Excessive phospholipid peroxidation distinguishes ferroptosis from other cell death modes including pyroptosis

Lipid peroxidation (LPO) drives ferroptosis execution. However, LPO has been shown to contribute also to other modes of regulated cell death (RCD). To clarify the role of LPO in different modes of RCD, we studied in a comprehensive approach the differential involvement of reactive oxygen species (RO...

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Published in:	Cell death & disease 2020-10, Vol.11 (10), p.922, Article 922
Main Authors:	Wiernicki, Bartosz, Dubois, Hanne, Tyurina, Yulia Y, Hassannia, Behrouz, Bayir, Hülya, Kagan, Valerian E, Vandenabeele, Peter, Wullaert, Andy, Vanden Berghe, Tom
Format:	Article
Language:	eng
Subjects:	Apoptosis Cell Death Cell membranes Cytotoxicity Ferroptosis - genetics Humans IL-1β Interleukin 18 Lipid peroxidation Lipid Peroxidation - genetics Lipidomics - methods Lipids Necroptosis Phosphatidylethanolamine Phospholipids Phospholipids - metabolism Pyroptosis - genetics Reactive oxygen species Transfection
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Summary:	Lipid peroxidation (LPO) drives ferroptosis execution. However, LPO has been shown to contribute also to other modes of regulated cell death (RCD). To clarify the role of LPO in different modes of RCD, we studied in a comprehensive approach the differential involvement of reactive oxygen species (ROS), phospholipid peroxidation products, and lipid ROS flux in the major prototype modes of RCD viz. apoptosis, necroptosis, ferroptosis, and pyroptosis. LC-MS oxidative lipidomics revealed robust peroxidation of three classes of phospholipids during ferroptosis with quantitative predominance of phosphatidylethanolamine species. Incomparably lower amounts of phospholipid peroxidation products were found in any of the other modes of RCD. Nonetheless, a strong increase in lipid ROS levels was detected in non-canonical pyroptosis, but only during cell membrane rupture. In contrast to ferroptosis, lipid ROS apparently was not involved in non-canonical pyroptosis execution nor in the release of IL-1β and IL-18, while clear dependency on CASP11 and GSDMD was observed. Our data demonstrate that ferroptosis is the only mode of RCD that depends on excessive phospholipid peroxidation for its cytotoxicity. In addition, our results also highlight the importance of performing kinetics and using different methods to monitor the occurrence of LPO. This should open the discussion on the implication of particular LPO events in relation to different modes of RCD.
ISSN:	2041-4889 2041-4889