2. Academic Validation
  3. MDM2 and MDMX promote ferroptosis by PPARα-mediated lipid remodeling

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.
Divya Venkatesh 1,  Nicholas A O'Brien 1,  Fereshteh Zandkarimi 1,  David R Tong 1,  Michael E Stokes 1,  Denise E Dunn 2,  Everett S Kengmana 1,  Allegra T Aron 3,  Alyssa M Klein 4,  Joleen M Csuka 1,  Sung-Hwan Moon 1,  Marcus Conrad 5,  Christopher J Chang 3 6,  Donald C Lo 2,  Angelo D'Alessandro 7,  Carol Prives 1,  Brent R Stockwell 1 8
Affiliations

Affiliations

  • 1 Department of Biological Sciences, Columbia University, New York, New York 10027, USA.
  • 2 Center for Drug Discovery, Department of Neurobiology, Duke University Medical Center, Durham, North Carolina 27710, USA.
  • 3 Department of Chemistry, University of California at Berkeley, Berkeley, California 94720, USA.
  • 4 Integrated Program in Cellular, Molecular, and Biomedical Studies, Columbia University, New York, New York 10032, USA.
  • 5 Helmholtz Zentrum München, Institute of Metabolism and Cell Death, Neuherberg 85764, Germany.
  • 6 Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, California 94720, USA.
  • 7 Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, Colorado 80045, USA.
  • 8 Department of Chemistry, Columbia University, New York, New York 10027, USA.
PMID: 32079652 DOI: 10.1101/gad.334219.119
Abstract

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.

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