IDH1 mutations drive an oxygen-sparing metabolic phenotype to permit tumour growth

Abstract

Since the description of mutations in isocitrate dehydrogenase 1 (IDH1) in adult glial tumours in 2008, many studies have focused on the role of the oncometabolite 2-hydroxyglutarate in determining the pheontype of affected gliomas. However, another aspect of IDH1 activity - its redox-dependency - may also represent an important determinant of IDH1-mutant glioma phenotype. To examine the effect of IDH1 mutations on redox homeostasis, we traced their use of redox-active metabolic pathways using nutrients enriched in the stable isotope, 13C. We found that cells expressing the IDH1 R132H mutant demonstrated enhanced proline synthesis, but that unexpectedly the proline produced was excreted rather than used for biosynthetic processes. As proline synthesis is a highly redox-dependent pathway, we hypothesised that this represented a metabolic response to altered isocitrate metabolism by the IDH1 mutant enzyme. We furthermore showed that metabolic response was dependent on pyrroline 5-carboxylate reductase 1 (PYCR1), and was important for the oxidation of mitochondrial NADH. Consistent with this, knockdown of PYCR1 resulted in a compensatory increase in cell respiration. We therefore show that cells with IDH1 mutations require proline synthesis in order to retain normal TCA cycle activity while using less oxygen. This may mean that IDH1 mutant tumours are in general less hypoxic, and therefore more responsive to treatment.