Rethinking carbon utilization in human cells

Hosted by the Department of Chemical Engineering Abstract Quantitative, systems-based approaches using isotopic tracers and mass spectrometry are effective tools for the identification of pathways and fluxes specifically utilized by proliferating cells. In response to genetic transformations or signals from the microenvironment, cells reprogram their metabolism to survive and proliferate. As a result, detailed analyses are required to understand how central carbon metabolism is regulated under physiologically relevant conditions. Acetyl coenzyme A (AcCoA) is the central biosynthetic precursor for fatty acid synthesis and protein acetylation, and in the conventional view of metabolism, AcCoA is thought to be generated primarily from glucose carbon via the citrate shuttle. Using 13C Metabolic Flux Analysis (MFA) we show that human cells employ reductive metabolism of glutamine to synthesize AcCoA for lipid synthesis. This reaction is catalyzed by isocitrate dehydrogenase 1 (IDH1), which competes for substrate with alpha-ketoglutarate (KG)-dependent dioxygenases in the cytosol. Furthermore, cancer cell lines grown under hypoxia rely almost entirely on the reductive carboxylation of glutamine-derived KG for lipogenesis. This metabolic "switch" is mediated, in part, by hypoxia inducible factor (HIF) stabilization and also triggered by loss of the von Hippel-Lindau tumor suppressor protein. These results fundamentally alter our understanding of cell metabolism and identify a critical role of O2 in regulating carbon utilization in human cells.