The Role of Mitochondrial NADPH-Dependent Isocitrate Dehydrogenase in Cancer Cells

Abstract

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.

Coactivator SRC-2–dependent metabolic reprogramming mediates prostate cancer survival and metastasis

“…Surprisingly, however, we observed a dramatic decrease in ACO enzymatic activity ( Figure 4A), but not IDH or citrate synthase (CS) activity ( Figure 4, B and C, and ref. 32), in SRC-2-depleted C4-2 cells compared with control C4-2 cells. ACO catalyzes the stereo-specific isomerization of citrate to isocitrate via cis-aconitate, and this reversible reaction is allosterically regulated by the intracellular zinc concentration (33).…”

Non-invasive in vivo assessment of IDH1 mutational status in glioma

“…In particular, ester derivatives of α-KG, including octyl- and fluorobenzyl-esters have been reported to permeate the cell membrane more effectively 45 . Such derivatives would lead to increased intracellular α-KG concentrations and potentially higher levels of 2-HG, and might also enable studies of IDH2 within the mitochondria 46,47 . Previous studies indicate that the use of ester derivatives creates additional resonances than could hamper spectral differentiation 48 .…”

Oxalomalate reduces expression and secretion of vascular endothelial growth factor in the retinal pigment epithelium and inhibits angiogenesis: Implications for age-related macular degeneration

“…IDH enzymes are evolutionarily conserved proteins that catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate and the reduction of NADP + to NADPH [39]. Specifically, IDH2 acts as a NADP + -consuming enzyme in the forward Krebs cycle, generating NADPH for the maintenance of reduced glutathione and peroxiredoxin systems, and for self-maintenance via the reactivation of cysteine-inactivated IDH2 by glutaredoxin 2 [39], [40].…”