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Ingold, I. ; Berndt, C.* ; Schmitt, S.* ; Doll, S. ; Poschmann, G.* ; Buday, K. ; Roveri, A.* ; Peng, X.* ; Porto Freitas, F. ; Seibt, T.* ; Mehr, L. ; Aichler, M. ; Walch, A.K. ; Lamp, D. ; Jastroch, M. ; Miyamoto, S.* ; Wurst, W. ; Ursini, F.* ; Arnér, E.S.J.* ; Fradejas-Villar, N.* ; Schweizer, U.* ; Zischka, H. ; Friedmann Angeli, J.P.F. ; Conrad, M.

Selenium utilization by GPX4 is required to prevent hydroperoxide-induced ferroptosis.

Cell 172, 409–422.e21 (2018)
Verlagsversion Forschungsdaten DOI PMC
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Acsl4 ; Ferroptosis ; Glutathione Peroxidase ; Gpx4 ; Lipid Peroxidation ; Mouse Genetics ; Selenium ; Selenocysteine ; Selenoproteins ; Trsp; Glutathione-peroxidase 4; Thioredoxin Reductase; Cell-death; Selenoprotein Expression; Embryonic Lethality; Transfer-rna; Selenocysteine; Deficiency; Seizures; Protein
ISSN (print) / ISBN 0092-8674
e-ISSN 1097-4172
Zeitschrift Cell
Quellenangaben Band: 172, Heft: 3, Seiten: 409–422.e21 Artikelnummer: , Supplement: ,
Verlag Cell Press
Verlagsort Cambridge, Mass.
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Metabolism and Cell Death (MCD)
Institute of Developmental Genetics (IDG)
Institute of Diabetes and Cancer (IDC)
Research Unit Analytical Pathology (AAP)
Institute of Diabetes and Obesity (IDO)
Institute of Molecular Toxicology and Pharmacology (TOXI)