Abstract
SummaryGain-of-function mutations in isocitrate dehydroge-nase 1 (IDH1) occur in multiple types of human cancer. Here, we show that these mutations significantly disrupt NADPH homeostasis by consuming NADPH for 2-hydroxyglutarate (2-HG) synthesis. Cells respond to 2-HG synthesis, but not exogenous administration of 2-HG, by increasing pentose phosphate pathway (PPP) flux. We show that 2-HG production competes with reductive biosynthesis and the buffering of oxidative stress, processes that also require NADPH. IDH1 mutants have a decreased capacity to synthesize palmitate and an increased sensitivity to oxidative stress. Our results demonstrate that, even when NADPH is limiting, IDH1 mutants continue to synthesize 2-HG at the expense of other NADPH-requiring pathways that are essential for cell viability. Thus, rather than attempting to decrease 2-HG synthesis in the clinic, the consumption of NADPH by mutant IDH1 may be exploited as a metabolic weakness that sensitizes tumor cells to ionizing radiation, a commonly used anti-cancer therapy.
Highlights
There are three subtypes of isocitrate dehydrogenase (IDH) that vary according to their cellular location and NADP+ or NAD+ dependency (Dang and Su, 2017)
Each subtype oxidatively decarboxylates isocitrate to alpha-ketoglutarate under most normal physiological conditions, but the NADP+-dependent isocitrate dehydrogenase 1 (IDH1) is uniquely situated in the cytosol, peroxisomes, and endoplasmic reticulum, whereas the NADP+-dependent IDH2 and the NAD+dependent IDH3 are in the mitochondrial matrix (Geisbrecht and Gould, 1999; Lewis et al, 2014; Margittai and Banhegyi, 2008)
We found that both of these cell lines do increase their production of NADPH by the phosphate pathway (PPP) to support 2-HG synthesis, the NADPH produced is insufficient for all NADPH-requiring reactions, under conditions of oxidative stress
Summary
There are three subtypes of isocitrate dehydrogenase (IDH) that vary according to their cellular location and NADP+ or NAD+ dependency (Dang and Su, 2017). Each subtype oxidatively decarboxylates isocitrate to alpha-ketoglutarate under most normal physiological conditions, but the NADP+-dependent IDH1 is uniquely situated in the cytosol, peroxisomes, and endoplasmic reticulum, whereas the NADP+-dependent IDH2 and the NAD+dependent IDH3 are in the mitochondrial matrix (Geisbrecht and Gould, 1999; Lewis et al, 2014; Margittai and Banhegyi, 2008). The cellular location of the IDH1 and IDH2 enzymes is important because NADPH does not have protein transporters to cross the inner mitochondrial membrane (Pollak et al, 2007). Both the cytosol and the mitochondria have essential NADPH demands. Each cellular compartment must independently balance their NADPH production and consumption rates
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