Mechanisms of Regulated Cell Death: Current Perspectives

2021 ◽  
pp. 030098582110055
Author(s):  
Sara Francesca Santagostino ◽  
Charles-Antoine Assenmacher ◽  
James C. Tarrant ◽  
Adeyemi O. Adedeji ◽  
Enrico Radaelli
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Regulated Cell Death ◽  
Morphologic Characteristics ◽  
Adaptive Processes ◽  
Molecular Machinery ◽  
Extracellular Microenvironment ◽  
Apoptosis And Necrosis ◽  
Microscopic Findings

Balancing cell survival and cell death is fundamental to development and homeostasis. Cell death is regulated by multiple interconnected signaling pathways and molecular mechanisms. Regulated cell death (RCD) is implicated in fundamental processes such as organogenesis and tissue remodeling, removal of unnecessary structures or cells, and regulation of cell numbers. RCD can also be triggered by exogenous perturbations of the intracellular or extracellular microenvironment when the adaptive processes that respond to stress fail. During the past few years, many novel forms of non-apoptotic RCD have been identified, and the characterization of RCD mechanisms at a molecular level has deepened our understanding of diseases encountered in human and veterinary medicine. Given the complexity of these processes, it has become clear that the identification of RCD cannot be based simply on morphologic characteristics and that descriptive and diagnostic terms presently used by pathologists—such as individual cell apoptosis or necrosis—appear inadequate and possibly misleading. In this review, the current understanding of the molecular machinery of each type of non-apoptotic RCD mechanisms is outlined. Due to the continuous discovery of new mechanisms or nuances of previously described processes, the limitations of the terms apoptosis and necrosis to indicate microscopic findings are also reported. In addition, the need for a standard panel of biomarkers and functional tests to adequately characterize the underlying RCD and its role as a mechanism of disease is considered.

scholarly journals The Evolving Role of Ferroptosis in Breast Cancer: Translational Implications Present and Future

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4576
Author(s):  
Hung-Yu Lin ◽  
Hui-Wen Ho ◽  
Yen-Hsiang Chang ◽  
Chun-Jui Wei ◽  
Pei-Yi Chu
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Drug Resistant ◽  
Therapeutic Targeting ◽  
The Past ◽  
Regulated Cell Death ◽  
Common Malignancy

Breast cancer (BC) is the most common malignancy among women worldwide. The discovery of regulated cell death processes has enabled advances in the treatment of BC. In the past decade, ferroptosis, a new form of iron-dependent regulated cell death caused by excessive lipid peroxidation has been implicated in the development and therapeutic responses of BC. Intriguingly, the induction of ferroptosis acts to suppress conventional therapy-resistant cells, and to potentiate the effects of immunotherapy. As such, pharmacological or genetic modulation targeting ferroptosis holds great potential for the treatment of drug-resistant cancers. In this review, we present a critical analysis of the current understanding of the molecular mechanisms and regulatory networks involved in ferroptosis, the potential physiological functions of ferroptosis in tumor suppression, its potential in therapeutic targeting, and explore recent advances in the development of therapeutic strategies for BC.

scholarly journals The emerging role of ferroptosis in non-cancer liver diseases: hype or increasing hope?

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Lihong Mao ◽  
Tianming Zhao ◽  
Yan Song ◽  
Lin Lin ◽  
Xiaofei Fan ◽  
...  
Keyword(s):  
Cell Death ◽  
Liver Diseases ◽  
Therapeutic Strategy ◽  
Kidney Injury ◽  
Hepatic Disease ◽  
Therapeutic Concept ◽  
Regulated Cell Death ◽  
Dependent Form ◽  
Molecular Machinery

Abstract Ferroptosis is an iron- and lipotoxicity-dependent form of regulated cell death (RCD). It is morphologically and biochemically distinct from characteristics of other cell death. This modality has been intensively investigated in recent years due to its involvement in a wide array of pathologies, including cancer, neurodegenerative diseases, and acute kidney injury. Dysregulation of ferroptosis has also been linked to various liver diseases and its modification may provide a hopeful and attractive therapeutic concept. Indeed, targeting ferroptosis may prevent the pathophysiological progression of several liver diseases, such as hemochromatosis, nonalcoholic steatohepatitis, and ethanol-induced liver injury. On the contrary, enhancing ferroptosis may promote sorafenib-induced ferroptosis and pave the way for combination therapy in hepatocellular carcinoma. Glutathione peroxidase 4 (GPx4) and system xc− have been identified as key players to mediate ferroptosis pathway. More recently diverse signaling pathways have also been observed. The connection between ferroptosis and other forms of RCD is intricate and compelling, where discoveries in this field advance our understanding of cell survival and fate. In this review, we summarize the central molecular machinery of ferroptosis, describe the role of ferroptosis in non-cancer hepatic disease conditions and discuss the potential to manipulate ferroptosis as a therapeutic strategy.

scholarly journals Comprehensive Map of the Regulated Cell Death Signaling Network: A Powerful Analytical Tool for Studying Diseases

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 990
Author(s):  
Jean-Marie Ravel ◽  
L. Cristobal Monraz Gomez ◽  
Nicolas Sompairac ◽  
Laurence Calzone ◽  
Boris Zhivotovsky ◽  
...  
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Signaling Network ◽  
Tumor Subtypes ◽  
Navigation Data ◽  
Manual Curation ◽  
Regulated Cell Death ◽  
Powerful Analytical Tool ◽  
Cell Death Signaling ◽  
The Difference

The processes leading to, or avoiding cell death are widely studied, because of their frequent perturbation in various diseases. Cell death occurs in three highly interconnected steps: Initiation, signaling and execution. We used a systems biology approach to gather information about all known modes of regulated cell death (RCD). Based on the experimental data retrieved from literature by manual curation, we graphically depicted the biological processes involved in RCD in the form of a seamless comprehensive signaling network map. The molecular mechanisms of each RCD mode are represented in detail. The RCD network map is divided into 26 functional modules that can be visualized contextually in the whole seamless network, as well as in individual diagrams. The resource is freely available and accessible via several web platforms for map navigation, data integration, and analysis. The RCD network map was employed for interpreting the functional differences in cell death regulation between Alzheimer’s disease and non-small cell lung cancer based on gene expression data that allowed emphasizing the molecular mechanisms underlying the inverse comorbidity between the two pathologies. In addition, the map was used for the analysis of genomic and transcriptomic data from ovarian cancer patients that provided RCD map-based signatures of four distinct tumor subtypes and highlighted the difference in regulations of cell death molecular mechanisms.

scholarly journals Discovery and molecular characterization of a Bcl-2-regulated cell death pathway in schistosomes

2011 ◽  
Vol 108 (17) ◽  
pp. 6999-7003 ◽  
Author(s):  
E. F. Lee ◽  
O. B. Clarke ◽  
M. Evangelista ◽  
Z. Feng ◽  
T. P. Speed ◽  
...  
Keyword(s):  
Cell Death ◽  
Molecular Characterization ◽  
Cell Death Pathway ◽  
Regulated Cell Death

scholarly journals Molecular Mechanisms of Ferroptosis and Its Roles in Hematologic Malignancies

2021 ◽  
Vol 11 ◽  
Author(s):  
Yan Zhao ◽  
Zineng Huang ◽  
Hongling Peng
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Hematological Malignancies ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Lipid Peroxide ◽  
Kidney Injury ◽  
Hematologic Malignancies ◽  
Regulated Cell Death ◽  
Normal Metabolism

Cell death is essential for the normal metabolism of human organisms. Ferroptosis is a unique regulated cell death (RCD) mode characterized by excess accumulation of iron-dependent lipid peroxide and reactive oxygen species (ROS) compared with other well-known programmed cell death modes. It has been currently recognized that ferroptosis plays a rather important role in the occurrence, development, and treatment of traumatic brain injury, stroke, acute kidney injury, liver damage, ischemia–reperfusion injury, tumor, etc. Of note, ferroptosis may be explained by the expression of various molecules and signaling components, among which iron, lipid, and amino acid metabolism are the key regulatory mechanisms of ferroptosis. Meanwhile, tumor cells of hematological malignancies, such as leukemia, lymphoma, and multiple myeloma (MM), are identified to be sensitive to ferroptosis. Targeting potential regulatory factors in the ferroptosis pathway may promote or inhibit the disease progression of these malignancies. In this review, a systematic summary was conducted on the key molecular mechanisms of ferroptosis and the current potential relationships of ferroptosis with leukemia, lymphoma, and MM. It is expected to provide novel potential therapeutic approaches and targets for hematological malignancies.

scholarly journals Mitochondrial active Ras2 protein promotes apoptosis and regulated cell death in a cAMP/PKA pathway-dependent manner in budding yeast.

2021 ◽  
Author(s):  
Barbara Bonomelli ◽  
Enzo Martegani ◽  
Sonia Colombo
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Cell Death ◽  
Acetic Acid ◽  
Dependent Manner ◽  
Ras Proteins ◽  
Wild Type ◽  
High Affinity ◽  
Regulated Cell Death ◽  
Molecular Machinery ◽  
Pka Pathway

In previous papers, using the eGFP-RBD3 probe, which binds Ras-GTP with high affinity, we showed that activated Ras proteins are localized to the plasma membrane and in the nucleus in wild-type Saccharomyces cerevisiae cells growing exponentially on glucose, while an aberrant accumulation of activated Ras in mitochondria correlates to mitochondrial dysfunction, accumulation of ROS and an increase of apoptosis. In this paper, we show that lack of TPS1, which is known to trigger apoptosis in S. cerevisiae, induces localization of active Ras proteins in mitochondria, confirming the above-mentioned correlation. Next, by characterizing the ras1Δ and ras2Δ mutants concerning localization of active Ras proteins and propensity to undergo cell death, we show that active Ras2 proteins, which accumulate in the mitochondria following addition of acetic acid, a well-known pro-apoptotic stimulus, might be the GTPases involved in regulated cell death, while active Ras1 proteins, constitutively localized in mitochondria, might be involved in a pro-survival molecular machinery. Finally, by characterizing the gpa2Δ and cyr1Δ mutants concerning the propensity to undergo cell death, we show that active mitochondrial Ras proteins promote apoptosis through the cAMP/PKA pathway.

scholarly journals Yeast Cells Exposed to Exogenous Palmitoleic Acid Either Adapt to Stress and Survive or Commit to Regulated Liponecrosis and Die

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Karamat Mohammad ◽  
Paméla Dakik ◽  
Younes Medkour ◽  
Mélissa McAuley ◽  
Darya Mitrofanova ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Lipid Metabolism ◽  
Lipid Droplets ◽  
Palmitoleic Acid ◽  
Molecular Mechanisms ◽  
Neutral Lipids ◽  
Yeast Cells ◽  
Cellular Processes ◽  
Regulated Cell Death

A disturbed homeostasis of cellular lipids and the resulting lipotoxicity are considered to be key contributors to many human pathologies, including obesity, metabolic syndrome, type 2 diabetes, cardiovascular diseases, and cancer. The yeast Saccharomyces cerevisiae has been successfully used for uncovering molecular mechanisms through which impaired lipid metabolism causes lipotoxicity and elicits different forms of regulated cell death. Here, we discuss mechanisms of the “liponecrotic” mode of regulated cell death in S. cerevisiae. This mode of regulated cell death can be initiated in response to a brief treatment of yeast with exogenous palmitoleic acid. Such treatment prompts the incorporation of exogenously added palmitoleic acid into phospholipids and neutral lipids. This orchestrates a global remodeling of lipid metabolism and transfer in the endoplasmic reticulum, mitochondria, lipid droplets, and the plasma membrane. Certain features of such remodeling play essential roles either in committing yeast to liponecrosis or in executing this mode of regulated cell death. We also outline four processes through which yeast cells actively resist liponecrosis by adapting to the cellular stress imposed by palmitoleic acid and maintaining viability. These prosurvival cellular processes are confined in the endoplasmic reticulum, lipid droplets, peroxisomes, autophagosomes, vacuoles, and the cytosol.

scholarly journals The Role of Necroptosis in ROS-Mediated Cancer Therapies and Its Promising Applications

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2185
Author(s):  
Sheng-Kai Hsu ◽  
Wen-Tsan Chang ◽  
I-Ling Lin ◽  
Yih-Fung Chen ◽  
Nitin Balkrushna Padalwar ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Biology ◽  
Molecular Mechanisms ◽  
Apoptotic Cell ◽  
Close Correlation ◽  
Apoptotic Cell Death ◽  
Cancer Therapies ◽  
Independent Form ◽  
Potential Strategy ◽  
Apoptosis And Necrosis

Over the past decades, promising therapies targeting different signaling pathways have emerged. Among these pathways, apoptosis has been well investigated and targeted to design diverse chemotherapies. However, some patients are chemoresistant to these therapies due to compromised apoptotic cell death. Hence, exploring alternative treatments aimed at different mechanisms of cell death seems to be a potential strategy for bypassing impaired apoptotic cell death. Emerging evidence has shown that necroptosis, a caspase-independent form of cell death with features between apoptosis and necrosis, can overcome the predicament of drug resistance. Furthermore, previous studies have also indicated that there is a close correlation between necroptosis and reactive oxygen species (ROS); both necroptosis and ROS play significant roles both under human physiological conditions such as the regulation of inflammation and in cancer biology. Several small molecules used in experiments and clinical practice eliminate cancer cells via the modulation of ROS and necroptosis. The molecular mechanisms of these promising therapies are discussed in detail in this review.

scholarly journals The Molecular Mechanisms of Iron Metabolism and Its Role in Cardiac Dysfunction and Cardioprotection

2020 ◽  
Vol 21 (21) ◽  
pp. 7889 ◽  
Author(s):  
Tanya Ravingerová ◽  
Lucia Kindernay ◽  
Monika Barteková ◽  
Miroslav Ferko ◽  
Adriana Adameová ◽  
...  
Keyword(s):  
Cell Death ◽  
Iron Metabolism ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion ◽  
Physiological Role ◽  
Cellular Respiration ◽  
Protective Mechanisms ◽  
Alcoholic Fatty Liver ◽  
Regulated Cell Death ◽  
Wide Range

Iron is an essential mineral participating in different functions of the organism under physiological conditions. Numerous biological processes, such as oxygen and lipid metabolism, protein production, cellular respiration, and DNA synthesis, require the presence of iron, and mitochondria play an important role in the processes of iron metabolism. In addition to its physiological role, iron may be also involved in the adaptive processes of myocardial “conditioning”. On the other hand, disorders of iron metabolism are involved in the pathological mechanisms of the most common human diseases and include a wide range of them, such as type 2 diabetes, obesity, and non-alcoholic fatty liver disease, and accelerate the development of atherosclerosis. Furthermore, iron also exerts potentially deleterious effects that may be manifested under conditions of ischemia/reperfusion (I/R) injury, myocardial infarction, heart failure, coronary artery angioplasty, or heart transplantation, due to its involvement in reactive oxygen species (ROS) production. Moreover, iron has been recently described to participate in the mechanisms of iron-dependent cell death defined as “ferroptosis”. Ferroptosis is a form of regulated cell death that is distinct from apoptosis, necroptosis, and other types of cell death. Ferroptosis has been shown to be associated with I/R injury and several other cardiac diseases as a significant form of cell death in cardiomyocytes. In this review, we will discuss the role of iron in cardiovascular diseases, especially in myocardial I/R injury, and protective mechanisms stimulated by different forms of “conditioning” with a special emphasis on the novel targets for cardioprotection.

scholarly journals Genome-wide characterization of SARS-CoV-2 cytopathogenic proteins in the search of antiviral targets

2021 ◽  
Author(s):  
Jiantao Zhang ◽  
Qi Li ◽  
Ruth S. Cruz Cosme ◽  
Vladimir Gerzanich ◽  
Qiyi Tang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Mammalian Cells ◽  
Cellular Proliferation ◽  
Nf Kappa B ◽  
Cytopathic Effects ◽  
Genome Wide ◽  
Antiviral Targets ◽  
Apoptosis And Necrosis

Therapeutic inhibition of critical viral functions is important for curtailing coronavirus disease-2019 (COVID-19). We sought to identify antiviral targets through genome-wide characterization of SARS-CoV-2 proteins that are crucial for viral pathogenesis and that cause harmful cytopathic effects. All twenty-nine viral proteins were tested in a fission yeast cell-based system using inducible gene expression. Twelve proteins including eight non-structural proteins (NSP1, NSP3, NSP4, NSP5, NSP6, NSP13, NSP14 and NSP15) and four accessory proteins (ORF3a, ORF6, ORF7a and ORF7b) were identified that altered cellular proliferation and integrity, and induced cell death. Cell death correlated with the activation of cellular oxidative stress. Of the twelve proteins, ORF3a was chosen for further study in mammalian cells. In human pulmonary and kidney epithelial cells, ORF3a induced cellular oxidative stress associated with apoptosis and necrosis, and caused activation of pro-inflammatory response with production of the cytokines TNF-alpha, IL-6, and IFN-beta1, possibly through the activation of NF-kappa B. To further characterize the mechanism, we tested a natural ORF3a Beta variant, Q57H, and a mutant with deletion of the highly conserved residue, deltaG188. Compared to wild type ORF3a, the delataG188 variant yielded more robust activation of cellular oxidative stress, cell death, and innate immune response. Since cellular oxidative stress and inflammation contribute to cell death and tissue damage linked to the severity of COVID-19, our findings suggest that ORF3a is a promising, novel therapeutic target against COVID-19.

Sign in / Sign up

Export Citation Format

Share Document