Redox Homeostasis and Beyond: The Role of Wild-Type Isocitrate Dehydrogenases for the Pathogenesis of Glioblastoma

Significance: Glioblastoma is an aggressive and devastating brain tumor characterized by a dismal prognosis and resistance to therapeutic intervention. To support catabolic processes critical for unabated cellular growth and defend against harmful reactive oxygen species, glioblastoma tumors upregulate the expression of wild-type isocitrate dehydrogenases (IDHs). IDH enzymes catalyze the oxidative decarboxylation of isocitrate to a-ketoglutarate (a-KG), NAD(P)H, and CO₂. On molecular levels, IDHs epigenetically control gene expression through effects on a-KG-dependent dioxygenases, maintain redox balance, and promote anaplerosis by providing cells with NADPH and precursor substrates for macromolecular synthesis. Recent Advances: While gain-of-function mutations in IDH1 and IDH2 represent one of the most comprehensively studied mechanisms of IDH pathogenic effects, recent studies identified wild-type IDHs as critical regulators of normal organ physiology and, when transcriptionally induced or down regulated, as contributing to glioblastoma progression. Critical Issues: Here, we will discuss molecular mechanisms of how wild-type IDHs control glioma pathogenesis, including the regulation of oxidative stress and de novo lipid biosynthesis, and provide an overview of current and future research directives that aim to fully characterize wild-type IDH-driven metabolic reprogramming and its contribution to the pathogenesis of glioblastoma. Future Directions: Future studies are required to further dissect mechanisms of metabolic and epigenomic reprogramming in tumors and the tumor microenvironment, and to develop pharmacological approaches to inhibit wild-type IDH function. Antioxid. Redox Signal. 39, 923–941.