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. 2015 Jan 30;2(3):e995047.
doi: 10.4161/23723556.2014.995047. eCollection 2015 Jul-Sep.

Glutathione peroxidase 4 (Gpx4) and ferroptosis: what's so special about it?

Marcus Conrad  1 , José Pedro Friedmann Angeli  1
Affiliations

Glutathione peroxidase 4 (Gpx4) and ferroptosis: what's so special about it?

Marcus Conrad et al. Mol Cell Oncol. .

Abstract

The system XC (-)/glutathione/glutathione peroxidase 4 (Gpx4) axis pivotally controls ferroptosis, a recently described form of regulated non-apoptotic cell death. Compelling evidence has established that this route of cell death is not only of high relevance for triggering cancer cell death, but also proves to be amenable for therapeutic intervention to halt ischemia/reperfusion-related diseases.

Keywords: cell death; lipid peroxidation; non-apoptotic cell death; regulated necrosis.

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Figures

Figure 1.
Figure 1.
Biochemical events in the upstream control of ferroptosis. The upstream events controlling ferroptotic signaling are depicted. Cystine, the oxidized form of cysteine (Cys-S-S-Cys), is taken up by the cystine/glutamate antiporter that consists of the 4F2 (Slc3a2) heavy chain and xCT (Slc7a11) light chain. Upon intracellular reduction, cysteine, along with glutamate and glycine, are used for protein and glutathione (GSH) biosynthesis. GSH is synthesized in 2 consecutive steps by the heterodimer γ-glutamylcysteine synthetase (γGCS consists of Gclc and Gclm) and glutathione synthetase (Gss, GS), each step requiring one molecule of ATP. Glutathione peroxidase 4 (Gpx4) is a central GSH-utilizing enzyme and counteracts lipoxygenase (Alox) activities and phospholipid/cardiolipin oxidation events. In the absence of Gpx4, cardiolipin oxidation followed by phospholipid peroxidation causes ferroptosis through still unknown mechanisms. Small-molecule inhibitors of the different players are shown on the right. Abbreviations: BSO, L-buthionine sulfoximine; GSSG, oxidized glutathione; γGlu-Cys, γ-glutamylcysteine.
See this image and copyright information in PMC

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