TY  - JOUR
AU  - Ingold, Irina
AU  - Berndt, Carsten
AU  - Schmitt, Sabine
AU  - Doll, Sebastian
AU  - Poschmann, Gereon
AU  - Buday, Katalin
AU  - Roveri, Antonella
AU  - Peng, Xiaoxiao
AU  - Porto Freitas, Florencio
AU  - Seibt, Tobias
AU  - Mehr, Lisa
AU  - Aichler, Michaela
AU  - Walch, Axel
AU  - Lamp, Daniel
AU  - Jastroch, Martin
AU  - Miyamoto, Sayuri
AU  - Wurst, Wolfgang
AU  - Ursini, Fulvio
AU  - Arnér, Elias S J
AU  - Fradejas-Villar, Noelia
AU  - Schweizer, Ulrich
AU  - Zischka, Hans
AU  - Friedmann Angeli, José Pedro
AU  - Conrad, Marcus
TI  - Selenium Utilization by GPX4 Is Required to Prevent Hydroperoxide-Induced Ferroptosis.
JO  - Cell
VL  - 172
IS  - 3
SN  - 0092-8674
CY  - New York, NY
PB  - Elsevier
M1  - DZNE-2020-06076
SP  - 409-422.e21
PY  - 2018
AB  - 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.
KW  - Animals
KW  - Apoptosis
KW  - Cell Survival
KW  - Cells, Cultured
KW  - Female
KW  - Glutathione Peroxidase: genetics
KW  - Glutathione Peroxidase: metabolism
KW  - HEK293 Cells
KW  - Humans
KW  - Hydrogen Peroxide: toxicity
KW  - Interneurons: metabolism
KW  - Lipid Peroxidation
KW  - Male
KW  - Mice
KW  - Mice, Inbred C57BL
KW  - Phospholipid Hydroperoxide Glutathione Peroxidase
KW  - Seizures: etiology
KW  - Seizures: metabolism
KW  - Selenium: metabolism
KW  - Hydrogen Peroxide (NLM Chemicals)
KW  - Phospholipid Hydroperoxide Glutathione Peroxidase (NLM Chemicals)
KW  - Glutathione Peroxidase (NLM Chemicals)
KW  - glutathione peroxidase 4, mouse (NLM Chemicals)
KW  - Selenium (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:29290465
DO  - DOI:10.1016/j.cell.2017.11.048
UR  - https://pub.dzne.de/record/139754
ER  -