Pub Date : 2023-11-14DOI: 10.3389/fceld.2023.1182239
Bjarne Goebel, Laura Carpanedo, Susanne Reif, Tamara Göbel, Svenja Simonyi, Nils Helge Schebb, Dieter Steinhilber, Ann-Kathrin Häfner
Since 2005, the original three cell death mechanisms apoptosis, autophagy and necrosis are accompanied by several new forms. The most recent member, ferroptosis, was first described in 2012 and is characterized by the accumulation of iron and increased lipid peroxidation. In this study, we present a model system to study ferroptotic states in stably transfected HEK293T cells, using acyl-CoA synthetase long chain family member 4 (ACSL4), a biomarker of ferroptosis, and/or lysophosphatidylcholine acyltransferase 2 (LPCAT2), a transferase responsible for the lipid remodeling process. In addition, we introduced an inducible expression system for 5-lipoxygenase (LO), 15-LO1 and 15-LO2, to trigger enzymatic lipid peroxidation. We characterized the system in terms of ACSL4, LPCAT2 and LO expression both on Western blot level and by laser scanning confocal microscopy as well as the intracellular localization of all enzymes. Furthermore, we verified inducibility and activity of our LOs and, in addition, analyzed non-esterified (free) and total amounts of oxylipins. When cells were incubated with the ferroptosis-inducing agents GPX4 inhibitor RSL3 or GSH reducing erastin, we observed a decrease in cell viability that was strongly enhanced in the presence of ACSL4 and LPCAT2. Interestingly, additional expression of LPCAT2 resulted in altered localization of 15-LO1, which shifted from the cytosol to the nuclear membrane. A similar localization occurred after treatment with RSL3. Therefore, on one hand, we propose that LPCAT2 is an acyltransferase that promotes ferroptotic conditions, and on the other hand, we introduce a new cell-based model system suitable for studying ferroptosis.
{"title":"Development of a cell-based model system for the investigation of ferroptosis","authors":"Bjarne Goebel, Laura Carpanedo, Susanne Reif, Tamara Göbel, Svenja Simonyi, Nils Helge Schebb, Dieter Steinhilber, Ann-Kathrin Häfner","doi":"10.3389/fceld.2023.1182239","DOIUrl":"https://doi.org/10.3389/fceld.2023.1182239","url":null,"abstract":"Since 2005, the original three cell death mechanisms apoptosis, autophagy and necrosis are accompanied by several new forms. The most recent member, ferroptosis, was first described in 2012 and is characterized by the accumulation of iron and increased lipid peroxidation. In this study, we present a model system to study ferroptotic states in stably transfected HEK293T cells, using acyl-CoA synthetase long chain family member 4 (ACSL4), a biomarker of ferroptosis, and/or lysophosphatidylcholine acyltransferase 2 (LPCAT2), a transferase responsible for the lipid remodeling process. In addition, we introduced an inducible expression system for 5-lipoxygenase (LO), 15-LO1 and 15-LO2, to trigger enzymatic lipid peroxidation. We characterized the system in terms of ACSL4, LPCAT2 and LO expression both on Western blot level and by laser scanning confocal microscopy as well as the intracellular localization of all enzymes. Furthermore, we verified inducibility and activity of our LOs and, in addition, analyzed non-esterified (free) and total amounts of oxylipins. When cells were incubated with the ferroptosis-inducing agents GPX4 inhibitor RSL3 or GSH reducing erastin, we observed a decrease in cell viability that was strongly enhanced in the presence of ACSL4 and LPCAT2. Interestingly, additional expression of LPCAT2 resulted in altered localization of 15-LO1, which shifted from the cytosol to the nuclear membrane. A similar localization occurred after treatment with RSL3. Therefore, on one hand, we propose that LPCAT2 is an acyltransferase that promotes ferroptotic conditions, and on the other hand, we introduce a new cell-based model system suitable for studying ferroptosis.","PeriodicalId":73072,"journal":{"name":"Frontiers in cell death","volume":"46 27","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134901714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-10-30DOI: 10.3389/fceld.2023.1281137
Katherine P. Lee, Benjamin Epstein, Camille M. Lake, Andrew L. Snow
For effective adaptive immunity, T lymphocytes must rapidly expand and contract in an antigen-specific manner to effectively control invading pathogens and preserve immunological memory, without sustaining excessive collateral damage to host tissues. Starting from initial antigen encounter, carefully calibrated programmed cell death pathways are critical for maintaining homeostasis over distinct phases of the T cell response. Restimulation-induced cell death (RICD), a self-regulatory apoptosis pathway triggered by re-engagement of the T cell receptor (TCR), is particularly important for constraining effector T cell expansion to preclude overt immunopathology; indeed, genetic disorders affecting key molecules involved in RICD execution can manifest in excessive lymphoproliferation, malignancy, and autoimmunity. Herein we review our current knowledge of how RICD sensitivity is ultimately regulated over the course of an immune response, including recent revelations on molecules that tune RICD by enforcing resistance or promoting susceptibility in expanding versus mature effector T cells, respectively. Detailed dissection of the molecular and temporal control of RICD also illuminates novel therapeutic strategies for correcting abnormal T cell responses noted in various immune disorders by ultimately tuning RICD sensitivity.
{"title":"Molecular and temporal control of restimulation-induced cell death (RICD) in T lymphocytes","authors":"Katherine P. Lee, Benjamin Epstein, Camille M. Lake, Andrew L. Snow","doi":"10.3389/fceld.2023.1281137","DOIUrl":"https://doi.org/10.3389/fceld.2023.1281137","url":null,"abstract":"For effective adaptive immunity, T lymphocytes must rapidly expand and contract in an antigen-specific manner to effectively control invading pathogens and preserve immunological memory, without sustaining excessive collateral damage to host tissues. Starting from initial antigen encounter, carefully calibrated programmed cell death pathways are critical for maintaining homeostasis over distinct phases of the T cell response. Restimulation-induced cell death (RICD), a self-regulatory apoptosis pathway triggered by re-engagement of the T cell receptor (TCR), is particularly important for constraining effector T cell expansion to preclude overt immunopathology; indeed, genetic disorders affecting key molecules involved in RICD execution can manifest in excessive lymphoproliferation, malignancy, and autoimmunity. Herein we review our current knowledge of how RICD sensitivity is ultimately regulated over the course of an immune response, including recent revelations on molecules that tune RICD by enforcing resistance or promoting susceptibility in expanding versus mature effector T cells, respectively. Detailed dissection of the molecular and temporal control of RICD also illuminates novel therapeutic strategies for correcting abnormal T cell responses noted in various immune disorders by ultimately tuning RICD sensitivity.","PeriodicalId":73072,"journal":{"name":"Frontiers in cell death","volume":"21 16","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136102801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-08-29DOI: 10.3389/fceld.2023.1219672
Géraldine Cuvelier, Perrine Vermonden, J. Rousseau, O. Féron, R. Rezsohazy, Y. Larondelle
In contrast to canonical ferroptosis inducers, highly peroxidable conjugated linolenic acids (CLnA) directly fuel the lipid peroxidation cascade upon their incorporation into membrane phospholipids. Little is known, however, about the cytotoxicity level of CLnAs to normal epithelial cells. Caco-2 cells, derived from colorectal adenocarcinoma, spontaneously differentiate into enterocyte-like cells over a period of 21 days of cell culturing, allowing for graduated phenotypic shift from proliferative, undifferentiated cells to a functional intestinal barrier. We exploited this property to assess the sensitivity of Caco-2 cells to CLnAs at different stages of differentiation. Our results show a significant decrease in CLnA-induced ferroptotic cell death over time. The acquired resistance aligned with decreases in cell proliferation and in the extent of lipid peroxidation, as well as with an increase in the expression of GPX4 upon differentiation. These results highlight that while CLnAs are highly toxic for proliferating cancer cells, differentiated epithelial cells are resistant to CLnA-induced ferroptosis. Therefore, this study gives credential to the therapeutic use of CLnAs as an anticancer strategy and offers a new model study to further investigate the safety of peroxidable fatty acids in differentiated cells.
{"title":"Resistance to CLnA-induced ferroptosis is acquired in Caco-2 cells upon differentiation","authors":"Géraldine Cuvelier, Perrine Vermonden, J. Rousseau, O. Féron, R. Rezsohazy, Y. Larondelle","doi":"10.3389/fceld.2023.1219672","DOIUrl":"https://doi.org/10.3389/fceld.2023.1219672","url":null,"abstract":"In contrast to canonical ferroptosis inducers, highly peroxidable conjugated linolenic acids (CLnA) directly fuel the lipid peroxidation cascade upon their incorporation into membrane phospholipids. Little is known, however, about the cytotoxicity level of CLnAs to normal epithelial cells. Caco-2 cells, derived from colorectal adenocarcinoma, spontaneously differentiate into enterocyte-like cells over a period of 21 days of cell culturing, allowing for graduated phenotypic shift from proliferative, undifferentiated cells to a functional intestinal barrier. We exploited this property to assess the sensitivity of Caco-2 cells to CLnAs at different stages of differentiation. Our results show a significant decrease in CLnA-induced ferroptotic cell death over time. The acquired resistance aligned with decreases in cell proliferation and in the extent of lipid peroxidation, as well as with an increase in the expression of GPX4 upon differentiation. These results highlight that while CLnAs are highly toxic for proliferating cancer cells, differentiated epithelial cells are resistant to CLnA-induced ferroptosis. Therefore, this study gives credential to the therapeutic use of CLnAs as an anticancer strategy and offers a new model study to further investigate the safety of peroxidable fatty acids in differentiated cells.","PeriodicalId":73072,"journal":{"name":"Frontiers in cell death","volume":"27 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91081004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-06-20DOI: 10.3389/fceld.2023.1209641
Sanjay Saini, Edward Owusu-Ansah
Ferroptosis is a specific form of non-apoptotic cell death that is driven by iron-dependent phospholipid peroxidation. Research over the past decade has contributed to our understanding of how this important cell death process is regulated in mammalian systems, especially with regard to the distinct modes of induction, the role of metabolic signals, the organelles involved, implications of ferroptosis for development and aging, and how our improved understanding of the process can be exploited for therapeutic purposes. Other studies have described variants of this ancient cell death process in cyanobacteria, plants and protozoans. Emerging evidence indicates that a ferroptosis-like form of cell death exists in fruit flies (Drosophila melanogaster). Due to the extensive homology of genes in Drosophila melanogaster and Drosophila suzukii, unique aspects of ferroptosis in Drosophila melanogaster may be of particular relevance for developing targeted pesticides against Drosophila suzukii—a major invasive agricultural pest of the berry and wine industry in Southeast Asia, Europe and America. Further, aspects of ferroptosis in Drosophila melanogaster that are conserved in insects in general may provide the basis for identifying new insecticides for controlling the spread of vector-borne diseases such as malaria. In this perspective, we highlight some of the studies in Drosophila melanogaster that have sought to improve our understanding of the ferroptosis-like form of cell death that operates in this organism and conclude with a discussion of the opportunities and challenges for studying this phenomenon in fruit flies.
{"title":"Dissecting the mechanism of regulation of a ferroptosis-like form of cell death in Drosophila melanogaster","authors":"Sanjay Saini, Edward Owusu-Ansah","doi":"10.3389/fceld.2023.1209641","DOIUrl":"https://doi.org/10.3389/fceld.2023.1209641","url":null,"abstract":"Ferroptosis is a specific form of non-apoptotic cell death that is driven by iron-dependent phospholipid peroxidation. Research over the past decade has contributed to our understanding of how this important cell death process is regulated in mammalian systems, especially with regard to the distinct modes of induction, the role of metabolic signals, the organelles involved, implications of ferroptosis for development and aging, and how our improved understanding of the process can be exploited for therapeutic purposes. Other studies have described variants of this ancient cell death process in cyanobacteria, plants and protozoans. Emerging evidence indicates that a ferroptosis-like form of cell death exists in fruit flies (Drosophila melanogaster). Due to the extensive homology of genes in Drosophila melanogaster and Drosophila suzukii, unique aspects of ferroptosis in Drosophila melanogaster may be of particular relevance for developing targeted pesticides against Drosophila suzukii—a major invasive agricultural pest of the berry and wine industry in Southeast Asia, Europe and America. Further, aspects of ferroptosis in Drosophila melanogaster that are conserved in insects in general may provide the basis for identifying new insecticides for controlling the spread of vector-borne diseases such as malaria. In this perspective, we highlight some of the studies in Drosophila melanogaster that have sought to improve our understanding of the ferroptosis-like form of cell death that operates in this organism and conclude with a discussion of the opportunities and challenges for studying this phenomenon in fruit flies.","PeriodicalId":73072,"journal":{"name":"Frontiers in cell death","volume":"59 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76954015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-06-16DOI: 10.3389/fceld.2023.1197400
R. Lockshin
The concept of biological cell death—that is, cell death that is neither accidental nor chaotic—has existed and has been obvious since at least the beginning of the 20th C, but it was noticed by other than specialists apt choices of words that caught the spirit of the time, “programmed cell death” and “apoptosis” caught the attention of a wider range of scientists. Then, by the early 1990s the recognition of at least two genes that were important to cancer and other diseases by controlling cell death (p53, Bcl-2, and Fas); recognition that cell death could be controlled by a highly conserved family of proteases; and the development of rapid and easy means of measuring cell death, led to the explosion of the field as a subject of research. Today we recognize many variations on the theme of biological cell death, but many mysteries remain. The most important of these remaining mysteries is that we recognize many of the penultimate and ultimate steps to kill cells, but it is rarely clear how and why these steps are activated. Most likely they are activated by an interaction of several metabolic steps, but we will need more high-powered analysis to determine how this interaction functions.
{"title":"One-half century (or more) of study of cell death: origins, present, and perhaps future","authors":"R. Lockshin","doi":"10.3389/fceld.2023.1197400","DOIUrl":"https://doi.org/10.3389/fceld.2023.1197400","url":null,"abstract":"The concept of biological cell death—that is, cell death that is neither accidental nor chaotic—has existed and has been obvious since at least the beginning of the 20th C, but it was noticed by other than specialists apt choices of words that caught the spirit of the time, “programmed cell death” and “apoptosis” caught the attention of a wider range of scientists. Then, by the early 1990s the recognition of at least two genes that were important to cancer and other diseases by controlling cell death (p53, Bcl-2, and Fas); recognition that cell death could be controlled by a highly conserved family of proteases; and the development of rapid and easy means of measuring cell death, led to the explosion of the field as a subject of research. Today we recognize many variations on the theme of biological cell death, but many mysteries remain. The most important of these remaining mysteries is that we recognize many of the penultimate and ultimate steps to kill cells, but it is rarely clear how and why these steps are activated. Most likely they are activated by an interaction of several metabolic steps, but we will need more high-powered analysis to determine how this interaction functions.","PeriodicalId":73072,"journal":{"name":"Frontiers in cell death","volume":"14 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72557402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-04-17DOI: 10.3389/fceld.2023.1169966
Debbra Y. Knorr, D. Demirbas, R. Heinrich
Elevated expression of acetylcholinesterase (AChE) is a common characteristic of apoptotic cells in both invertebrate and vertebrate species. While increased levels of acetylcholinesterase sensitize cells to apoptogenic stimuli, its absence or pharmacological inactivation interferes with apoptotic cell death. acetylcholinesterase may exert its pro-apoptotic function directly as an integral component of the apoptotic molecular machinery or indirectly by limiting the availability of receptor ligands and structural binding partners that promote cell survival under non-apoptogenic conditions. acetylcholinesterase promotes formation of the apoptosome and degrades DNA after nuclear accumulation. Its esterase activity limits the availability of acetylcholine as ligand for cell membrane-located nicotinic and muscarinic ACh-receptors and mitochondrial nicotinic ACh-receptors that normally support vital physiological states. Studies on insects suggest, that cytokine-activated cell-protective pathways may suppress acetylcholinesterase overexpression under apoptogenic conditions to prevent apoptotic cell death. We provide an overview of studies on various organisms and cell types that summarizes the contribution of acetylcholinesterase to the progress of apoptosis via multiple mechanisms.
{"title":"Multifaceted promotion of apoptosis by acetylcholinesterase","authors":"Debbra Y. Knorr, D. Demirbas, R. Heinrich","doi":"10.3389/fceld.2023.1169966","DOIUrl":"https://doi.org/10.3389/fceld.2023.1169966","url":null,"abstract":"Elevated expression of acetylcholinesterase (AChE) is a common characteristic of apoptotic cells in both invertebrate and vertebrate species. While increased levels of acetylcholinesterase sensitize cells to apoptogenic stimuli, its absence or pharmacological inactivation interferes with apoptotic cell death. acetylcholinesterase may exert its pro-apoptotic function directly as an integral component of the apoptotic molecular machinery or indirectly by limiting the availability of receptor ligands and structural binding partners that promote cell survival under non-apoptogenic conditions. acetylcholinesterase promotes formation of the apoptosome and degrades DNA after nuclear accumulation. Its esterase activity limits the availability of acetylcholine as ligand for cell membrane-located nicotinic and muscarinic ACh-receptors and mitochondrial nicotinic ACh-receptors that normally support vital physiological states. Studies on insects suggest, that cytokine-activated cell-protective pathways may suppress acetylcholinesterase overexpression under apoptogenic conditions to prevent apoptotic cell death. We provide an overview of studies on various organisms and cell types that summarizes the contribution of acetylcholinesterase to the progress of apoptosis via multiple mechanisms.","PeriodicalId":73072,"journal":{"name":"Frontiers in cell death","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77340781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-04-06DOI: 10.3389/fceld.2023.1184041
Daniel Domínguez, Yun Fan
The role of caspases, or cysteine-aspartic proteases, in apoptosis has been well-studied across multiple organisms. These apoptotic caspases can be divided into initiator and effector caspases, with the former cleaving and activating the latter to trigger cell death. However, emerging evidence is supporting non-lethal roles of caspases in development, tissue homeostasis and disease. In comparison to effector caspases, less is known about the non-apoptotic functions of initiator caspases because of their more restricted activities and fewer known substrates. This review focuses on some recent findings in Drosophila on non-lethal roles of the initiator caspase Dronc. We discuss their biological importance, underlying regulatory mechanisms, and implications for our understanding of their mammalian counterparts. Deciphering the non-apoptotic functions of Dronc will provide valuable insights into the multifaceted functions of caspases during development and in diseases including cancer.
{"title":"Non-lethal roles of the initiator caspase Dronc in Drosophila","authors":"Daniel Domínguez, Yun Fan","doi":"10.3389/fceld.2023.1184041","DOIUrl":"https://doi.org/10.3389/fceld.2023.1184041","url":null,"abstract":"The role of caspases, or cysteine-aspartic proteases, in apoptosis has been well-studied across multiple organisms. These apoptotic caspases can be divided into initiator and effector caspases, with the former cleaving and activating the latter to trigger cell death. However, emerging evidence is supporting non-lethal roles of caspases in development, tissue homeostasis and disease. In comparison to effector caspases, less is known about the non-apoptotic functions of initiator caspases because of their more restricted activities and fewer known substrates. This review focuses on some recent findings in Drosophila on non-lethal roles of the initiator caspase Dronc. We discuss their biological importance, underlying regulatory mechanisms, and implications for our understanding of their mammalian counterparts. Deciphering the non-apoptotic functions of Dronc will provide valuable insights into the multifaceted functions of caspases during development and in diseases including cancer.","PeriodicalId":73072,"journal":{"name":"Frontiers in cell death","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83205560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-04-05DOI: 10.3389/fceld.2023.1127330
Maria Ladik, Hana Valenta, M. Erard, P. Vandenabeele, Franck B. Riquet
The formation of molecular complexes is a key feature of intracellular signaling pathways which governs to the initiation and execution of dedicated cellular processes. Tumor Necrosis Factor (TNF) and Reactive Oxygen Species (ROS) function as signaling molecules and are both involved in balancing cell fate decision between cell survival or cell demise. As master regulators of cell signaling, they are also instrumental in controlling various cellular processes towards tissue homeostasis, innate immunity and inflammation. Interestingly, TNF and ROS are interlinked and involved in regulating each other’s production via the engagement of molecular signaling complexes. This relationship calls for detailed reviewing of both TNF-induced and ROS-producing molecular complexes in the context of regulated cell death (RCD) modalities. Here, we outline biotechnological approaches that were used to investigate the TNF- and, concerning ROS, the NADPH oxidase-related molecular complexes with an emphasis on different regulated cell death modalities. This systematic review highlights how the cell death field has benefited from both biochemical and live-cell fluorescence imaging approaches. This knowledge and established workflows are highly generalizable, can be of a broader use for any protein-complex studies, and well suited for addressing new challenges in signaling dynamics. These will help understand molecular signaling complexes as ensembles organized into signaling platforms, most likely the key sites of signaling dynamics integration toward cell fate regulation.
{"title":"From TNF-induced signaling to NADPH oxidase enzyme activity: Methods to investigate protein complexes involved in regulated cell death modalities","authors":"Maria Ladik, Hana Valenta, M. Erard, P. Vandenabeele, Franck B. Riquet","doi":"10.3389/fceld.2023.1127330","DOIUrl":"https://doi.org/10.3389/fceld.2023.1127330","url":null,"abstract":"The formation of molecular complexes is a key feature of intracellular signaling pathways which governs to the initiation and execution of dedicated cellular processes. Tumor Necrosis Factor (TNF) and Reactive Oxygen Species (ROS) function as signaling molecules and are both involved in balancing cell fate decision between cell survival or cell demise. As master regulators of cell signaling, they are also instrumental in controlling various cellular processes towards tissue homeostasis, innate immunity and inflammation. Interestingly, TNF and ROS are interlinked and involved in regulating each other’s production via the engagement of molecular signaling complexes. This relationship calls for detailed reviewing of both TNF-induced and ROS-producing molecular complexes in the context of regulated cell death (RCD) modalities. Here, we outline biotechnological approaches that were used to investigate the TNF- and, concerning ROS, the NADPH oxidase-related molecular complexes with an emphasis on different regulated cell death modalities. This systematic review highlights how the cell death field has benefited from both biochemical and live-cell fluorescence imaging approaches. This knowledge and established workflows are highly generalizable, can be of a broader use for any protein-complex studies, and well suited for addressing new challenges in signaling dynamics. These will help understand molecular signaling complexes as ensembles organized into signaling platforms, most likely the key sites of signaling dynamics integration toward cell fate regulation.","PeriodicalId":73072,"journal":{"name":"Frontiers in cell death","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75368004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-01Epub Date: 2023-07-03DOI: 10.3389/fceld.2023.1223926
James H Schofield, Zachary T Schafer
The induction of apoptosis, a programmed cell death pathway governed by activation of caspases, can result in fundamental changes in metabolism that either facilitate or restrict the execution of cell death. In addition, metabolic adaptations can significantly impact whether cells in fact initiate the apoptotic cascade. In this mini-review, we will highlight and discuss the interconnectedness of apoptotic regulation and metabolic alterations, two biological outcomes whose regulators are intertwined.
{"title":"Regulators mount up: the metabolic roles of apoptotic proteins.","authors":"James H Schofield, Zachary T Schafer","doi":"10.3389/fceld.2023.1223926","DOIUrl":"10.3389/fceld.2023.1223926","url":null,"abstract":"<p><p>The induction of apoptosis, a programmed cell death pathway governed by activation of caspases, can result in fundamental changes in metabolism that either facilitate or restrict the execution of cell death. In addition, metabolic adaptations can significantly impact whether cells in fact initiate the apoptotic cascade. In this mini-review, we will highlight and discuss the interconnectedness of apoptotic regulation and metabolic alterations, two biological outcomes whose regulators are intertwined.</p>","PeriodicalId":73072,"journal":{"name":"Frontiers in cell death","volume":"2 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10373711/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9916139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-01Epub Date: 2023-02-26DOI: 10.3389/fceld.2023.1147605
Samantha J Hack, Wendy S Beane, Kelly Ai-Sun Tseng
Recent studies have furthered our understanding of how dying and living cells interact in different physiological contexts, however the signaling that initiates and mediates apoptosis and apoptosis-induced proliferation are more complex than previously thought. One increasingly important area of study is the biophysical control of apoptosis. In addition to biochemical regulation, biophysical signals (including redox chemistry, bioelectric gradients, acoustic and magnetic stimuli) are also known yet understudied regulators of both cell death and apoptosis-induced proliferation. Mounting evidence suggests biophysical signals may be key targets for therapeutic interventions. This review highlights what is known about the role of biophysical signals in controlling cell death mechanisms during development, regeneration, and carcinogenesis. Since biophysical signals can be controlled spatiotemporally, bypassing the need for genetic manipulation, further investigation may lead to fine-tuned modulation of apoptotic pathways to direct desired therapeutic outcomes.
{"title":"Biophysics at the edge of life and death: radical control of apoptotic mechanisms.","authors":"Samantha J Hack, Wendy S Beane, Kelly Ai-Sun Tseng","doi":"10.3389/fceld.2023.1147605","DOIUrl":"10.3389/fceld.2023.1147605","url":null,"abstract":"<p><p>Recent studies have furthered our understanding of how dying and living cells interact in different physiological contexts, however the signaling that initiates and mediates apoptosis and apoptosis-induced proliferation are more complex than previously thought. One increasingly important area of study is the biophysical control of apoptosis. In addition to biochemical regulation, biophysical signals (including redox chemistry, bioelectric gradients, acoustic and magnetic stimuli) are also known yet understudied regulators of both cell death and apoptosis-induced proliferation. Mounting evidence suggests biophysical signals may be key targets for therapeutic interventions. This review highlights what is known about the role of biophysical signals in controlling cell death mechanisms during development, regeneration, and carcinogenesis. Since biophysical signals can be controlled spatiotemporally, bypassing the need for genetic manipulation, further investigation may lead to fine-tuned modulation of apoptotic pathways to direct desired therapeutic outcomes.</p>","PeriodicalId":73072,"journal":{"name":"Frontiers in cell death","volume":"71 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11784940/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86599346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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