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

被引：2995

作者：

Angeli, Jose Pedro Friedmann ^{[1
]}

Schneider, Manuela ^{[2
]}

Proneth, Bettina ^{[1
]}

Tyurina, Yulia Y. ^{[3
]}

Tyurin, Vladimir A. ^{[3
]}

Hammond, Victoria J. ^{[4
]}

Herbach, Nadja ^{[5
]}

Aichler, Michaela ^{[6
]}

Walch, Axel ^{[6
]}

Eggenhofer, Elke ^{[7
]}

Basavarajappa, Devaraj ^{[8
]}

Radmark, Olof ^{[8
]}

Kobayashi, Sho ^{[1
,9
]}

Seibt, Tobias ^{[1
]}

Beck, Heike ^{[10
]}

Neff, Frauke ^{[6
]}

Esposito, Irene ^{[11
]}

Wanke, Ruediger ^{[5
]}

Foerster, Heidi ^{[1
]}

Yefremova, Olena ^{[1
]}

Heinrichmeyer, Marc ^{[1
]}

Bornkamm, Georg W. ^{[12
]}

Geissler, Edward K. ^{[7
]}

Thomas, Stephen B. ^{[13
,14
]}

Stockwell, Brent R. ^{[13
,14
]}

O'Donnell, Valerie B. ^{[4
]}

Kagan, Valerian E. ^{[3
]}

Schick, Joel A. ^{[1
]}

Conrad, Marcus ^{[1
]}

机构：

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

[2] Univ Munich, Klinikum Univ Munchen, Inst Stroke & Dementia Res, D-81377 Munich, Germany

[3] Univ Pittsburgh, Dept Environm & Occupat Hlth, Pittsburgh, PA 15219 USA

[4] Cardiff Univ, Sch Med, Dept Infect Immun & Biochem, Cardiff CF14 4XN, S Glam, Wales

[5] Univ Munich, Ctr Clin Vet Med, Inst Vet Pathol, D-80539 Munich, Germany

[6] Helmholtz Zentrum Munchen, Inst Pathol, D-85764 Neuherberg, Germany

[7] Univ Med Ctr Regensburg, Dept Surg, D-93053 Regensburg, Germany

[8] Karolinska Inst, Div Physiol Chem 2, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden

[9] Yamagata Univ, Dept Food & Appl Life Sci, Fac Agr, Tsuruoka, Yamagata 9978555, Japan

[10] Univ Munich, Walter Brendel Ctr Expt Med, Munich Heart Alliance, D-81377 Munich, Germany

[11] Tech Univ Munich, Inst Pathol, D-81675 Munich, Germany

[12] Helmholtz Zentrum Munchen, Inst Clin Mol Biol & Tumor Genet, D-81377 Neuherberg, Germany

[13] Columbia Univ, Howard Hughes Med Inst, Dept Biol Sci, New York, NY 10027 USA

[14] Columbia Univ, Howard Hughes Med Inst, Dept Chem, New York, NY 10027 USA

来源：

NATURE CELL BIOLOGY | 2014年 / 16卷 / 12期

基金：

日本学术振兴会;

关键词：

CELL-DEATH; OXIDATIVE STRESS; CYTOCHROME-C; GLUTATHIONE; IRON; 5-LIPOXYGENASE; PHOSPHOLIPIDS; INFLAMMATION; CARDIOLIPIN; DISRUPTION;

D O I：

10.1038/ncb3064

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：1180 / U120

页数：23

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