Ferroptosis propagates to neighboring cells via cell-cell contacts

Roeck, Bernhard Florian; Vorndran, Michael R. H.; García‐Sáez, Ana J.

doi:10.1101/2023.03.24.534081

Cited by 3 publications

(1 citation statement)

References 52 publications

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“…The formed truncated PLs, which are known to permeabilize lipid membranes (23)(24)(25)(26), are promising candidates to cause loss of membrane integrity and mediate ferroptotic membrane permeabilization (27). Consistent with this model, during late-stage ferroptosis, it has been reported that plasma membrane pores form leading to cell swelling, calcium influx and recruitment of membrane repair machinery (28)(29)(30)(31). potassium (Na + /K + )-ATPase were identified as critical steps contributing to loss of the plasma membrane cation gradient (32).…”

Section: Introductionmentioning

confidence: 71%

MRP1 inhibition by lipid-derived electrophiles during ferroptosis illustrates a role for protein alkylation in ferroptotic cell death

Van Kessel,

Cosa

2023

Preprint

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Ferroptosis is a regulated form of cell death characterized by lipid peroxidation and lipid hydroperoxide (LOOH) generation that offers new therapeutic opportunities. However, the molecular mechanism through which LOOH accumulation leads to cell death remains poorly understood. Importantly, LOOH breakdown forms truncated phospholipids (PLs) and highly reactive lipid-derived electrophiles (LDEs) capable of altering protein function through cysteine alkylation. While truncated PLs have been shown to mediate ferroptotic membrane permeabilization, a functional role for LDEs in the ferroptotic cell death mechanism has not been established. Here, using multidrug resistance protein 1 (MRP1) activity as an example, we demonstrate that LDEs mediate altered protein functionduring ferroptosis. Applying live cell fluorescence imaging, we first identified that inhibition of MRP1-mediated LDE detoxification occurs across a panel of ferroptosis inducers (FINs) with differing mechanisms of ferroptosis induction (Types I-IV FINs erastin, RSL3, FIN56 and FINO2). This MRP1 inhibition was recreated by both initiation of lipid peroxidation and treatment with the LDE 4-hydroxy-2-nonenal (4-HNE). Importantly, treatment with radical-trapping antioxidants prevented impaired MRP1 activity when working with both FINs and lipid peroxidation initiators but not 4-HNE, pinpointing LDEs as the cause of inhibited MRP1 activity during ferroptosis. Our findings, when combined with reports of widespread LDE-alkylation of key proteins during ferroptosis, sets a precedent for LDEs as critical mediators of ferroptotic cell death. LOOH breakdown to truncated phospholipids and LDEs may fully explain membrane permeabilization and modified protein function during late stage ferroptosis, offering a unified explanation of the molecular ferroptotic cell death mechanism.

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Section: Introductionmentioning

confidence: 71%

MRP1 inhibition by lipid-derived electrophiles during ferroptosis illustrates a role for protein alkylation in ferroptotic cell death

Van Kessel,

Cosa

2023

Preprint

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Lipid-derived electrophiles inhibit the function of membrane channels during ferroptosis

Van Kessel,

Cosa

2024

Proc. Natl. Acad. Sci. U.S.A.

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The therapeutic targeting of ferroptosis requires full understanding of the molecular mechanism of this regulated cell death pathway. While lipid-derived electrophiles (LDEs), including 4-hydroxy-2-nonenal (4-HNE), are important biomarkers of ferroptosis, a functional role for these highly reactive species in ferroptotic cell death execution has not been established. Here, through mechanistic characterization of LDE-detoxification impairment, we demonstrate that LDEs mediate altered protein function during ferroptosis. Applying live cell fluorescence imaging, we first identified that export of glutathione-LDE-adducts through multidrug resistance-associated protein (MRP) channels is inhibited following exposure to a panel of ferroptosis inducers (FINs) with different modes of action (type I-IV FINs erastin, RSL3, FIN56, and FINO 2 ). This channel inhibition was recreated by both initiation of lipid peroxidation and treatment with 4-HNE. Importantly, treatment with radical-trapping antioxidants prevented impaired LDE-adduct export when working with both FINs and lipid peroxidation initiators but not 4-HNE, pinpointing LDEs as the cause of this inhibited MRP activity observed during ferroptosis. Our findings, when combined with reports of widespread LDE alkylation of key proteins following ferroptosis induction, including MRP1, set a precedent for LDEs as critical mediators of ferroptotic cell damage. Lipid hydroperoxide breakdown to form truncated phospholipids and LDEs may fully explain membrane permeabilization and modified protein function downstream of lipid peroxidation, offering a unified explanation of the molecular cell death mechanism of ferroptosis.

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Regulated cell death in chronic kidney disease: current evidence and future clinical perspectives

Giuliani,

Adams,

Healy

et al. 2024

Front. Cell Dev. Biol.

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Chronic kidney disease (CKD) is the progressive loss of kidney function/structure over a period of at least 3 months. It is characterised histologically by the triad of cell loss, inflammation and fibrosis. This literature review focuses on the forms of cell death that trigger downstream inflammation and fibrosis, collectively called regulated cell death (RCD) pathways. Discrete forms of RCD have emerged as central mediators of CKD pathology. In particular, pathways of regulated necrosis – including mitochondrial permeability transition pore (mPTP)-mediated necrosis, necroptosis, ferroptosis and pyroptosis – have been shown to mediate kidney pathology directly or through the release of danger signals that trigger a pro-inflammatory response, further amplifying tissue injury in a cellular process called necroinflammation. Despite accumulating evidence in pre-clinical models, no clinical studies have yet targeted these RCD modes in human CKD. The review summarizes recent advances in our understanding of RCD pathways in CKD, looks at inter-relations between the pathways (with the emphasis on propagation of death signals) and the evidence for therapeutic targeting of molecules in the RCD pathways to prevent or treat CKD.

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Ferroptosis propagates to neighboring cells via cell-cell contacts

Cited by 3 publications

References 52 publications

MRP1 inhibition by lipid-derived electrophiles during ferroptosis illustrates a role for protein alkylation in ferroptotic cell death

MRP1 inhibition by lipid-derived electrophiles during ferroptosis illustrates a role for protein alkylation in ferroptotic cell death

Lipid-derived electrophiles inhibit the function of membrane channels during ferroptosis

Regulated cell death in chronic kidney disease: current evidence and future clinical perspectives

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