Oncogenic R132 IDH1 Mutations Limit NADPH for De Novo Lipogenesis through (D)2-Hydroxyglutarate Production in Fibrosarcoma Sells

Mehmet G. Badur, Thangaselvam Muthusamy, Seth J. Parker, Shenghong Ma, Samuel K. McBrayer, Thekla Cordes, Jose H. Magana, Kun Liang Guan, Christian M. Metallo

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Neomorphic mutations in NADP-dependent isocitrate dehydrogenases (IDH1 and IDH2) contribute to tumorigenesis in several cancers. Although significant research has focused on the hypermethylation phenotypes associated with (D)2-hydroxyglutarate (D2HG) accumulation, the metabolic consequences of these mutations may also provide therapeutic opportunities. Here we apply flux-based approaches to genetically engineered cell lines with an endogenous IDH1 mutation to examine the metabolic impacts of increased D2HG production and altered IDH flux as a function of IDH1 mutation or expression. D2HG synthesis in IDH1-mutant cells consumes NADPH at rates similar to de novo lipogenesis. IDH1-mutant cells exhibit increased dependence on exogenous lipid sources for in vitro growth, as removal of medium lipids slows growth more dramatically in IDH1-mutant cells compared with those expressing wild-type or enzymatically inactive alleles. NADPH regeneration may be limiting for lipogenesis and potentially redox homeostasis in IDH1-mutant cells, highlighting critical links between cellular biosynthesis and redox metabolism. Badur et al. apply metabolic flux analysis to understand how oncogenic mutations in IDH1 alter redox metabolism. Production of (D)2-hydroxyglutarate (D2HG) consumes NADPH at levels similar to de novo lipogenesis, and removal of lipids compromises in vitro growth of IDH1-mutant cells.

Original languageEnglish (US)
Pages (from-to)1018-1026.e4
JournalCell Reports
Volume25
Issue number4
DOIs
StatePublished - Oct 23 2018
Externally publishedYes

Keywords

  • 2-hydroxyglutrate (2HG)
  • IDH1
  • IDH2
  • NADPH
  • cancer
  • deuterium
  • metabolic flux analysis
  • metabolism
  • redox metabolism

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Badur, M. G., Muthusamy, T., Parker, S. J., Ma, S., McBrayer, S. K., Cordes, T., Magana, J. H., Guan, K. L., & Metallo, C. M. (2018). Oncogenic R132 IDH1 Mutations Limit NADPH for De Novo Lipogenesis through (D)2-Hydroxyglutarate Production in Fibrosarcoma Sells. Cell Reports, 25(4), 1018-1026.e4. https://doi.org/10.1016/j.celrep.2018.09.074