Selenium Utilization by GPX4 Is Required to Prevent Hydroperoxide-Induced Ferroptosis

Author(s):Show less -

Ingold, Irina ^[1] ; Berndt, Carsten ^[2] ; Schmitt, Sabine ^[3] ; Doll, Sebastian ^[1] ; Poschmann, Gereon ^[4] ; Buday, Katalin ^[1] ; Roveri, Antonella ^[5] ; Peng, Xiaoxiao ^[6] ; Freitas, Florencio Porto ^[1] ; Seibt, Tobias ^[7] ; Mehr, Lisa ^[1] ; Aichler, Michaela ^[8] ; Walch, Axel ^[8] ; Lamp, Daniel ^{[9, 10, 11]} ; Jastroch, Martin ^{[9, 10, 11]} ; Miyamoto, Sayuri ^[12] ; Wurst, Wolfgang ^{[13, 1, 14]} ; Ursini, Fulvio ; Amer, Elias S. J. ^[15] ; Fradejas-Villar, Noelia ^[16] ; Schweizer, Ulrich ^[16] ; Zischka, Hans ^{[3, 17]} ; Angeli, Jose Pedro Friedmann ^{[1, 18]} ; Conrad, Marcus ^[1]

Affiliation:Show less -

^[1] Helmholtz Zentrum Munchen, Inst Dev Genet, D-85764 Neuherberg - Germany

^[2] Heinrich Heine Univ, Med Fac, Dept Neurol, D-40255 Dusseldorf - Germany

^[3] Tech Univ Munich, Inst Toxicol & Environm Hyg, D-80802 Munich - Germany

^[4] Univ Dusseldorf, Mol Prote Lab, Biomed Res Ctr BMFZ, D-40225 Dusseldorf - Germany

^[5] Univ Padua, Dept Mol Med, Padua - Italy

^[6] AstraZeneca, CVMD Translat Med Unit, IMED Biotech Unit, Early Clin Dev, Gothenburg - Sweden

^[7] Klinikum Univ Munchen, Med Klin & Poliklin 4, Dept Nephrol, D-80336 Munich - Germany

^[8] Helmholtz Zentrum Munchen, Res Unit Analyt Pathol, D-85764 Neuherberg - Germany

^[9] Helmholtz Zentrum Munchen, Helmholtz Diabet Ctr, D-85764 Neuherberg - Germany

^[10] Helmholtz Zentrum Munchen, German Diabet Ctr DZD, D-85764 Neuherberg - Germany

^[11] Helmholtz Zentrum Munchen, Inst Diabet & Obes, D-85748 Garching - Germany

^[12] Univ Sao Paulo, Inst Quim, Dept Bioquim, Sao Paulo - Brazil

^[13] German Ctr Neurodegenerat Dis DZNE, D-81377 Munich - Germany

^[14] Tech Univ Munchen Weihenstephan, Chair Dev Genet, Helmholtz Zentrum Munchen, D-85764 Neuherberg - Germany

^[15] Karolinska Inst, Dept Med Biochem & Biophys, Div Biochem, S-17177 Stockholm - Sweden

^[16] Rhein Friedrich Wilhelms Univ Bonn, Inst Biochem & Mol Biol, D-53115 Bonn - Germany

^[17] Helmholtz Zentrum Munchen, Inst Mol Toxicol & Pharmacol, D-85764 Neuherberg - Germany

^[18] Univ Wurzburg, Rudolf Virchow Ctr Expt Biomed, D-97080 Wurzburg - Germany

• Document type: Journal article
• Source: Cell; v. 172, n. 3, p. 409+, JAN 25 2018.
• Web of Science Citations: 87

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 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. (AU)

• FAPESP's process: 13/07937-8 - Redoxome - Redox Processes in Biomedicine
• Grantee: Ohara Augusto
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC