Editorial: Yeast Differentiation: From Cell-to-Cell Heterogeneity to Replicative Aging and Regulated Cell Death

AbstractRegulated cell death is essential in development and cellular homeostasis. Multi-protein platforms, including the Death-Inducing Signaling Complex (DISC), co-ordinate cell fate via a core FADD:Caspase-8 complex and its regulatory partners, such as the cell death inhibitor c-FLIP. Here, using electron microscopy, we visualize full-length procaspase-8 in complex with FADD. Our structural analysis now reveals how the FADD-nucleated tandem death effector domain (tDED) helical filament is required to orientate the procaspase-8 catalytic domains, enabling their activation via anti-parallel dimerization. Strikingly, recruitment of c-FLIPS into this complex inhibits Caspase-8 activity by altering tDED triple helix architecture, resulting in steric hindrance of the canonical tDED Type I binding site. This prevents both Caspase-8 catalytic domain assembly and tDED helical filament elongation. Our findings reveal how the plasticity, composition and architecture of the core FADD:Caspase-8 complex critically defines life/death decisions not only via the DISC, but across multiple key signaling platforms including TNF complex II, the ripoptosome, and RIPK1/RIPK3 necrosome.

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Lytic regulated cell death in aquaculture fish

Reviews in Aquaculture ◽

10.1111/raq.12533 ◽

2021 ◽

Author(s):

Xiaojing Xia ◽

Bin He ◽

Xiulin Zhang ◽

Zhe Cheng ◽

Mingcheng Liu ◽

...

Keyword(s):

Cell Death ◽

Regulated Cell Death ◽

Aquaculture Fish

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Implication of ferroptosis in aging

Cell Death Discovery ◽

10.1038/s41420-021-00553-6 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Maryam Mazhar ◽

Ahmad Ud Din ◽

Hamid Ali ◽

Guoqiang Yang ◽

Wei Ren ◽

...

Keyword(s):

Cell Death ◽

Neurological Disorders ◽

Accelerated Aging ◽

Underlying Mechanism ◽

Toxic Chemicals ◽

Whole Body ◽

Regulated Cell Death ◽

Age Related ◽

The Subject ◽

Conventional Cell

AbstractLife is indeed continuously going through the irreversible and inevitable process of aging. The rate of aging process depends on various factors and varies individually. These factors include various environmental stimuli including exposure to toxic chemicals, psychological stress whereas suffering with various illnesses specially the chronic diseases serve as endogenous triggers. The basic underlying mechanism for all kinds of stresses is now known to be manifested as production of excessive ROS, exhaustion of ROS neutralizing antioxidant enzymes and proteins leading to imbalance in oxidation and antioxidant processes with subsequent oxidative stress induced inflammation affecting the cells, tissues, organs and the whole body. All these factors lead to conventional cell death either through necrosis, apoptosis, or autophagy. Currently, a newly identified mechanism of iron dependent regulated cell death called ferroptosis, is of special interest for its implication in pathogenesis of various diseases such as cardiovascular disease, neurological disorders, cancers, and various other age-related disorders (ARD). In ferroptosis, the cell death occur neither by conventional apoptosis, necrosis nor by autophagy, rather dysregulated iron in the cell mediates excessive lipid peroxidation of accumulated lethal lipids. It is not surprising to assume its role in aging as previous research have identified some solid cues on the subject. In this review, we will highlight the factual evidences to support the possible role and implication of ferroptosis in aging in order to declare the need to identify and explore the interventions to prevent excessive ferroptosis leading to accelerated aging and associated liabilities of aging.

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Biomarkers of Radiotherapy-Induced Immunogenic Cell Death

Cells ◽

10.3390/cells10040930 ◽

2021 ◽

Vol 10 (4) ◽

pp. 930

Author(s):

Rianne D. W. Vaes ◽

Lizza E. L. Hendriks ◽

Marc Vooijs ◽

Dirk De Ruysscher

Keyword(s):

Cell Death ◽

Immune Responses ◽

Tumor Cells ◽

Immunogenic Cell Death ◽

Type I ◽

Future Studies ◽

Regulated Cell Death ◽

Molecular Patterns ◽

Damage Associated Molecular Patterns ◽

Potential Biomarkers

Radiation therapy (RT) can induce an immunogenic variant of regulated cell death that can initiate clinically relevant tumor-targeting immune responses. Immunogenic cell death (ICD) is accompanied by the exposure and release of damage-associated molecular patterns (DAMPs), chemokine release, and stimulation of type I interferon (IFN-I) responses. In recent years, intensive research has unraveled major mechanistic aspects of RT-induced ICD and has resulted in the identification of immunogenic factors that are released by irradiated tumor cells. However, so far, only a limited number of studies have searched for potential biomarkers that can be used to predict if irradiated tumor cells undergo ICD that can elicit an effective immunogenic anti-tumor response. In this article, we summarize the available literature on potential biomarkers of RT-induced ICD that have been evaluated in cancer patients. Additionally, we discuss the clinical relevance of these findings and important aspects that should be considered in future studies.

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Oxidative stress and regulated cell death in Parkinson’s disease

Ageing Research Reviews ◽

10.1016/j.arr.2021.101263 ◽

2021 ◽

Vol 67 ◽

pp. 101263

Author(s):

P.A. Dionísio ◽

J.D. Amaral ◽

C.M.P. Rodrigues

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cell Death ◽

Regulated Cell Death

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Lipid peroxidation and the subsequent cell death transmitting from ferroptotic cells to neighboring cells

Cell Death and Disease ◽

10.1038/s41419-021-03613-y ◽

2021 ◽

Vol 12 (4) ◽

Author(s):

Hironari Nishizawa ◽

Mitsuyo Matsumoto ◽

Guan Chen ◽

Yusho Ishii ◽

Keisuke Tada ◽

...

Keyword(s):

Lipid Peroxidation ◽

Cell Death ◽

Lipid Peroxide ◽

Nih3t3 Cells ◽

Regulated Cell Death ◽

Primary Mouse ◽

Ischemic Diseases ◽

A Chain ◽

Dying Cells

AbstractFerroptosis is a regulated cell death due to the iron-dependent accumulation of lipid peroxide. Ferroptosis is known to constitute the pathology of ischemic diseases, neurodegenerative diseases, and steatohepatitis and also works as a suppressing mechanism against cancer. However, how ferroptotic cells affect surrounding cells remains elusive. We herein report the transfer phenomenon of lipid peroxidation and cell death from ferroptotic cells to nearby cells that are not exposed to ferroptotic inducers (FINs). While primary mouse embryonic fibroblasts (MEFs) and NIH3T3 cells contained senescence-associated β-galactosidase (SA-β-gal)-positive cells, they were decreased upon induction of ferroptosis with FINs. The SA-β-gal decrease was inhibited by ferroptotic inhibitors and knockdown of Atg7, pointing to the involvement of lipid peroxidation and activated autophagosome formation during ferroptosis. A transfer of cell culture medium of cells treated with FINs, type 1 or 2, caused the reduction in SA-β-gal-positive cells in recipient cells that had not been exposed to FINs. Real-time imaging of Kusabira Orange-marked reporter MEFs cocultured with ferroptotic cells showed the generation of lipid peroxide and deaths of the reporter cells. These results indicate that lipid peroxidation and its aftereffects propagate from ferroptotic cells to surrounding cells, even when the surrounding cells are not exposed to FINs. Ferroptotic cells are not merely dying cells but also work as signal transmitters inducing a chain of further ferroptosis.

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Ion channels in regulated cell death

Cellular and Molecular Life Sciences ◽

10.1007/s00018-016-2208-z ◽

2016 ◽

Vol 73 (11-12) ◽

pp. 2387-2403 ◽

Cited By ~ 46

Author(s):

Karl Kunzelmann

Keyword(s):

Cell Death ◽

Ion Channels ◽

Regulated Cell Death

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AnIn VivoZebrafish Model for Interrogating ROS-Mediated Pancreaticβ-Cell Injury, Response, and Prevention

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/1324739 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8 ◽

Cited By ~ 7

Author(s):

Abhishek A. Kulkarni ◽

Abass M. Conteh ◽

Cody A. Sorrell ◽

Anjali Mirmira ◽

Sarah A. Tersey ◽

...

Keyword(s):

Cell Death ◽

Caspase 3 ◽

Cell Injury ◽

Zebrafish Model ◽

Chemical Genetic ◽

Regulated Cell Death ◽

Specific Manner ◽

High Doses

It is well known that a chronic state of elevated reactive oxygen species (ROS) in pancreaticβ-cells impairs their ability to release insulin in response to elevated plasma glucose. Moreover, at its extreme, unmitigated ROS drives regulated cell death. This dysfunctional state of ROS buildup can result both from genetic predisposition and environmental factors such as obesity and overnutrition. Importantly, excessive ROS buildup may underlie metabolic pathologies such as type 2 diabetes mellitus. The ability to monitor ROS dynamics inβ-cells in situ and to manipulate it via genetic, pharmacological, and environmental means would accelerate the development of novel therapeutics that could abate this pathology. Currently, there is a lack of models with these attributes that are available to the field. In this study, we use a zebrafish model to demonstrate that ROS can be generated in aβ-cell-specific manner using a hybrid chemical genetic approach. Using a transgenic nitroreductase-expressing zebrafish line,Tg(ins:Flag-NTR)s950, treated with the prodrug metronidazole (MTZ), we found that ROS is rapidly and explicitly generated inβ-cells. Furthermore, the level of ROS generated was proportional to the dosage of prodrug added to the system. At high doses of MTZ, caspase 3 was rapidly cleaved,β-cells underwent regulated cell death, and macrophages were recruited to the islet to phagocytose the debris. Based on our findings, we propose a model for the mechanism of NTR/MTZ action in transgenic eukaryotic cells and demonstrate the robust utility of this system to model ROS-related disease pathology.

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Recent progress in small-molecule inhibitors for critical therapeutic targets of necroptosis

Future Medicinal Chemistry ◽

10.4155/fmc-2020-0386 ◽

2021 ◽

Author(s):

Zhennan Fang ◽

Huiqiang Wei ◽

Wenfeng Gou ◽

Leyuan Chen ◽

Changfen Bi ◽

...

Keyword(s):

Cell Death ◽

Small Molecule ◽

Future Development ◽

Recent Progress ◽

Small Molecule Inhibitors ◽

Cell Necrosis ◽

Significant Progress ◽

Regulated Cell Death ◽

Associated Proteins ◽

Widespread Interest

Nonapoptotic types of regulated cell death have attracted widespread interest since the discovery that certain forms of cell necrosis can be regulated. In particular, research into cell necroptosis has made significant progress in connection with kidney, inflammatory, degenerative and neoplastic diseases. Inhibitors targeting the critical necroptosis-associated proteins RIPK1/3 and MLKL have been in development for more than a decade. Herein the authors compile a list of the known small-molecule inhibitors of these enzymes and representative structures of compounds co-crystallized with these proteins and put forward some thoughts regarding their future development.

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Abstract P419: A Systematic Characterization of Brain Endothelial Cell Death in Intracerebral Hemorrhage

Stroke ◽

10.1161/str.52.suppl_1.p419 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Maulana Ikhsan ◽

Marietta Zille

Keyword(s):

Cell Death ◽

Intracerebral Hemorrhage ◽

Brain Tissue ◽

Vascular Integrity ◽

Regulated Cell Death ◽

Injury Mechanisms ◽

Endothelial Cell Death ◽

Cell Death Mechanisms ◽

Underlying Mechanisms

Introduction: Intracerebral hemorrhage (ICH) is a type of stroke caused by the loss of vascular integrity leading to bleeding within the brain tissue. Hematoma-derived factors cause secondary injury mechanisms such as cell death days to weeks after the event and in regions distant from the primary insult. Increasing evidence suggests that hemoglobin released by the hematoma is one of the major contributors to neuronal injury in ICH. To date, it is unclear whether brain endothelial cells (EC) are similarly vulnerable to hemolysis products and undergo regulated cell death. Hypothesis: We hypothesized that brain EC undergo multiple, different modes of cell death after ICH and that the underlying mechanisms are different compared to neurons. Methods: We systematically investigated cell death mechanisms in brain EC after exposure to the hemolysis product hemin. We used chemical inhibitors of apoptosis, autophagy, ferroptosis, necroptosis, and parthanatos and assessed biochemical markers of these cell death modes. Results: Brain EC viability was concentration-dependently decreased, starting at higher hemin concentrations than neurons. Treatment of EC with ferroptosis inhibitors protective against hemin toxicity in neurons and against ICH in vivo showed that only N-acetylcysteine and deferoxamine protected brain EC, while ferrostatin-1 and U0126 did not abrogate EC death. The autophagy inhibitor bafilomycin A1 also reduced EC death and hemin increased the expression of the autophagy marker LC3. While inhibitors against apoptosis and parthanatos were not effective, the necroptosis inhibitor GSK872 demonstrated a partial protective effect. Conclusions: Our data suggest that ICH induces different mechanisms of death in EC (ferroptosis and autophagy) compared to neurons (ferroptosis and necroptosis) and may thus warrant a combinatorial therapeutic approach. Further investigations in human and ovine ICH brain tissue are ongoing.

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