IDH-Mutant Gliomas Reprogram Glutamine Metabolism and Pyruvate Utilization: 1H NMR Spectroscopy based Consumption and Release Investigations

Motivation: IDH-mutant gliomas are associated with a favorable prognosis; however, the unique metabolic and cellular adaptations distinguishing IDH-mutant from IDH-wild-type gliomas are not yet comprehensively unraveled. Goal(s): Investigate and quantify the metabolic pool and kinetics in IDH-mutant and wild-type gliomas using intracellular metabolite-profiling and Consumption and Release (CORE) dynamic measurements. Approach: Metabolic pool and CORE dynamics were investigated using 1H-NMR (700 MHz), quantifying LN229 intracellular-metabolites together with CORE-measurements using metabolite estimations from Fresh-and-Spent media. Results: IDH mutants showed higher Ki-67 and proliferation rate, significantly elevated intracellular-glutamine and glucose concentrations accompanied-with enhanced consumption of glutamine and glucose, and disrupted Pyruvate utilization in Anaplerotic and TCA-pathways. Impact: 1H-NMR-based investigations and transcriptomic-profiling suggests that IDH-mutant gliomas undergo unique metabolic-adaptations, showing increased glutamine-glutamate dependency, disrupted pyruvate pathways, enhanced release of lactate. These findings indicate Glutamine-addiction in IDH-mutant-gliomas, pointing towards potential therapeutics targeted at glutamine metabolism for management of IDH-mutant-gliomas.