Clemente, Laura Prieto, Rabenau, Malena, Tang, Stephan, Stanka, Josefina, Cors, Eileen, Stroh, Jenny, Culmsee, Carsten and von Karstedt, Silvia ORCID: 0000-0002-7816-5919 (2020). Dynasore Blocks Ferroptosis through Combined Modulation of Iron Uptake and Inhibition of Mitochondrial Respiration. Cells, 9 (10). BASEL: MDPI. ISSN 2073-4409

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Abstract

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Clemente, Laura PrietoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rabenau, MalenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tang, StephanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stanka, JosefinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cors, EileenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stroh, JennyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Culmsee, CarstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
von Karstedt, SilviaUNSPECIFIEDorcid.org/0000-0002-7816-5919UNSPECIFIED
URN: urn:nbn:de:hbz:38-316398
DOI: 10.3390/cells9102259
Journal or Publication Title: Cells
Volume: 9
Number: 10
Date: 2020
Publisher: MDPI
Place of Publication: BASEL
ISSN: 2073-4409
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
SPINAL-CORD-INJURY; CELL-DEATH; TRANSFERRIN RECEPTOR; PEROXIDATION; ANTIOXIDANT; METABOLISM; MECHANISM; RECOVERY; FISSIONMultiple languages
Cell BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/31639

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