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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)
Publ. Version/Full Text Research data DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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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Publication type Article: Journal article
Document type Scientific Article
Keywords 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
Language english
Publication Year 2018
Prepublished in Year 2017
HGF-reported in Year 2017
ISSN (print) / ISBN 0092-8674
e-ISSN 1097-4172
Journal Cell
Quellenangaben Volume: 172, Issue: 3, Pages: 409–422.e21 Article Number: , Supplement: ,
Publisher Cell Press
Publishing Place Cambridge, Mass.
Reviewing status Peer reviewed
Institute(s) 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 (TOX)
POF-Topic(s) 30203 - Molecular Targets and Therapies
30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
90000 - German Center for Diabetes Research
30205 - Bioengineering and Digital Health
30204 - Cell Programming and Repair
Research field(s) Genetics and Epidemiology
Helmholtz Diabetes Center
Enabling and Novel Technologies
PSP Element(s) G-506900-001
G-500500-004
G-501900-253
G-500390-001
G-501900-221
G-500500-001
G-505200-003
G-508100-030
DOI 10.1016/j.cell.2017.11.048
WOS ID WOS:000423447600004
Scopus ID 85041924851
PubMed ID 29290465
Erfassungsdatum 2018-01-03
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