Lipid Peroxidation-Dependent Cell Death Regulated by GPx4 and Ferroptosis
Top Cited Papers
- 1 January 2016
- book chapter
- review article
- Published by Springer Science and Business Media LLC in Current Topics in Microbiology and Immunology
- Vol. 403, 143-170
- https://doi.org/10.1007/82_2016_508
Abstract
Glutathione peroxidase 4 (Phospholipid hydroperoxide glutathione peroxidase, PHGPx) can directly reduce phospholipid hydroperoxide. Depletion of GPx4 induces lipid peroxidation-dependent cell death in embryo, testis, brain, liver, heart, and photoreceptor cells of mice. Administration of vitamin E in tissue specific GPx4 KO mice restored tissue damage in testis, liver, and heart. These results indicate that suppression of phospholipid peroxidation is essential for cell survival in normal tissues in mice. Ferroptosis is an iron-dependent non-apoptotic cell death that can elicited by pharmacological inhibiting the cystine/glutamate antiporter, system Xc− (type I) or directly binding and loss of activity of GPx4 (Type II) in cancer cells with high level RAS-RAF-MEK pathway activity or p53 expression, but not in normal cells. Ferroptosis by Erastin (Type I) and RSL3 (RAS-selective lethal 3, Type II) treatment was suppressed by an iron chelator, vitamin E and Ferrostatin-1, antioxidant compound. GPx4 can regulate ferroptosis by suppression of phospholipid peroxidation in erastin and RSL3-induced ferroptosis. Recent works have identified several regulatory factors of erastin and RSL3-induced ferroptosis. In our established GPx4-deficient MEF cells, depletion of GPx4 induce iron and 15LOX-independent lipid peroxidation at 26 h and caspase-independent cell death at 72 h, whereas erastin and RSL3 treatment resulted in iron-dependent ferroptosis by 12 h. These results indicated the possibility that the mechanism of GPx4-depleted cell death might be different from that of ferroptosis induced by erastin and RSL3.This publication has 83 references indexed in Scilit:
- RSL3 and Erastin differentially regulate redox signaling to promote Smac mimetic-induced cell deathOncotarget, 2016
- Glutathione peroxidase 4 and vitamin E cooperatively prevent hepatocellular degenerationRedox Biology, 2016
- Glutathione peroxidase 4 prevents necroptosis in mouse erythroid precursorsBlood, 2016
- NCOA4 Deficiency Impairs Systemic Iron HomeostasisCell Reports, 2016
- Erastin sensitizes glioblastoma cells to temozolomide by restraining xCT and cystathionine-γ-lyase functionOncology Reports, 2015
- Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in miceNature, 2014
- The Nuclear Form of Phospholipid Hydroperoxide Glutathione Peroxidase Is a Protein Thiol Peroxidase Contributing to Sperm Chromatin StabilityMolecular and Cellular Biology, 2005
- Abnormal Uterus with Polycysts, Accumulation of Uterine Prostaglandins, and Reduced Fertility in Mice Heterozygous for Acyl-CoA Synthetase 4 DeficiencyBiochemical and Biophysical Research Communications, 2001
- Mitochondrial Phospholipid Hydroperoxide Glutathione Peroxidase Plays a Major Role in Preventing Oxidative Injury to CellsPublished by Elsevier BV ,1999
- Import into Mitochondria of Phospholipid Hydroperoxide Glutathione Peroxidase Requires a Leader SequenceBiochemical and Biophysical Research Communications, 1996