Journal Article

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

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

2014

Overview

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. Ferroptosis is a form of non-apoptotic cell death with unclear physiological relevance. Conrad and colleagues now report that unrestrained ferroptosis can lead to renal failure. They also identify a small molecule that limits ferroptosis in vivo .

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 49/98 / 631/80/82 / 82/47 / Acute Kidney Injury - pathology / Acute renal failure / Animals / Apoptosis / Arachidonate 12-Lipoxygenase - metabolism / Arachidonate 15-Lipoxygenase - metabolism / Cancer Research / Cardiolipins - metabolism / Cell Biology / Cell Line / Development and progression / Developmental Biology / Gene mutations / Genetic aspects / Glutathione Peroxidase - genetics / Humans / Imidazoles - pharmacology / In Situ Nick-End Labeling / Inactivation / Indoles - pharmacology / Kidney - metabolism / Kidney - pathology / Life Sciences / Lipid Peroxidation / Male / Mice / Mice, Inbred C57BL / Mice, Knockout / Mitochondria - metabolism / Mortality / Oxidation / Peroxidase / Peroxidases - pharmacology / Phosphatidylcholines - metabolism / Phosphatidylethanolamines - metabolism / Properties / Quinoxalines - pharmacology / Reperfusion Injury - pathology / Spiro Compounds - pharmacology / Stem Cells