IDH1 mutations alter citric acid cycle metabolism and increase dependence on oxidative mitochondrial metabolism

Cancer Res. 2014 Jun 15;74(12):3317-31. doi: 10.1158/0008-5472.CAN-14-0772-T. Epub 2014 Apr 22.


Oncogenic mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) occur in several types of cancer, but the metabolic consequences of these genetic changes are not fully understood. In this study, we performed (13)C metabolic flux analysis on a panel of isogenic cell lines containing heterozygous IDH1/2 mutations. We observed that under hypoxic conditions, IDH1-mutant cells exhibited increased oxidative tricarboxylic acid metabolism along with decreased reductive glutamine metabolism, but not IDH2-mutant cells. However, selective inhibition of mutant IDH1 enzyme function could not reverse the defect in reductive carboxylation activity. Furthermore, this metabolic reprogramming increased the sensitivity of IDH1-mutant cells to hypoxia or electron transport chain inhibition in vitro. Lastly, IDH1-mutant cells also grew poorly as subcutaneous xenografts within a hypoxic in vivo microenvironment. Together, our results suggest therapeutic opportunities to exploit the metabolic vulnerabilities specific to IDH1 mutation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Cell Hypoxia
  • Citric Acid Cycle*
  • Enzyme Inhibitors / pharmacology
  • Glutamine / metabolism
  • HCT116 Cells
  • Humans
  • Isocitrate Dehydrogenase / antagonists & inhibitors
  • Isocitrate Dehydrogenase / genetics*
  • Isocitrate Dehydrogenase / metabolism
  • Mice
  • Mitochondria / metabolism*
  • Mutation, Missense*
  • Oxidation-Reduction
  • Stress, Physiological
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Glutamine
  • IDH2 protein, human
  • Isocitrate Dehydrogenase
  • IDH1 protein, human