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

Jose Pedro Friedmann Angeli; Manuela Schneider; Bettina Proneth; Yulia Y Tyurina; Vladimir A Tyurin; Victoria J Hammond; Nadja Herbach; Michaela Aichler; Axel Walch; Elke Eggenhofer; Devaraj Basavarajappa; Olof Rådmark; Sho Kobayashi; Tobias Seibt; Heike Beck; Frauke Neff; Irene Esposito; Rüdiger Wanke; Heidi Förster; Olena Yefremova; Marc Heinrichmeyer; Georg W Bornkamm; Edward K Geissler; Stephen B Thomas; Brent R Stockwell; Valerie B O'Donnell; Valerian E Kagan; Joel A Schick; Marcus Conrad

doi:10.1038/ncb3064

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. Epub 2014 Nov 17.

Authors

Jose Pedro Friedmann Angeli¹, Manuela Schneider², Bettina Proneth¹, Yulia Y Tyurina³, Vladimir A Tyurin³, Victoria J Hammond⁴, Nadja Herbach⁵, Michaela Aichler⁶, Axel Walch⁶, Elke Eggenhofer⁷, Devaraj Basavarajappa⁸, Olof Rådmark⁸, Sho Kobayashi⁹, Tobias Seibt¹, Heike Beck¹⁰, Frauke Neff⁶, Irene Esposito¹¹, Rüdiger Wanke⁵, Heidi Förster¹, Olena Yefremova¹, Marc Heinrichmeyer¹, Georg W Bornkamm¹², Edward K Geissler⁷, Stephen B Thomas¹³, Brent R Stockwell¹³, Valerie B O'Donnell⁴, Valerian E Kagan³, Joel A Schick¹, Marcus Conrad¹

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
PMCID: PMC4894846
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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acute Kidney Injury / pathology*
Animals
Apoptosis*
Arachidonate 12-Lipoxygenase / metabolism
Arachidonate 15-Lipoxygenase / metabolism
Cardiolipins / metabolism
Cell Line
Glutathione Peroxidase / genetics*
Humans
Imidazoles / pharmacology
In Situ Nick-End Labeling
Indoles / pharmacology
Kidney / metabolism
Kidney / pathology
Lipid Peroxidation
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mitochondria / metabolism
Peroxidases / pharmacology
Phosphatidylcholines / metabolism
Phosphatidylethanolamines / metabolism
Phospholipid Hydroperoxide Glutathione Peroxidase
Quinoxalines / pharmacology*
Reperfusion Injury / pathology*
Spiro Compounds / pharmacology*

Substances

Cardiolipins
Imidazoles
Indoles
Phosphatidylcholines
Phosphatidylethanolamines
Quinoxalines
Spiro Compounds
liproxstatin-1
necrostatin-1
phosphatidylethanolamine
Peroxidases
arachidonic acid peroxide peroxidase
Phospholipid Hydroperoxide Glutathione Peroxidase
Glutathione Peroxidase
Alox15 protein, mouse
Arachidonate 12-Lipoxygenase
Arachidonate 15-Lipoxygenase

Grants and funding

P01 HL114453/HL/NHLBI NIH HHS/United States