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Dynasore Blocks Ferroptosis through Combined Modulation of Iron Uptake and Inhibition of Mitochondrial Respiration

1
Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, University Hospital of Cologne, 50931 Cologne, Germany
2
CECAD Cluster of Excellence, University of Cologne, 50931 Cologne, Germany
3
Institute for Pharmacology and Clinical Pharmacy, Biochemical-Pharmacological Center Marburg, University of Marburg, 35032 Marburg, Germany
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Center for Mind, Brain and Behavior- CMBB, University of Marburg, 35032 Marburg, Germany
5
Center for Molecular Medicine Cologne, Medical Faculty, University Hospital of Cologne, 50931 Cologne, Germany
*
Author to whom correspondence should be addressed.
Cells 2020, 9(10), 2259; https://doi.org/10.3390/cells9102259
Received: 14 July 2020 / Revised: 25 September 2020 / Accepted: 3 October 2020 / Published: 9 October 2020
(This article belongs to the Section Cell Signaling)
Ferroptosis is a form of regulated necrosis characterized by a chain-reaction of detrimental membrane lipid peroxidation following collapse of glutathione peroxidase 4 (Gpx4) activity. This lipid peroxidation is catalyzed by labile ferric iron. Therefore, iron import mediated via transferrin receptors and both, enzymatic and non-enzymatic iron-dependent radical formation are crucial prerequisites for the execution of ferroptosis. Intriguingly, the dynamin inhibitor dynasore, which has been shown to block transferrin receptor endocytosis, can protect from ischemia/reperfusion injury as well as neuronal cell death following spinal cord injury. Yet, it is unknown how dynasore exerts these cell death-protective effects. Using small interfering RNA suppression, lipid reactive oxygen species (ROS), iron tracers and bona fide inducers of ferroptosis, we find that dynasore treatment in lung adenocarcinoma and neuronal cell lines strongly protects these from ferroptosis. Surprisingly, while the dynasore targets dynamin 1 and 2 promote extracellular iron uptake, their silencing was not sufficient to block ferroptosis suggesting that this route of extracellular iron uptake is dispensable for acute induction of ferroptosis and dynasore must have an additional off-target activity mediating full ferroptosis protection. Instead, in intact cells, dynasore inhibited mitochondrial respiration and thereby mitochondrial ROS production which can feed into detrimental lipid peroxidation and ferroptotic cell death in the presence of labile iron. In addition, in cell free systems, dynasore showed radical scavenger properties and acted as a broadly active antioxidant which is superior to N-acetylcysteine (NAC) in blocking ferroptosis. Thus, dynasore can function as a highly active inhibitor of ROS-driven types of cell death via combined modulation of the iron pool and inhibition of general ROS by simultaneously blocking two routes required for ROS and lipid-ROS driven cell death, respectively. These data have important implications for the interpretation of studies observing tissue-protective effects of this dynamin inhibitor as well as raise awareness that off-target ROS scavenging activities of small molecules used to interrogate the ferroptosis pathway should be taken into consideration. View Full-Text
Keywords: ferroptosis; radical scavenger; dynasore ferroptosis; radical scavenger; dynasore
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MDPI and ACS Style

Clemente, L.P.; Rabenau, M.; Tang, S.; Stanka, J.; Cors, E.; Stroh, J.; Culmsee, C.; von Karstedt, S. Dynasore Blocks Ferroptosis through Combined Modulation of Iron Uptake and Inhibition of Mitochondrial Respiration. Cells 2020, 9, 2259. https://doi.org/10.3390/cells9102259

AMA Style

Clemente LP, Rabenau M, Tang S, Stanka J, Cors E, Stroh J, Culmsee C, von Karstedt S. Dynasore Blocks Ferroptosis through Combined Modulation of Iron Uptake and Inhibition of Mitochondrial Respiration. Cells. 2020; 9(10):2259. https://doi.org/10.3390/cells9102259

Chicago/Turabian Style

Clemente, Laura P., Malena Rabenau, Stephan Tang, Josefina Stanka, Eileen Cors, Jenny Stroh, Carsten Culmsee, and Silvia von Karstedt. 2020. "Dynasore Blocks Ferroptosis through Combined Modulation of Iron Uptake and Inhibition of Mitochondrial Respiration" Cells 9, no. 10: 2259. https://doi.org/10.3390/cells9102259

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