MDM2 and MDMX promote ferroptosis by PPARα-mediated lipid remodeling

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 Q 10 , 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.

The Regulation of Ferroptosis by Tumor Suppressor p53 and its Pathway

“…Although MDM2 and MDM4 are critical negative regulators of p53, many studies have shown that MDM2 and MDM4 also exert oncogenic effects independently of their activities to inhibit p53 function [37,38]. Interestingly, a recent study reported that MDM2 and MDM4 also display a p53-independent function to promote ferroptosis [133]. Both inhibitors of MDM2 (MEL23) and MDM4 (NCS207895) protect cells from ferroptosis induced by erastin and RSL3 through enhancing the levels of ferroptosis suppressor protein 1 (FSP1), an enzyme that reduces coenzyme Q10, an endogenous lipophilic antioxidant, to ubiquinol, which in turn enhances the levels of coenzyme Q10 [133].…”

“…Interestingly, a recent study reported that MDM2 and MDM4 also display a p53-independent function to promote ferroptosis [133]. Both inhibitors of MDM2 (MEL23) and MDM4 (NCS207895) protect cells from ferroptosis induced by erastin and RSL3 through enhancing the levels of ferroptosis suppressor protein 1 (FSP1), an enzyme that reduces coenzyme Q10, an endogenous lipophilic antioxidant, to ubiquinol, which in turn enhances the levels of coenzyme Q10 [133]. Further, the MDM2-MDM4 complex reprograms lipid metabolism by altering the activity of PPARα, leading to enhanced lipid peroxidation and ferroptosis independently of p53 [133].…”

“…Both inhibitors of MDM2 (MEL23) and MDM4 (NCS207895) protect cells from ferroptosis induced by erastin and RSL3 through enhancing the levels of ferroptosis suppressor protein 1 (FSP1), an enzyme that reduces coenzyme Q10, an endogenous lipophilic antioxidant, to ubiquinol, which in turn enhances the levels of coenzyme Q10 [133]. Further, the MDM2-MDM4 complex reprograms lipid metabolism by altering the activity of PPARα, leading to enhanced lipid peroxidation and ferroptosis independently of p53 [133]. These results suggest that cancers with MDM2/MDM4 amplification and/or overexpression might be more sensitive to ferroptosis inducers, which can be tested as a potential therapeutic strategy for these cancers.…”

The Intersection of DNA Damage Response and Ferroptosis—A Rationale for Combination Therapeutics

“…Interestingly, a recent study has suggested that MDM2–MDMX regulates ferroptosis in a p53-independent manner. MDM2 antagonists (nutlin-3 or MEL23) and MDMX inhibitors both protect cells against ferroptosis by increasing FSP1 proteins and levels of coenzyme Q10 [ 87 ]. Furthermore, MDM2–MDMX promotes lipid peroxidation and ferroptosis through lipid reprogramming via PPARα (peroxisome, proliferator-activated receptor α) [ 49 ].…”

The p53 Pathway and Metabolism: The Tree That Hides the Forest

“…Beside the well-recognized role of p53 in ferroptosis, which involves the transcriptional and the non-transcriptional regulation of inducers and regulators of ferroptosis, recent work from Venkatesh et al showed that MDM2 and MDM4 interfere with the ability of cells to build up defenses against lipid peroxidation. Inhibition of MDM2 and/or MDM4 allows cells to accumulate endogenous lipophilic antioxidants such as CoenzymeQ10 (CoQ), an effect mediated by PPARα and FSP1 [ 71 ]. Interestingly, p53-mediated control of the mevalonate pathway has also been shown to contribute to CoQ biosynthesis, suggesting that p53, MDM2, and MDM4 control synergistic metabolic functions converging on this key metabolite [ 72 , 73 ].…”