the Czech Republic, Vídeňská 1083, CZ-14220 Prague, Czech RepublicIsocitrate dehydrogenase 2 (IDH2) is located in the mitochondrial matrix. IDH2 acts in the forward Krebs cycle as an NADP+-consuming enzyme, providing NADPH for maintenance of the reduced glutathione and peroxiredoxin systems and for self-maintenance by reactivation of cystine-inactivated IDH2 by glutaredoxin 2. In highly respiring cells, the resulting NAD+ accumulation then induces sirtuin-3-mediated activating IDH2 deacetylation, thus increasing its protective function. Reductive carboxylation of 2-oxoglutarate by IDH2 (in the reverse Krebs cycle direction), which consumes NADPH, may follow glutaminolysis of glutamine to 2-oxoglutarate in cancer cells. When the reverse aconitase reaction and citrate efflux are added, this overall “anoxic” glutaminolysis mode may help highly malignant tumors survive aglycemia during hypoxia. Intermittent glycolysis would hypothetically be required to provide ATP. When oxidative phosphorylation is dormant, this mode causes substantial oxidative stress. Arg172 mutants of human IDH2—frequently found with similar mutants of cytosolic IDH1 in grade 2 and 3 gliomas, secondary glioblastomas, and acute myeloid leukemia—catalyze reductive carboxylation of 2-oxoglutarate and reduction to D-2-hydroxyglutarate, which strengthens the neoplastic phenotype by competitive inhibition of histone demethylation and 5-methylcytosine hydroxylation, leading to genome-wide histone and DNA methylation alternations. D-2-hydroxyglutarate also interferes with proline hydroxylation and thus may stabilize hypoxia-induced factor α.http://dx.doi.org/10.1155/2012/273947 |
| spellingShingle | Katarína Smolková Petr Ježek The Role of Mitochondrial NADPH-Dependent Isocitrate Dehydrogenase in Cancer Cells International Journal of Cell Biology |
| title | The Role of Mitochondrial NADPH-Dependent Isocitrate Dehydrogenase in Cancer Cells |
| title_full | The Role of Mitochondrial NADPH-Dependent Isocitrate Dehydrogenase in Cancer Cells |
| title_fullStr | The Role of Mitochondrial NADPH-Dependent Isocitrate Dehydrogenase in Cancer Cells |
| title_full_unstemmed | The Role of Mitochondrial NADPH-Dependent Isocitrate Dehydrogenase in Cancer Cells |
| title_short | The Role of Mitochondrial NADPH-Dependent Isocitrate Dehydrogenase in Cancer Cells |
| title_sort | role of mitochondrial nadph dependent isocitrate dehydrogenase in cancer cells |
| url | http://dx.doi.org/10.1155/2012/273947 |
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