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

2019 ◽  
Author(s):  
Lohans Pedrera ◽  
Rafael A. Espiritu ◽  
Uris Ros ◽  
Anja Schmitt ◽  
Stephan Hailfinger ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Plasma Membrane ◽  
Membrane Damage ◽  
Protective Mechanism ◽  
Membrane Repair ◽  
Plasma Membrane Damage ◽  
Molecular Events ◽  
Regulated Necrosis ◽  
Dependent Form

SummaryFerroptosis is an iron-dependent form of regulated necrosis associated with lipid peroxidation. Despite its key role in the inflammatory outcome of ferroptosis, little is known about the molecular events leading to the disruption of the plasma membrane during this type of cell death. Here we show that a sustained increase in cytosolic Ca2+ is a hallmark of ferroptosis that precedes complete bursting of the cell. We report that plasma membrane damage leading to ferroptosis is associated with membrane nanopores of few nanometers in radius and that ferroptosis, but not lipid peroxidation, can be delayed by osmoprotectants. Importantly, Ca2+ fluxes during ferroptosis correlate with the activation of ESCRT-III-mediated membrane repair, which counterbalances the kinetics of cell death and modulates the inflammatory signature of ferroptosis. Our findings with ferroptosis provide a unifying concept that sustained high levels of cytosolic Ca2+ prior to plasma membrane disruption are a common feature of regulated necrosis and position ESCRT-III as a general protective mechanism in these inflammatory cell death pathways.

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

2020 ◽  
Author(s):  
Lohans Pedrera ◽  
Rafael A. Espiritu ◽  
Uris Ros ◽  
Josephine Weber ◽  
Anja Schmitt ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Plasma Membrane ◽  
Membrane Damage ◽  
Protective Mechanism ◽  
Membrane Repair ◽  
Membrane Rupture ◽  
Plasma Membrane Damage ◽  
Regulated Necrosis ◽  
Sustained Increase

AbstractFerroptosis is an iron-dependent form of regulated necrosis associated with lipid peroxidation. Despite its key role in the inflammatory outcome of ferroptosis, little is known about the molecular events leading to the disruption of the plasma membrane during this type of cell death. Here we show that a sustained increase in cytosolic Ca2+ is a hallmark of ferroptosis that precedes complete bursting of the cell. We report that plasma membrane damage leading to ferroptosis is associated with membrane nanopores of a few nanometers in radius and that ferroptosis, but not lipid peroxidation, can be delayed by osmoprotectants. Importantly, Ca2+ fluxes during ferroptosis induce the activation of the ESCRT-III-dependent membrane repair machinery, which counterbalances the kinetics of cell death and modulates the immunological signature of ferroptosis. Our findings with ferroptosis provide a unifying concept that sustained increase of cytosolic Ca2+ prior to plasma membrane rupture is a common feature of regulated types of necrosis and position ESCRT-III activation as a general protective mechanism in these lytic cell death pathways.

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

2020 ◽  
Vol 21 (7) ◽  
pp. 2412 ◽  
Author(s):  
Uris Ros ◽  
Lohans Pedrera ◽  
Ana J. Garcia-Saez
Keyword(s):  
Cell Death ◽  
Plasma Membrane ◽  
Membrane Damage ◽  
Kinase Domain ◽  
Membrane Permeabilization ◽  
Plasma Membrane Damage ◽  
Intracellular Content ◽  
Regulated Necrosis ◽  
Inflammatory Phenotype ◽  
Cellular Components

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.

scholarly journals Ferroptosis in infection, inflammation, and immunity

2021 ◽  
Vol 218 (6) ◽  
Author(s):  
Xin Chen ◽  
Rui Kang ◽  
Guido Kroemer ◽  
Daolin Tang
Keyword(s):  
Cell Death ◽  
Membrane Damage ◽  
Iron Toxicity ◽  
Innate And Adaptive Immunity ◽  
Plasma Membrane Damage ◽  
Novel Treatment ◽  
Regulated Necrosis ◽  
Health And Disease ◽  
Enzymatic Pathways ◽  
Disease Understanding

Ferroptosis is a type of regulated necrosis that is triggered by a combination of iron toxicity, lipid peroxidation, and plasma membrane damage. The upstream inducers of ferroptosis can be divided into two categories (biological versus chemical) and activate two major pathways (the extrinsic/transporter versus the intrinsic/enzymatic pathways). Excessive or deficient ferroptotic cell death is implicated in a growing list of physiological and pathophysiological processes, coupled to a dysregulated immune response. This review focuses on new discoveries related to how ferroptotic cells and their spilled contents shape innate and adaptive immunity in health and disease. Understanding the immunological characteristics and activity of ferroptotic death not only illuminates an intersection between cell death and immunity but may also lead to the development of novel treatment approaches for immunopathological diseases.

scholarly journals Changes in plasma membrane damage inducing cell death after treatment with near‐infrared photoimmunotherapy

2018 ◽  
Vol 109 (9) ◽  
pp. 2889-2896 ◽  
Author(s):  
Kohei Nakajima ◽  
Hideo Takakura ◽  
Yoichi Shimizu ◽  
Mikako Ogawa
Keyword(s):  
Cell Death ◽  
Plasma Membrane ◽  
Near Infrared ◽  
Membrane Damage ◽  
Plasma Membrane Damage

scholarly journals Splitting up to heal: mitochondrial shape regulates signaling for focal membrane repair

2020 ◽  
Vol 48 (5) ◽  
pp. 1995-2002
Author(s):  
Adam Horn ◽  
Jyoti K. Jaiswal
Keyword(s):  
Plasma Membrane ◽  
Stress Responses ◽  
Shape Change ◽  
Membrane Damage ◽  
Mitochondrial Fragmentation ◽  
Membrane Repair ◽  
Membrane Injury ◽  
Plasma Membrane Damage ◽  
Focal Injury ◽  
Signaling Organelles

Mitochondria are central to the health of eukaryotic cells. While commonly known for their bioenergetic role, mitochondria also function as signaling organelles that regulate cell stress responses capable of restoring homeostasis or leading the stressed cell to eventual death. Damage to the plasma membrane is a potentially fatal stressor incurred by all cells. Repairing plasma membrane damage requires cells to mount a rapid and localized response to injury. Accumulating evidence has identified a role for mitochondria as an important facilitator of this acute and localized repair response. However, as mitochondria are organized in a cell-wide, interconnected network, it is unclear how they collectively sense and respond to a focal injury. Here we will discuss how mitochondrial shape change is an integral part of this localized repair response. Mitochondrial fragmentation spatially restricts beneficial repair signaling, enabling a localized response to focal injury. Conservation of mitochondrial fragmentation in response to cell and tissue damage across species demonstrates that this is a universal pro-survival adaptation to injury and suggests that mitochondrial fragmentation may provide cells a mechanism to facilitate localized signaling in contexts beyond repairing plasma membrane injury.

The Role of Biomembranes in Chromium (III)-induced Toxicity In Vitro

2005 ◽  
Vol 33 (3) ◽  
pp. 249-259 ◽  
Author(s):  
Emil Rudolf ◽  
Miroslav Červinka
Keyword(s):  
Cell Death ◽  
Plasma Membrane ◽  
Human Fibroblasts ◽  
Membrane Damage ◽  
Continuous Exposure ◽  
Plasma Membrane Damage ◽  
Chromium Acetate

The role of biomembranes in the chronic toxicity of environmentally occurring chromium acetate hydroxide was investigated by using primary human fibroblasts. Transport of chromium acetate hydroxide across the plasma membrane of the cell, and the effects of chromium (III) ions on the plasma membrane as well as other intracellular membranes, were determined during six weeks of continuous exposure by using atomic absorption spectrometry, observation of cell morphology, membrane integrity assays (for lactate dehydrogenase leakage and lysosomal membrane disruption), and mitochondrial assays (for mitochondrial dehydrogenase activity and mitochondrial transmembrane potential analysis). The type of cell death induced by long-term exposure was determined in terms of phosphatidylserine externalisation, caspase-3 activation, and chromatin fragmentation. Chromium acetate hydroxide, at a concentration of 100μmol/l, accumulated in exposed cells, inflicting plasma membrane damage and suppressing mitochondrial function. Antioxidant co-enzyme Q, at a concentration of 10μmol/l, partially prevented plasma membrane damage and mitochondrial dysfunction. Exposure to chromium acetate hydroxide produced apoptosis, necrosis and an intermediate type of cell death in primary human fibroblasts. These results show that the plasma membrane and mitochondrial membrane are important targets for chronic chromium acetate hydroxide toxicity, and that this in vitro system holds promise for studying the toxicity resulting from long-term exposure to metal ions.

Early interconnectivity between metabolic and defense events against oxidative stress induced by cadmium in roots of four citrus rootstocks

2016 ◽  
Vol 43 (10) ◽  
pp. 973 ◽  
Author(s):  
Griselda Podazza ◽  
Marta Arias ◽  
Fernando E. Prado
Keyword(s):  
Oxidative Stress ◽  
Lipid Peroxidation ◽  
Plasma Membrane ◽  
Membrane Damage ◽  
Soluble Phenolics ◽  
Rangpur Lime ◽  
Plasma Membrane Damage ◽  
H2o2 Accumulation ◽  
Volkamer Lemon ◽  
Main Driver

The effect of cadmium on roots of four citrus rootstocks was studied to assess the relationships between oxidative stress, carbohydrates, phenolics and antioxidant responses. Swingle citrumelo (SC), Rangpur lime (RL), Troyer citrange (TC) and Volkamer lemon (VL) genotypes were exposed to 0, 5 and 10 µM Cd over 7 days, after which Cd accumulation was markedly higher in roots compared with stems and leaves. Malondialdehyde (MDA) and lipoxygenase (LOX) activity increased in Cd-treated SC and RL roots, suggesting that a lipid peroxidation is the main driver of plasma membrane damage. In contrast, in TC and VL genotypes, LOX-mediated lipid peroxidation does not appear to play a key role in Cd-induced lipid peroxidation, but H2O2 accumulation seems to be responsible of less plasma membrane damage. Catalase (CAT), superoxide dismutase (SOD) and guaiacol and syringaldazine peroxidases (G-POD and S-POD respectively) were differentially affected by Cd. Lipid profile and ATPase-dependant proton extrusion indicated higher disfunctionalities of root plasma membrane in SC and RL genotypes than in TC and VL genotypes. Differences in carbohydrates and phenolic compounds were also observed. Histochemical analysis of G-POD activity and lignin and suberin deposition revealed differences among genotypes. A model to explain the relationships among carbohydrates, soluble phenolics, lipid peroxidation and H2O2 accumulation in Cd-exposed roots was proposed.

scholarly journals A cryo–electron tomography workflow reveals protrusion-mediated shedding on injured plasma membrane

2021 ◽  
Vol 7 (13) ◽  
pp. eabc6345
Author(s):  
Shrawan Kumar Mageswaran ◽  
Wei Yuan Yang ◽  
Yogaditya Chakrabarty ◽  
Catherine M. Oikonomou ◽  
Grant J. Jensen
Keyword(s):  
Plasma Membrane ◽  
Molecular Mechanisms ◽  
Electron Tomography ◽  
Membrane Damage ◽  
Light And Electron Microscopy ◽  
Actin Dynamics ◽  
Endosomal Sorting ◽  
Plasma Membrane Damage ◽  
Cryo Electron Tomography ◽  
Vacuolar Protein

Cryo–electron tomography (cryo-ET) provides structural context to molecular mechanisms underlying biological processes. Although straightforward to implement for studying stable macromolecular complexes, using it to locate short-lived structures and events can be impractical. A combination of live-cell microscopy, correlative light and electron microscopy, and cryo-ET will alleviate this issue. We developed a workflow combining the three to study the ubiquitous and dynamic process of shedding in response to plasma membrane damage in HeLa cells. We found filopodia-like protrusions enriched at damage sites and acting as scaffolds for shedding, which involves F-actin dynamics, myosin-1a, and vacuolar protein sorting 4B (a component of the ‘endosomal sorting complex required for transport’ machinery). Overall, shedding is more complex than current models of vesiculation from flat membranes. Its similarities to constitutive shedding in enterocytes argue for a conserved mechanism. Our workflow can also be adapted to study other damage response pathways and dynamic cellular events.

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