1. Selenium utilization by GPX4 is required to prevent hydroperoxide-induced ferroptosis
- Author
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Martin Jastroch, Florencio Porto Freitas, Carsten Berndt, Daniel Lamp, Marcus Conrad, Antonella Roveri, Sabine Schmitt, Ulrich Schweizer, Lisa Mehr, Wolfgang Wurst, Fulvio Ursini, Axel Walch, Katalin Buday, Elias S.J. Arnér, Tobias Seibt, Xiaoxiao Peng, Sebastian Doll, José Pedro Friedmann Angeli, Noelia Fradejas-Villar, Michaela Aichler, Irina Ingold, Gereon Poschmann, Sayuri Miyamoto, and Hans Zischka
- Subjects
0301 basic medicine ,Male ,Apoptosis ,metabolism [Selenium] ,ACSL4 ,GPX4 ,Trsp ,ferroptosis ,glutathione peroxidase ,lipid peroxidation ,mouse genetics ,selenium ,selenocysteine ,selenoproteins ,glutathione peroxidase 4, mouse ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Acsl4 ,Ferroptosis ,Glutathione Peroxidase ,Gpx4 ,Lipid Peroxidation ,Mouse Genetics ,Selenium ,Selenocysteine ,Selenoproteins ,Cells, Cultured ,metabolism [Interneurons] ,chemistry.chemical_classification ,integumentary system ,Glutathione peroxidase ,etiology [Seizures] ,Amino acid ,Biochemistry ,Female ,Cell Survival ,metabolism [Seizures] ,genetics [Glutathione Peroxidase] ,chemistry.chemical_element ,Biology ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Interneurons ,Seizures ,Animals ,Humans ,Viability assay ,ddc:610 ,Hydrogen Peroxide ,toxicity [Hydrogen Peroxide] ,PROTEÍNAS ,Phospholipid Hydroperoxide Glutathione Peroxidase ,Mice, Inbred C57BL ,metabolism [Glutathione Peroxidase] ,030104 developmental biology ,HEK293 Cells ,chemistry ,Selenoprotein ,030217 neurology & neurosurgery ,Cysteine - Abstract
Selenoproteins are rare proteins among all kingdoms of life containing the 21 st 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 Gpx4 cys/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. The trace element selenium protects a critical population of interneurons from ferroptotic cell death.
- Published
- 2018