Abstract
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.
Highlights
Up to this day, multiple types of regulated cell death (RCD) have been identified[1]
To enable a comprehensive side by side comparison of the role of oxidized phospholipids (oxPLs) in the different modes of RCD in a single cell type, we chose to work with primary bone-marrow-derived macrophages (BMDMs) because, depending on the trigger, these cells are able to undergo apoptosis, necroptosis, pyroptosis and ferroptosis (Supplementary Fig. 1a)
To determine the role of oxPLs in the execution of different modes of RCD, we subjected BMDMs at the early stage of cell death (Supplementary Fig. 1b) to oxidative lipidomics to evaluate in an unbiased way oxPLs events preceding cell membrane permeabilization
Summary
Multiple types of regulated cell death (RCD) have been identified[1]. Most ferroptosis inducers rely on blocking the activity of glutathione peroxidase 4 (GPX4)—an enzyme able to reduce PLhydroperoxide (PL-OOH) to its alcohol form (PL-OH). Aside from ferroptosis, some specific LPO events have been described in apoptosis[5], necroptosis[6], and pyroptosis[7,8]. Those studies, differ in terms of used models and detection methods for LPO. To clarify the role of LPO, in particular oxPLs, in different RCDs, we subjected bone-marrow-derived macrophages (BMDMs) to apoptosis, necroptosis, ferroptosis as well as canonical and non-canonical pyroptosis and performed liquid chromatography-mass spectrometrybased redox-lipidomics analysis, further coined as the oxidative lipidomics approach, a gold standard method
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