2. Academic Validation
  3. The oncometabolite 2-hydroxyglutarate produced by mutant IDH1 sensitizes cells to ferroptosis

The oncometabolite 2-hydroxyglutarate produced by mutant IDH1 sensitizes cells to ferroptosis

  • Cell Death Dis. 2019 Oct 7;10(10):755. doi: 10.1038/s41419-019-1984-4.
Tian-Xiang Wang 1,  Jun-Yun Liang 1,  Cheng Zhang 1,  Yue Xiong 2,  Kun-Liang Guan 3,  Hai-Xin Yuan 4
Affiliations

Affiliations

  • 1 The Fifth People's Hospital of Shanghai and the Molecular and Cell Biology Research Lab of the Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
  • 2 Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
  • 3 Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, California, USA.
  • 4 The Fifth People's Hospital of Shanghai and the Molecular and Cell Biology Research Lab of the Institutes of Biomedical Sciences, Fudan University, Shanghai, China. [email protected].
PMID: 31591388 DOI: 10.1038/s41419-019-1984-4
Abstract

Ferroptosis is a non-apoptotic form of cell death characterized by the iron-dependent lipid peroxidation and is implicated in several human pathologies, such as tissue ischemia, neurodegeneration, and Cancer. Ferroptosis appears to be high cell-context dependent and the regulation of Ferroptosis by physiological or pathological conditions are unclear. Here, we report that tumor-derived IDH1 mutation sensitizes cells to Ferroptosis. Deletion of the mutant IDH1 allele in IDH1 heterozygous tumor cells or pharmacological inhibition of mutant IDH1 to produce the oncometabolite D-2-hydroxyglutarate (D-2-HG) confers resistance to erastin-induced Ferroptosis. Conversely, ectopic expression of mutant IDH1 or treatment of cells with cell-permeable D-2-HG promotes the accumulation of lipid Reactive Oxygen Species (ROS) and subsequently Ferroptosis. Mechanistically, mutant IDH1 reduces the protein level of the Glutathione Peroxidase 4 (GPX4), a key Enzyme in removing lipid ROS and Ferroptosis, and promotes depletion of glutathione. Our results uncover a new role of mutant IDH1 and 2-HG in Ferroptosis.

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