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

Mehmet G Badur1, Thangaselvam Muthusamy1, Seth J Parker1

  • 1Department of Bioengineering, University of California, San Diego, La Jolla, CA 92037, USA.

Cell Reports
|October 26, 2018
PubMed

Insights

Neomorphic mutations in isocitrate dehydrogenases (IDH1/2) drive cancer. IDH1-mutant cells show increased reliance on lipids due to altered metabolism and NADPH consumption, offering potential therapeutic targets.

Area of Science:

  • Biochemistry
  • Cancer Metabolism
  • Molecular Biology

Background:

  • Neomorphic mutations in isocitrate dehydrogenases (IDH1 and IDH2) are implicated in various cancers.
  • Research has focused on hypermethylation and (D)2-hydroxyglutarate (D2HG) accumulation, but metabolic consequences offer therapeutic avenues.

Purpose of the Study:

  • To investigate the metabolic impacts of IDH1 mutations and D2HG production using flux-based approaches.
  • To examine how IDH1 mutation or expression affects cellular metabolism and growth.

Main Methods:

  • Utilized genetically engineered cell lines with endogenous IDH1 mutations.
  • Applied flux-based approaches to analyze metabolic alterations.
  • Assessed cell growth dependence on exogenous lipids under varying conditions.

Main Results:

  • D2HG synthesis in IDH1-mutant cells consumes NADPH at rates comparable to de novo lipogenesis.
  • IDH1-mutant cells display heightened dependence on exogenous lipids for in vitro growth.
  • NADPH regeneration appears limited in IDH1-mutant cells, impacting lipogenesis and redox homeostasis.

Conclusions:

  • IDH1 mutations create critical links between cellular biosynthesis and redox metabolism.
  • Altered metabolic pathways and NADPH consumption in IDH1-mutant cells present potential therapeutic vulnerabilities.
  • Targeting lipid metabolism or NADPH regeneration could be a strategy against IDH1-mutant cancers.
Keywords:
2-hydroxyglutrate (2HG)IDH1IDH2NADPHcancerdeuteriummetabolic flux analysismetabolismredox metabolism

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