Figure 5.

Proposed hypothesis of different effects of the IDH1^R132H mutation in glial and tumor cells: We found that the IDH1^R132H mutation differently affects the redox state of glial cells and tumor cells. Wildtype IDH1 provides essential amounts of NADPH for the cell whereas IDH1^R132H consumes α-KG and NAPDH, leading to abnormally high concentrations of 2-HG, reduced concentrations of α-KG and downstream TCA cycle metabolites, as well as an imbalance between NADPH and NADP⁺ levels. Based on our observations, we hypothesize that in astrocytes, the increased NADPH consumption by IDH1^R132H can still be compensated for by elevating the total NADP pool via the induction of NADK and the NAD⁺ synthesizing enzyme NAMPT. Malignant, proliferating cells, however, cannot compensate for the imbalance of NADPH/NADP⁺ due to IDH1^R132H, leading to decreased NADPH and NAD⁺ levels. This could be due to the increased requirement of NAD⁺ and/or NADPH in proliferating cells or insufficient upregulation of NAD synthesis pathways, potentially accompanied by additional inhibition of NAMPT expression due to the IDH1^R132H. Abbreviations: NAD = nicotinamide adenine dinucleotide, NADP = nicotinamide adenine dinucleotide phosphate, NMRK1 = nicotinamide riboside kinase, NAMPT = nicotinaminde phosphoribosyltransferase, QPRT = quinolinic acid phosphoribosyltransferase, NADK = NAD-Kinase.