IDH1 mutation inhibits differentiation of astrocytes and glioma cells with low OGDH expression by disturbing α-ketoglutarate-related metabolism and epigenetic modification

Abstract

Isocitrate dehydrogenase (IDH) mutations frequently occurr in lower-grade gliomas and secondary glioblastomas. Mutant IDHs exhibit a gain-of-function activity, leading to the production of D-2-hydroxyglutarate (D-2HG) by reducing α-ketoglutarate (α-KG), a central player in metabolism and epigenetic modifications. However, the role of α-KG homeostasis in IDH-mutated gliomagenesis remains elusive. In this study, we found that low expression of oxoglutarate dehydrogenase (OGDH) is a common feature in IDH-mutated gliomas, as well as in astrocytes. This low expression of OGDH results in the accumulation of α-KG and promotes astrocyte maturation. However, IDH1 mutation significantly reduces α-KG levels, and increases glutaminolysis and DNA/histone methylation in astrocytes. These metabolic and epigenetic alterations inhibit astrocyte maturation, and lead to cortical dysplasia in mice. Moreover, our results also indicated that reduced OGDH expression can promote the differentiation of glioma cells, while IDH1 mutations impeded the differentiation of glioma cells with low OGDH by reducing the accumulation of α-K and increasing glutaminolysis. Finally, we found that L-glutamine increased α-KG levels and augmented the differentiation-promoting effects of AGI5198, an IDH1-mutant inhibitor, in IDH1-mutant glioma cells. Collectively, this study reveals that low OGDH expression is a crucial metabolic characteristic of IDH-mutant gliomas, providing a potential strategy for the treatment of IDH-mutant gliomas by targeting α-KG homeostasis.