Two independent pathways of regulated necrosis mediate ischemia–reperfusion injury
Andreas Linkermann,Jan Hinrich Bräsen,Maurice Darding,Mi Kyung Jin,Ana Belen Sanz,Jan Ole Heller,Federica De Zen,Ricardo Weinlich,Alberto Ortiz,Henning Walczak,Joel M. Weinberg,Douglas R. Green,Ulrich Kunzendorf,Stefan Krautwald +13 more
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TLDR
It is demonstrated that necroptosis in ischemia–reperfusion injury (IRI) in mice occurs as primary organ damage, independent of the immune system, and that mice deficient for RIPK3, the essential downstream partner of RIPK1 in necroPTosis, are protected from IRI.Abstract:
Regulated necrosis (RN) may result from cyclophilin (Cyp)D-mediated mitochondrial permeability transition (MPT) and receptor-interacting protein kinase (RIPK)1-mediated necroptosis, but it is currently unclear whether there is one common pathway in which CypD and RIPK1 act in or whether separate RN pathways exist. Here, we demonstrate that necroptosis in ischemia–reperfusion injury (IRI) in mice occurs as primary organ damage, independent of the immune system, and that mice deficient for RIPK3, the essential downstream partner of RIPK1 in necroptosis, are protected from IRI. Protection of RIPK3-knockout mice was significantly stronger than of CypD-deficient mice. Mechanistically, in vivo analysis of cisplatin-induced acute kidney injury and hyperacute TNF-shock models in mice suggested the distinctness of CypD-mediated MPT from RIPK1/RIPK3-mediated necroptosis. We, therefore, generated CypD-RIPK3 double-deficient mice that are viable and fertile without an overt phenotype and that survived prolonged IRI, which was lethal to each single knockout. Combined application of the RIPK1 inhibitor necrostatin-1 and the MPT inhibitor sanglifehrin A confirmed the results with mutant mice. The data demonstrate the pathophysiological coexistence and corelevance of two separate pathways of RN in IRI and suggest that combination therapy targeting distinct RN pathways can be beneficial in the treatment of ischemic injury.read more
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Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease
Brent R. Stockwell,José Pedro Friedmann Angeli,Hülya Bayır,Ashley I. Bush,Marcus Conrad,Scott J. Dixon,Simone Fulda,Susan Gascon,Stavroula K. Hatzios,Valerian E. Kagan,Kay Noel,Xuejun Jiang,Andreas Linkermann,Maureen E. Murphy,Michael Overholtzer,Atsushi Oyagi,Gabriela Carolina Pagnussat,Jason Park,Qitao Ran,Craig S. Rosenfeld,Konstantin Salnikow,Daolin Tang,Daolin Tang,Frank M. Torti,Suzy V. Torti,Shinya Toyokuni,K. A. Woerpel,Donna D. Zhang +27 more
TL;DR: The mechanisms underlying ferroptosis are reviewed, connections to other areas of biology and medicine are highlighted, and tools and guidelines for studying this emerging form of regulated cell death are recommended.
Journal ArticleDOI
Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice
José Pedro Friedmann Angeli,Manuela Schneider,Bettina Proneth,Yulia Y. Tyurina,Vladimir A. Tyurin,Victoria Jayne Hammond,Nadja Herbach,Michaela Aichler,Axel Walch,E. 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 +28 more
TL;DR: It is demonstrated that ferroptosis is a pervasive and dynamic form of cell death, which, when impeded, promises substantial cytoprotection.
Journal ArticleDOI
Acute kidney injury
TL;DR: Evidence suggests that patients who have had acute kidney injury are at increased risk of subsequent chronic kidney disease, and new diagnostic techniques (eg, renal biomarkers) might help with early diagnosis.
Journal ArticleDOI
The role of iron and reactive oxygen species in cell death
TL;DR: The different roles of iron in triggering cell death, targets of iron-dependent ROS that mediate cell death and a new form ofIron-dependent cell death termed ferroptosis are described to suggest new therapeutic avenues to treat cancer, organ damage and degenerative disease.
Journal ArticleDOI
Necroptosis and its role in inflammation
TL;DR: The mechanisms regulating necroptosis and its potential role in inflammation and disease are discussed and RIPK1 has important kinase-dependent and scaffolding functions that inhibit or trigger necroPTosis and apoptosis.
References
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Journal ArticleDOI
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Grace Y. Chen,Gabriel Núñez +1 more
TL;DR: The triggers and receptor pathways that result in sterile inflammation and its impact on human health are reviewed.
Journal ArticleDOI
Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury
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TL;DR: It is demonstrated that necroptosis contributes to delayed mouse ischemic brain injury in vivo through a mechanism distinct from that of apoptosis and offers a new therapeutic target for stroke with an extended window for neuroprotection.
Journal ArticleDOI
Ischemia and reperfusion—from mechanism to translation
Holger K. Eltzschig,Tobias Eckle +1 more
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