2. Academic Validation
  3. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice

Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice

  • Nat Cell Biol. 2014 Dec;16(12):1180-91. doi: 10.1038/ncb3064.
Jose Pedro Friedmann Angeli 1,  Manuela Schneider 2,  Bettina Proneth 1,  Yulia Y Tyurina 3,  Vladimir A Tyurin 3,  Victoria J Hammond 4,  Nadja Herbach 5,  Michaela Aichler 6,  Axel Walch 6,  Elke Eggenhofer 7,  Devaraj Basavarajappa 8,  Olof Rådmark 8,  Sho Kobayashi 9,  Tobias Seibt 1,  Heike Beck 10,  Frauke Neff 6,  Irene Esposito 11,  Rüdiger Wanke 5,  Heidi Förster 1,  Olena Yefremova 1,  Marc Heinrichmeyer 1,  Georg W Bornkamm 12,  Edward K Geissler 7,  Stephen B Thomas 13,  Brent R Stockwell 13,  Valerie B O'Donnell 4,  Valerian E Kagan 3,  Joel A Schick 1,  Marcus Conrad 1
Affiliations

Affiliations

  • 1 Helmholtz Zentrum München, Institute of Developmental Genetics, Ingolstädter Landstr. 1 85764 Neuherberg, Germany.
  • 2 Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University Munich, Marchioninistr. 15 81377 Munich, Germany.
  • 3 Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA.
  • 4 Department of Infection, Immunity and Biochemistry, School of Medicine, Cardiff University, Heath Park Cardiff CF14 4XN, UK.
  • 5 Institute of Veterinary Pathology, Center for Clinical Veterinary Medicine, Ludwig-Maximilians-University Munich, Veterinaerstr. 13 80539 Munich, Germany.
  • 6 Institute of Pathology, Helmholtz Zentrum München, Ingolstädter Landstr. 1 85764 Neuherberg, Germany.
  • 7 Department of Surgery, University Medical Center of Regensburg, Franz-Josef-Strauss Allee 11 93053 Regensburg, Germany.
  • 8 Department of Medical Biochemistry and Biophysics, Division of Physiological Chemistry II, Karolinska Institutet, S-17177 Stockholm, Sweden.
  • 9 1] Helmholtz Zentrum München, Institute of Developmental Genetics, Ingolstädter Landstr. 1 85764 Neuherberg, Germany [2] Department of Food and Applied Life Sciences, Faculty of Agriculture, Yamagata University, Tsuruoka, Yamagata 997-8555, Japan.
  • 10 Walter Brendel Centre of Experimental Medicine, Munich Heart Alliance, Ludwig-Maximilians-University, Marchioninistr. 15 81377 Munich, Germany.
  • 11 Institute of Pathology, Technische Universität München, Ismaningerstr. 22 81675 Munich, Germany.
  • 12 Institute of Clinical Molecular Biology and Tumor Genetics, Helmholtz Zentrum München, Marchioninistr. 25 81377 Munich, Germany.
  • 13 Department of Biological Sciences and Department of Chemistry, Howard Hughes Medical Institute, Columbia University, 550 West 120th Street, Northwest Corner Building, MC 4846 New York, New York 10027, USA.
PMID: 25402683 DOI: 10.1038/ncb3064
Abstract

Ferroptosis is a non-apoptotic form of cell death induced by small molecules in specific tumour types, and in engineered cells overexpressing oncogenic Ras. Yet, its relevance in non-transformed cells and tissues is unexplored and remains enigmatic. Here, we provide direct genetic evidence that the knockout of Glutathione Peroxidase 4 (Gpx4) causes cell death in a pathologically relevant form of Ferroptosis. Using inducible Gpx4(-/-) mice, we elucidate an essential role for the glutathione/Gpx4 axis in preventing lipid-oxidation-induced acute renal failure and associated death. We furthermore systematically evaluated a library of small molecules for possible Ferroptosis inhibitors, leading to the discovery of a potent spiroquinoxalinamine derivative called Liproxstatin-1, which is able to suppress Ferroptosis in cells, in Gpx4(-/-) mice, and in a pre-clinical model of ischaemia/reperfusion-induced hepatic damage. In sum, we demonstrate that Ferroptosis is a pervasive and dynamic form of cell death, which, when impeded, promises substantial cytoprotection.

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