Peroxisome proliferator-activated receptor δ rescues xCT-deficient cells from ferroptosis by targeting peroxisomes - 09/10/21
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Abstract |
Ferroptosis is a recently recognized process of cell death characterized by accumulation of iron-dependent lipid peroxides. Herein, we demonstrate that peroxisome proliferator-activated receptor δ (PPARδ) inhibits ferroptosis of mouse embryonic fibroblasts (MEFs) derived from cysteine/glutamate transporter (xCT)-knockout mice. Activation of PPARδ by the specific ligand GW501516 led to a dose-dependent decrease in ferroptotic cell death triggered by xCT deficiency, along with decreased levels of intracellular iron accumulation and lipid peroxidation. These effects of GW501516 were abolished by PPARδ-targeting small interfering RNA (siRNA) and the PPARδ inhibitor GSK0660, indicating that PPARδ inhibits xCT deficiency-induced ferroptosis. In addition, GW501516-activated PPARδ time- and dose-dependently upregulated catalase expression at both the mRNA and protein levels. This PPARδ-mediated upregulation of catalase was markedly attenuated in cells treated with PPARδ-targeting siRNA and GSK0660, indicating that expression of catalase is dependent on PPARδ. Consistently, the effects of GW501516 on ferroptosis of xCT-deficient MEFs were counteracted in the presence of 3-amino-1,2,4-triazole, a specific inhibitor of catalase, suggesting that catalase is essential for the effect of PPARδ on ferroptosis triggered by xCT deficiency. GW501516-activated PPARδ stabilized peroxisomes through catalase upregulation by targeting peroxisomal hydrogen peroxide-mediated lysosomal rupture, which led to ferroptosis of xCT-deficient MEFs. Collectively, these results demonstrate that PPARδ modulates ferroptotic signals in xCT-deficient MEFs by regulating catalase expression.
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Highlights |
• | PPARδ rescues MEFs from xCT deficiency which triggers ferroptotic cell death. |
• | PPARδ upregulates the expression of catalase, an oxidoreductase typically expressed in peroxisomes. |
• | PPARδ stabilizes the peroxisomes through cellular redox homeostasis. |
• | PPARδ prevents lysosomal rupture by quenching peroxisomal hydrogen peroxide. |
Abbreviations : 2-ME, 3-AT, AO, FoxO3, GPX4, GSH, HO-1, MEFs, NF-Y, OCT-1, PPARδ, ROS, siRNA, SOD, SP1, Trx1, xCT, ZnPPIX
Keywords : Catalase, Ferroptosis, Peroxisome proliferator-activated receptor δ, Reactive oxygen species, XCT
Plan
Vol 143
Article 112223- novembre 2021 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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