Journal Article

DZNE-2020-06076

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Selenium Utilization by GPX4 Is Required to Prevent Hydroperoxide-Induced Ferroptosis.

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. ; Lamp, D. ; Jastroch, M. ; Miyamoto, S. ; Wurst, W.DZNE* ; Ursini, F. ; Arnér, E. S. J. ; Fradejas-Villar, N. ; Schweizer, U. ; Zischka, H. ; Friedmann Angeli, J. P. ; Conrad, M. (Corresponding author)

2018
Elsevier New York, NY

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Please use a persistent id in citations: doi:10.1016/j.cell.2017.11.048

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.

Keyword(s): Animals (MeSH) ; Apoptosis (MeSH) ; Cell Survival (MeSH) ; Cells, Cultured (MeSH) ; Female (MeSH) ; Glutathione Peroxidase: genetics (MeSH) ; Glutathione Peroxidase: metabolism (MeSH) ; HEK293 Cells (MeSH) ; Humans (MeSH) ; Hydrogen Peroxide: toxicity (MeSH) ; Interneurons: metabolism (MeSH) ; Lipid Peroxidation (MeSH) ; Male (MeSH) ; Mice (MeSH) ; Mice, Inbred C57BL (MeSH) ; Phospholipid Hydroperoxide Glutathione Peroxidase (MeSH) ; Seizures: etiology (MeSH) ; Seizures: metabolism (MeSH) ; Selenium: metabolism (MeSH) ; Hydrogen Peroxide ; Phospholipid Hydroperoxide Glutathione Peroxidase ; Glutathione Peroxidase ; glutathione peroxidase 4, mouse ; Selenium

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Contributing Institute(s):

1. Genome Engineering (AG Wurst)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2018

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 60 ; JCR ; Nationallizenz ; SCOPUS ; Web of Science Core Collection

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