Ferroptotic pores induce Ca<sup>2+</sup> fluxes and ESCRT-III activation to modulate cell death kinetics

Pedrera, Lohans; Espiritu, Rafael A.; Ros, Uris; Schmitt, Anja; Hailfinger, Stephan; García‐Sáez, Ana J.

doi:10.1101/867564

Cited by 8 publications

(8 citation statements)

References 51 publications

(91 reference statements)

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“…1 B). The catalytic role of iron in ferroptosis has been highlighted [ 30 , 31 ]. By staining cells with FerroOrange (to detect ferrous ions), we found that NaIO 3 and Erastin-treated cells accumulated excessive ferrous ions, which were significantly blocked by pre-incubation with Fer-1 or DFO, as revealed by the decreased orange fluorescence ( Fig.…”

Section: Resultsmentioning

confidence: 99%

HO-1-mediated ferroptosis as a target for protection against retinal pigment epithelium degeneration

et al. 2021

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Oxidative stress-mediated retinal pigment epithelium (RPE) degeneration plays a vital role in retinal degeneration with irreversible visual impairment, most notably in age-related macular degeneration (AMD), but a key pathogenic factor and the targeted medical control remain controversial and unclear. In this work, by sophisticated high-throughput sequencing and biochemistry investigations, the major pathologic processes during RPE degeneration in the sodium iodate-induced oxidative stress model has been identified to be heme oxygenase-1 (HO-1)-regulated ferroptosis, which is controlled by the Nrf2–SLC7A11–HO-1 hierarchy, through which ferrous ion accumulation and lethal oxidative stress cause RPE death and subsequently photoreceptor degeneration. By direct knockdown of HO-1 or using HO-1 inhibitor ZnPP, the specific inhibition of HO-1 overexpression has been determined to significantly block RPE ferroptosis. In mice, treatment with ZnPP effectively rescued RPE degeneration and achieved superior therapeutic effects: substantial recovery of the retinal structure and visual function. These findings highlight that targeting HO-1-mediated RPE ferroptosis could serve as an effectively retinal-protective strategy for retinal degenerative diseases prevention, including AMD.

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Section: Resultsmentioning

confidence: 99%

HO-1-mediated ferroptosis as a target for protection against retinal pigment epithelium degeneration

et al. 2021

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“…Evidence suggests that MLKL forms small and selective pores or channels that mediate the movement of ion fluxes but not big molecules in necroptosis [47,49]. In ferroptosis, the exact mechanism of membrane permeabilization is less clear but also seems to involve pore formation in the plasma membrane [67]. Therefore, pore formation has emerged as a common feature underlying different types of regulated necrosis.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, pore formation has emerged as a common feature underlying different types of regulated necrosis. As an opposing mechanism, membrane repair by the ESCRT machinery counterbalances all these types of cell death by removing the damage sections of the plasma membrane [20,22,67].…”

Section: Discussionmentioning

confidence: 99%

“…Mitochondrial fragmentation, cristae disassembly, and mitochondrial outer membrane permeabilization are some of the dramatic changes in mitochondria morphology observed during ferroptosis [14,61]. Recently, we proposed that plasma membrane damage in ferroptosis involves the formation of pores of few nanometers in size that are linked to the increase of cytosolic Ca 2+ [67]. In agreement with its role in other types of regulated necrosis, increase in cytosolic Ca 2+ upon membrane damage correlated with the activation of ESCRT-mediated membrane repair, which had a pro-survival role by counterbalancing the kinetics of cell death and modulated the inflammatory signature of ferroptosis.…”

Section: Lipid Peroxidation In Membranes During Ferroptosismentioning

confidence: 99%

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Partners in Crime: The Interplay of Proteins and Membranes in Regulated Necrosis

Ros

Pedrera

García‐Sáez

2020

IJMS

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Pyroptosis, necroptosis, and ferroptosis are well-characterized forms of regulated necrosis that have been associated with human diseases. During regulated necrosis, plasma membrane damage facilitates the movement of ions and molecules across the bilayer, which finally leads to cell lysis and release of intracellular content. Therefore, these types of cell death have an inflammatory phenotype. Each type of regulated necrosis is mediated by a defined machinery comprising protein and lipid molecules. Here, we discuss how the interaction and reshaping of these cellular components are essential and distinctive processes during pyroptosis, necroptosis, and ferroptosis. We point out that although the plasma membrane is the common target in regulated necrosis, different mechanisms of permeabilization have emerged depending on the cell death form. Pore formation by gasdermins (GSDMs) is a hallmark of pyroptosis, while mixed lineage kinase domain-like (MLKL) protein facilitates membrane permeabilization in necroptosis, and phospholipid peroxidation leads to membrane damage in ferroptosis. This diverse repertoire of mechanisms leading to membrane permeabilization contributes to define the specific inflammatory and immunological outcome of each type of regulated necrosis. Current efforts are focused on new therapies that target critical protein and lipid molecules on these pathways to fight human pathologies associated with inflammation.

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“…Although it supports the hypothesis of pores due to lipid oxidation. Also in a manuscript of Lohans Pedrera et al, it was reported that, nanoscale pores are formed prior to lipid oxidation and cause Ca2+ influx into the cell [102].…”

Section: Lipid Oxidation and Pore Formation Beyond Electroporationmentioning

confidence: 99%

On the permeability of cell membranes subjected to lipid oxidation

Wiczew

Szulc

Tarek

2020

Preprint

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The formation of transient hydrophilic pores in their membranes is a well-recognized mechanism of permeabilization of cells exposed to high-intensity electric pulses. However, the formation of such pores alone is not able to explain all aspects of the so-called electroporation phenomenon. In particular, the reasons for the sustained permeability of cell membranes, which persist long after the pulses' application, remain elusive: The complete resealing of the cell membranes takes indeed orders of magnitude longer than the time of electropore closure as reported from molecular modelling investigations. A possible alternative mechanism to explain the observed long-lived permeability of cell membranes, lipid peroxidation, has been previously suggested but the theoretical investigations of membrane lesions, containing excess amounts of hydroperoxides, have shown that the conductivities of such lesions were not high enough to reasonably explain the entire range of experimental measurements. Here, we expand on these studies and investigate the permeability of cell membrane lesions that underwent secondary oxidation. Molecular dynamics simulations and free energy calculations on lipid bilayer in different states show that such lesions provide a better model for post-pulsed permeable and conductive electropermeabilized cells. Furthermore, the results of the article are further discussed in the context of a type of cell death - ferroptosis, which is associated with lipid oxidation.

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Ferroptotic pores induce Ca²⁺ fluxes and ESCRT-III activation to modulate cell death kinetics

Cited by 8 publications

References 51 publications

HO-1-mediated ferroptosis as a target for protection against retinal pigment epithelium degeneration

HO-1-mediated ferroptosis as a target for protection against retinal pigment epithelium degeneration

Partners in Crime: The Interplay of Proteins and Membranes in Regulated Necrosis

On the permeability of cell membranes subjected to lipid oxidation

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Ferroptotic pores induce Ca2+ fluxes and ESCRT-III activation to modulate cell death kinetics

Cited by 8 publications

References 51 publications

HO-1-mediated ferroptosis as a target for protection against retinal pigment epithelium degeneration

HO-1-mediated ferroptosis as a target for protection against retinal pigment epithelium degeneration

Partners in Crime: The Interplay of Proteins and Membranes in Regulated Necrosis

On the permeability of cell membranes subjected to lipid oxidation

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Ferroptotic pores induce Ca²⁺ fluxes and ESCRT-III activation to modulate cell death kinetics