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. 2018 Jan 25;172(3):409-422.e21.
doi: 10.1016/j.cell.2017.11.048. Epub 2017 Dec 28.

Selenium Utilization by GPX4 Is Required to Prevent Hydroperoxide-Induced Ferroptosis

Irina Ingold  1 , Carsten Berndt  2 , Sabine Schmitt  3 , Sebastian Doll  1 , Gereon Poschmann  4 , Katalin Buday  1 , Antonella Roveri  5 , Xiaoxiao Peng  6 , Florencio Porto Freitas  1 , Tobias Seibt  7 , Lisa Mehr  1 , Michaela Aichler  8 , Axel Walch  8 , Daniel Lamp  9 , Martin Jastroch  9 , Sayuri Miyamoto  10 , Wolfgang Wurst  11 , Fulvio Ursini  5 , Elias S J Arnér  12 , Noelia Fradejas-Villar  13 , Ulrich Schweizer  13 , Hans Zischka  14 , José Pedro Friedmann Angeli  1 , Marcus Conrad  15
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Free article

Selenium Utilization by GPX4 Is Required to Prevent Hydroperoxide-Induced Ferroptosis

Irina Ingold et al. Cell. .
Free article

Abstract

Selenoproteins are rare proteins among all kingdoms of life containing the 21st amino acid, selenocysteine. Selenocysteine resembles cysteine, differing only by the substitution of selenium for sulfur. Yet the actual advantage of selenolate- versus thiolate-based catalysis has remained enigmatic, as most of the known selenoproteins also exist as cysteine-containing homologs. Here, we demonstrate that selenolate-based catalysis of the essential mammalian selenoprotein GPX4 is unexpectedly dispensable for normal embryogenesis. Yet the survival of a specific type of interneurons emerges to exclusively depend on selenocysteine-containing GPX4, thereby preventing fatal epileptic seizures. Mechanistically, selenocysteine utilization by GPX4 confers exquisite resistance to irreversible overoxidation as cells expressing a cysteine variant are highly sensitive toward peroxide-induced ferroptosis. Remarkably, concomitant deletion of all selenoproteins in Gpx4cys/cys cells revealed that selenoproteins are dispensable for cell viability provided partial GPX4 activity is retained. Conclusively, 200 years after its discovery, a specific and indispensable role for selenium is provided.

Keywords: ACSL4; GPX4; Trsp; ferroptosis; glutathione peroxidase; lipid peroxidation; mouse genetics; selenium; selenocysteine; selenoproteins.

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Comment in

  • An Element of Life.
    Green DR. Green DR. Cell. 2018 Jan 25;172(3):389-390. doi: 10.1016/j.cell.2018.01.003. Cell. 2018. PMID: 29373826
  • Selenium cysteine and epileptic seizures.
    Schibler U. Schibler U. Nat Rev Mol Cell Biol. 2018 Dec;19(12):753. doi: 10.1038/s41580-018-0050-x. Nat Rev Mol Cell Biol. 2018. PMID: 30061711 No abstract available.

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