IDH1, lipid metabolism and cancer: Shedding new light on old ideas

Since the initial discovery of mutations in the isocitrate dehydrogenase 1 (IDH1) gene in a large subset of human low-grade gliomas and acute myelogenous leukemia (AML), much interest focused on the function of IDH1 and on the relationship between mutations in IDH1 and tumor progression. To date, mutations in the IDH1 gene have been found in numerous cancers with the highest frequencies occurring in gliomas, chondrosarcomas/enchondromas and cholangiocarcinomas.

IDH1 was first described in the scientific literature as early as 1950. Early researchers proposed that the enzyme likely functions in cellular lipid metabolism based on the observation that the enzymatic reaction produces NADPH and partially localizes to peroxisomes. This article highlights the studies implicating IDH1 in cytoplasmic and peroxisomal lipid metabolism from the early researchers to the recent studies examining mutant IDH1(R132), the most common IDH1 mutation found in cancer.

While a role for IDH1 in lipid biosynthesis in the liver and adipose tissue is now established, a role in lipid metabolism in the brain and tumors is beginning to be examined. The recent discoveries that IDH1(R132H) interferes with the metabolism of phospholipids in gliomas and that IDH1 activity could participate in the synthesis of acetyl-CoA from glutamine in hypoxic tumors highlight roles for IDH1 in lipid metabolism in a broad spectrum of tissues.

Interferences in cytoplasmic and peroxisomal lipid metabolism by IDH1(R132) may contribute to the more favorable clinical outcome in patients whose tumors express mutations in the IDH1 gene.