MDM2 and MDMX promote ferroptosis by PPARα-mediated lipid remodeling

Genes Dev. 2020 Apr 1;34(7-8):526-543. doi: 10.1101/gad.334219.119. Epub 2020 Feb 20.


MDM2 and MDMX, negative regulators of the tumor suppressor p53, can work separately and as a heteromeric complex to restrain p53's functions. MDM2 also has pro-oncogenic roles in cells, tissues, and animals that are independent of p53. There is less information available about p53-independent roles of MDMX or the MDM2-MDMX complex. We found that MDM2 and MDMX facilitate ferroptosis in cells with or without p53. Using small molecules, RNA interference reagents, and mutant forms of MDMX, we found that MDM2 and MDMX, likely working in part as a complex, normally facilitate ferroptotic death. We observed that MDM2 and MDMX alter the lipid profile of cells to favor ferroptosis. Inhibition of MDM2 or MDMX leads to increased levels of FSP1 protein and a consequent increase in the levels of coenzyme Q10, an endogenous lipophilic antioxidant. This suggests that MDM2 and MDMX normally prevent cells from mounting an adequate defense against lipid peroxidation and thereby promote ferroptosis. Moreover, we found that PPARα activity is essential for MDM2 and MDMX to promote ferroptosis, suggesting that the MDM2-MDMX complex regulates lipids through altering PPARα activity. These findings reveal the complexity of cellular responses to MDM2 and MDMX and suggest that MDM2-MDMX inhibition might be useful for preventing degenerative diseases involving ferroptosis. Furthermore, they suggest that MDM2/MDMX amplification may predict sensitivity of some cancers to ferroptosis inducers.

Keywords: CoQ10; FSP1; MDM2; MDMX; PPARα; cancer; ferroptosis; lipid metabolism; p53-independent.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Brain / metabolism
  • Brain / physiopathology
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Ferroptosis / genetics*
  • Glioblastoma / physiopathology
  • HCT116 Cells
  • Humans
  • Lipid Metabolism / genetics*
  • Mutation
  • PPAR alpha / metabolism*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors
  • Proto-Oncogene Proteins c-mdm2 / genetics
  • Proto-Oncogene Proteins c-mdm2 / metabolism*
  • RNA Interference
  • Rats
  • Tumor Suppressor Protein p53 / metabolism
  • Ubiquinone / analogs & derivatives
  • Ubiquinone / metabolism


  • Cell Cycle Proteins
  • MDM4 protein, human
  • PPAR alpha
  • Proto-Oncogene Proteins
  • Tumor Suppressor Protein p53
  • Ubiquinone
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • coenzyme Q10