Morphological Features of Cell Death

Physiology ◽  
2004 ◽  
Vol 19 (3) ◽  
pp. 124-128 ◽  
Author(s):  
U. Ziegler ◽  
P. Groscurth
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Morphological Features ◽  
Dependent Form ◽  
Energy Dependent ◽  
Apoptosis And Necrosis

Cell death is discriminated into two main forms: apoptosis and necrosis. In contrast to necrosis, apoptosis is a regulated, energy-dependent form of cell death leading to phagocytosis of cellular remnants by neighboring cells. Characteristic morphological features of these two forms of cell death will be discussed and correlated to underlying molecular mechanisms.

scholarly journals Recommendations from the INHAND Apoptosis/Necrosis Working Group

2016 ◽  
Vol 44 (2) ◽  
pp. 173-188 ◽  
Author(s):  
Susan A. Elmore ◽  
Darlene Dixon ◽  
James R. Hailey ◽  
Takanori Harada ◽  
Ronald A. Herbert ◽  
...  
Keyword(s):  
Cell Death ◽  
Single Cell ◽  
Diagnostic Criteria ◽  
General Term ◽  
Morphological Features ◽  
Cell Necrosis ◽  
Cellular Mechanisms ◽  
Mechanisms Of Toxicity ◽  
Current Guidance ◽  
Apoptosis And Necrosis

Historically, there has been confusion relating to the diagnostic nomenclature for individual cell death. Toxicologic pathologists have generally used the terms “single cell necrosis” and “apoptosis” interchangeably. Increased research on the mechanisms of cell death in recent years has led to the understanding that apoptosis and necrosis involve different cellular pathways and that these differences can have important implications when considering overall mechanisms of toxicity, and, for these reasons, the separate terms of apoptosis and necrosis should be used whenever differentiation is possible. However, it is also recognized that differentiation of the precise pathway of cell death may not be important, necessary, or possible in routine toxicity studies and so a more general term to indicate cell death is warranted in these situations. Morphological distinction between these two forms of cell death can sometimes be straightforward but can also be challenging. This article provides a brief discussion of the cellular mechanisms and morphological features of apoptosis and necrosis as well as guidance on when the pathologist should use these terms. It provides recommended nomenclature along with diagnostic criteria (in hematoxylin and eosin [H&E]-stained sections) for the most common forms of cell death (apoptosis and necrosis). This document is intended to serve as current guidance for the nomenclature of cell death for the International Harmonization of Nomenclature and Diagnostic Criteria Organ Working Groups and the toxicologic pathology community at large. The specific recommendations are: Use necrosis and apoptosis as separate diagnostic terms. Use modifiers to denote the distribution of necrosis (e.g., necrosis, single cell; necrosis, focal; necrosis, diffuse; etc.). Use the combined term apoptosis/single cell necrosis when There is no requirement or need to split the processes, or When the nature of cell death cannot be determined with certainty, or When both processes are present together. The diagnosis should be based primarily on the morphological features in H&E-stained sections. When needed, additional, special techniques to identify and characterize apoptosis can also be used.

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 Ferroptosis: molecular mechanisms and health implications

Cell Research ◽  
2020 ◽  
Author(s):  
Daolin Tang ◽  
Xin Chen ◽  
Rui Kang ◽  
Guido Kroemer
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Tissue Injury ◽  
Current Knowledge ◽  
Apoptotic Cell ◽  
Oxidation Products ◽  
Redox Active ◽  
Lipid Oxidation Products ◽  
Dependent Form ◽  
And Function

AbstractCell death can be executed through different subroutines. Since the description of ferroptosis as an iron-dependent form of non-apoptotic cell death in 2012, there has been mounting interest in the process and function of ferroptosis. Ferroptosis can occur through two major pathways, the extrinsic or transporter-dependent pathway and the intrinsic or enzyme-regulated pathway. Ferroptosis is caused by a redox imbalance between the production of oxidants and antioxidants, which is driven by the abnormal expression and activity of multiple redox-active enzymes that produce or detoxify free radicals and lipid oxidation products. Accordingly, ferroptosis is precisely regulated at multiple levels, including epigenetic, transcriptional, posttranscriptional and posttranslational layers. The transcription factor NFE2L2 plays a central role in upregulating anti-ferroptotic defense, whereas selective autophagy may promote ferroptotic death. Here, we review current knowledge on the integrated molecular machinery of ferroptosis and describe how dysregulated ferroptosis is involved in cancer, neurodegeneration, tissue injury, inflammation, and infection.

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 Progress in understanding the role of lncRNA in programmed cell death

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Na Jiang ◽  
Xiaoyu Zhang ◽  
Xuejun Gu ◽  
Xiaozhuang Li ◽  
Lei Shang
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Molecular Mechanisms ◽  
Membrane Receptors ◽  
Gene Expressions ◽  
Apoptosis Pathway ◽  
Stem Cell Pluripotency ◽  
Extrinsic Apoptosis ◽  
Related Proteins ◽  
Cycle Regulation

AbstractLong non-coding RNAs (lncRNAs) are transcripts longer than 200 nucleotides but not translated into proteins. LncRNAs regulate gene expressions at multiple levels, such as chromatin, transcription, and post-transcription. Further, lncRNAs participate in various biological processes such as cell differentiation, cell cycle regulation, and maintenance of stem cell pluripotency. We have previously reported that lncRNAs are closely related to programmed cell death (PCD), which includes apoptosis, autophagy, necroptosis, and ferroptosis. Overexpression of lncRNA can suppress the extrinsic apoptosis pathway by downregulating of membrane receptors and protect tumor cells by inhibiting the expression of necroptosis-related proteins. Some lncRNAs can also act as competitive endogenous RNA to prevent oxidation, thereby inhibiting ferroptosis, while some are known to activate autophagy. The relationship between lncRNA and PCD has promising implications in clinical research, and reports have highlighted this relationship in various cancers such as non-small cell lung cancer and gastric cancer. This review systematically summarizes the advances in the understanding of the molecular mechanisms through which lncRNAs impact PCD.

scholarly journals Molecular Mechanisms behind Inherited Neurodegeneration of the Optic Nerve

Biomolecules ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 496
Author(s):  
Alessandra Maresca ◽  
Valerio Carelli
Keyword(s):  
Optic Nerve ◽  
Mitochondrial Dysfunction ◽  
Molecular Mechanisms ◽  
Ganglion Cells ◽  
Mitochondrial Dynamics ◽  
Unmet Need ◽  
Deep Understanding ◽  
Genetic Landscape ◽  
Innovative Therapies ◽  
Energy Dependent

Inherited neurodegeneration of the optic nerve is a paradigm in neurology, as many forms of isolated or syndromic optic atrophy are encountered in clinical practice. The retinal ganglion cells originate the axons that form the optic nerve. They are particularly vulnerable to mitochondrial dysfunction, as they present a peculiar cellular architecture, with axons that are not myelinated for a long intra-retinal segment, thus, very energy dependent. The genetic landscape of causative mutations and genes greatly enlarged in the last decade, pointing to common pathways. These mostly imply mitochondrial dysfunction, which leads to a similar outcome in terms of neurodegeneration. We here critically review these pathways, which include (1) complex I-related oxidative phosphorylation (OXPHOS) dysfunction, (2) mitochondrial dynamics, and (3) endoplasmic reticulum-mitochondrial inter-organellar crosstalk. These major pathogenic mechanisms are in turn interconnected and represent the target for therapeutic strategies. Thus, their deep understanding is the basis to set and test new effective therapies, an urgent unmet need for these patients. New tools are now available to capture all interlinked mechanistic intricacies for the pathogenesis of optic nerve neurodegeneration, casting hope for innovative therapies to be rapidly transferred into the clinic and effectively cure inherited optic neuropathies.

scholarly journals Fibrillar α-synuclein induces neurotoxic astrocyte activation via RIP kinase signaling and NF-κB

2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Tsui-Wen Chou ◽  
Nydia P. Chang ◽  
Medha Krishnagiri ◽  
Aisha P. Patel ◽  
Marissa Lindman ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Biology ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Neuronal Cell ◽  
Dopamine Neurons ◽  
Functional Markers ◽  
Kinase Signaling ◽  
Astrocyte Activation ◽  
Transcriptional Responses

AbstractParkinson’s disease (PD) is a neurodegenerative disorder characterized by the death of midbrain dopamine neurons. The pathogenesis of PD is poorly understood, though misfolded and/or aggregated forms of the protein α-synuclein have been implicated in several neurodegenerative disease processes, including neuroinflammation and astrocyte activation. Astrocytes in the midbrain play complex roles during PD, initiating both harmful and protective processes that vary over the course of the disease. However, despite their significant regulatory roles during neurodegeneration, the cellular and molecular mechanisms that promote pathogenic astrocyte activity remain mysterious. Here, we show that α-synuclein preformed fibrils (PFFs) induce pathogenic activation of human midbrain astrocytes, marked by inflammatory transcriptional responses, downregulation of phagocytic function, and conferral of neurotoxic activity. These effects required the necroptotic kinases RIPK1 and RIPK3, but were independent of MLKL and necroptosis. Instead, both transcriptional and functional markers of astrocyte activation occurred via RIPK-dependent activation of NF-κB signaling. Our study identifies a previously unknown function for α-synuclein in promoting neurotoxic astrocyte activation, as well as new cell death-independent roles for RIP kinase signaling in the regulation of glial cell biology and neuroinflammation. Together, these findings highlight previously unappreciated molecular mechanisms of pathologic astrocyte activation and neuronal cell death with implications for Parkinsonian neurodegeneration.

scholarly journals Molecular mechanisms of cell death in neurological diseases

2021 ◽  
Author(s):  
Diane Moujalled ◽  
Andreas Strasser ◽  
Jeffrey R. Liddell
Keyword(s):  
Cell Death ◽  
Neurodegenerative Diseases ◽  
Molecular Mechanisms ◽  
Neuronal Development ◽  
Neurological Diseases ◽  
Treatment Strategies ◽  
Current Treatment ◽  
Response To Therapy ◽  
Signalling Cascades ◽  
The Brain

AbstractTightly orchestrated programmed cell death (PCD) signalling events occur during normal neuronal development in a spatially and temporally restricted manner to establish the neural architecture and shaping the CNS. Abnormalities in PCD signalling cascades, such as apoptosis, necroptosis, pyroptosis, ferroptosis, and cell death associated with autophagy as well as in unprogrammed necrosis can be observed in the pathogenesis of various neurological diseases. These cell deaths can be activated in response to various forms of cellular stress (exerted by intracellular or extracellular stimuli) and inflammatory processes. Aberrant activation of PCD pathways is a common feature in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, resulting in unwanted loss of neuronal cells and function. Conversely, inactivation of PCD is thought to contribute to the development of brain cancers and to impact their response to therapy. For many neurodegenerative diseases and brain cancers current treatment strategies have only modest effect, engendering the need for investigations into the origins of these diseases. With many diseases of the brain displaying aberrations in PCD pathways, it appears that agents that can either inhibit or induce PCD may be critical components of future therapeutic strategies. The development of such therapies will have to be guided by preclinical studies in animal models that faithfully mimic the human disease. In this review, we briefly describe PCD and unprogrammed cell death processes and the roles they play in contributing to neurodegenerative diseases or tumorigenesis in the brain. We also discuss the interplay between distinct cell death signalling cascades and disease pathogenesis and describe pharmacological agents targeting key players in the cell death signalling pathways that have progressed through to clinical trials.

scholarly journals LONP1 and ClpP cooperatively regulate mitochondrial proteostasis for cancer cell survival

Oncogenesis ◽  
2021 ◽  
Vol 10 (2) ◽  
Author(s):  
Yu Geon Lee ◽  
Hui Won Kim ◽  
Yeji Nam ◽  
Kyeong Jin Shin ◽  
Yu Jin Lee ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Growth ◽  
Cell Survival ◽  
Cancer Cell ◽  
Stress Responses ◽  
Molecular Mechanisms ◽  
Tca Cycle ◽  
Mitochondrial Matrix ◽  
Mitochondrial Functions ◽  
Cancer Cell Survival

AbstractMitochondrial proteases are key components in mitochondrial stress responses that maintain proteostasis and mitochondrial integrity in harsh environmental conditions, which leads to the acquisition of aggressive phenotypes, including chemoresistance and metastasis. However, the molecular mechanisms and exact role of mitochondrial proteases in cancer remain largely unexplored. Here, we identified functional crosstalk between LONP1 and ClpP, which are two mitochondrial matrix proteases that cooperate to attenuate proteotoxic stress and protect mitochondrial functions for cancer cell survival. LONP1 and ClpP genes closely localized on chromosome 19 and were co-expressed at high levels in most human cancers. Depletion of both genes synergistically attenuated cancer cell growth and induced cell death due to impaired mitochondrial functions and increased oxidative stress. Using mitochondrial matrix proteomic analysis with an engineered peroxidase (APEX)-mediated proximity biotinylation method, we identified the specific target substrates of these proteases, which were crucial components of mitochondrial functions, including oxidative phosphorylation, the TCA cycle, and amino acid and lipid metabolism. Furthermore, we found that LONP1 and ClpP shared many substrates, including serine hydroxymethyltransferase 2 (SHMT2). Inhibition of both LONP1 and ClpP additively increased the amount of unfolded SHMT2 protein and enhanced sensitivity to SHMT2 inhibitor, resulting in significantly reduced cell growth and increased cell death under metabolic stress. Additionally, prostate cancer patients with higher LONP1 and ClpP expression exhibited poorer survival. These results suggest that interventions targeting the mitochondrial proteostasis network via LONP1 and ClpP could be potential therapeutic strategies for cancer.

scholarly journals Overexpression of Transcripts Coding for Renin-b but Not for Renin-a Reduce Oxidative Stress and Increase Cardiomyoblast Survival under Starvation Conditions

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1204
Author(s):  
Heike Wanka ◽  
Philipp Lutze ◽  
Alexander Albers ◽  
Janine Golchert ◽  
Doreen Staar ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
B Cells ◽  
Apoptotic Cell ◽  
Renin Angiotensin System ◽  
Glucose Deprivation ◽  
Protective Effects ◽  
Glucose Depletion ◽  
A Cells ◽  
Apoptosis And Necrosis

A stimulated renin-angiotensin system is known to promote oxidative stress, apoptosis, necrosis and fibrosis. Renin transcripts (renin-b; renin-c) encoding a cytosolic renin isoform have been discovered that may in contrast to the commonly known secretory renin (renin-a) exert protective effects Here, we analyzed the effect of renin-a and renin-b overexpression in H9c2 cardiomyoblasts on apoptosis and necrosis as well as on potential mechanisms involved in cell death processes. To mimic ischemic conditions, cells were exposed to glucose starvation, anoxia or combined oxygen–glucose deprivation (OGD) for 24 h. Under OGD, control cells exhibited markedly increased necrotic and apoptotic cell death accompanied by enhanced ROS accumulation, loss of mitochondrial membrane potential and decreased ATP levels. The effects of OGD on necrosis were exaggerated in renin-a cells, but markedly diminished in renin-b cells. However, with respect to apoptosis, the effects of OGD were almost completely abolished in renin-b cells but interestingly also moderately diminished in renin-a cells. Under glucose depletion we found opposing responses between renin-a and renin-b cells; while the rate of necrosis and apoptosis was aggravated in renin-a cells, it was attenuated in renin-b cells. Based on our results, strategies targeting the regulation of cytosolic renin-b as well as the identification of pathways involved in the protective effects of renin-b may be helpful to improve the treatment of ischemia-relevant diseases.

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