%0 Journal Article
%T The Role of Mitochondrial NADPH-Dependent Isocitrate Dehydrogenase in Cancer Cells
%A Katar¨ªna Smolkov¨¢
%A Petr Je£¿ek
%J International Journal of Cell Biology
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/273947
%X 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¡ªfrequently found with similar mutants of cytosolic IDH1 in grade 2 and 3 gliomas, secondary glioblastomas, and acute myeloid leukemia¡ªcatalyze 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 . 1. Oxidative Phosphorylation and Glutaminolysis in Cancer Cells 1.1. Strategies for Survival of Malignant Tumors During malignant transformation, cells undergo stages of gene expression reprogramming and mutagenesis that alter their metabolic phenotype(s) [1¨C5]. Initial stimuli (not all known) dysregulate information signaling and activate oncogenes and/or cancer stem cells, resulting in a partial glycolytic ¡°Warburg¡± phenotype [1¨C5] in which pyruvate is diverted, at least to a certain extent, from oxidative phosphorylation (OXPHOS). High proliferation and impaired angiogenesis subsequently cause hypoxia in certain regions within a growing tumor, and then hypoxia-mediated metabolic reprogramming (such as that promoted by hypoxia-induced factor, HIF [6¨C8]) further intensifies the glycolytic phenotype and may nearly completely divert pyruvate from pyruvate dehydrogenase (PDH), that is, from OXPHOS. The sustained high rate of cell proliferation, however, results in aglycemia, initiating the revival of OXPHOS in conjunction
%U http://www.hindawi.com/journals/ijcb/2012/273947/