Talk:Cell Death 1

From CellBiology


2013 Lecture Audio

MCF-7 breast cancer cells - lack both caspase-3 and beclin-1 and hence are (relatively) apoptosis- and autophagy-incompetent.


2016

Recommendations from the INHAND Apoptosis/Necrosis Working Group

Toxicol Pathol. 2016 Feb;44(2):173-88. doi: 10.1177/0192623315625859. Epub 2016 Feb 14.

Elmore SA1, Dixon D2, Hailey JR3, Harada T4, Herbert RA5, Maronpot RR6, Nolte T7, Rehg JE8, Rittinghausen S9, Rosol TJ10, Satoh H11, Vidal JD12, Willard-Mack CL13, Creasy DM13.

Abstract

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 whenThere is no requirement or need to split the processes, orWhen the nature of cell death cannot be determined with certainty, orWhen 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. © The Author(s) 2016. KEYWORDS: INHAND; apoptosis; cell death; guidance; necrosis; single cell necrosis

PMID 26879688

Control of adult neurogenesis by programmed cell death in the mammalian brain

Mol Brain. 2016 Apr 21;9:43. doi: 10.1186/s13041-016-0224-4.

Ryu JR1, Hong CJ2, Kim JY1, Kim EK2,3, Sun W4, Yu SW5,6.

Abstract

The presence of neural stem cells (NSCs) and the production of new neurons in the adult brain have received great attention from scientists and the public because of implications to brain plasticity and their potential use for treating currently incurable brain diseases. Adult neurogenesis is controlled at multiple levels, including proliferation, differentiation, migration, and programmed cell death (PCD). Among these, PCD is the last and most prominent process for regulating the final number of mature neurons integrated into neural circuits. PCD can be classified into apoptosis, necrosis, and autophagic cell death and emerging evidence suggests that all three may be important modes of cell death in neural stem/progenitor cells. However, the molecular mechanisms that regulate PCD and thereby impact the intricate balance between self-renewal, proliferation, and differentiation during adult neurogenesis are not well understood. In this comprehensive review, we focus on the extent, mechanism, and biological significance of PCD for the control of adult neurogenesis in the mammalian brain. The role of intrinsic and extrinsic factors in the regulation of PCD at the molecular and systems levels is also discussed. Adult neurogenesis is a dynamic process, and the signals for differentiation, proliferation, and death of neural progenitor/stem cells are closely interrelated. A better understanding of how adult neurogenesis is influenced by PCD will help lead to important insights relevant to brain health and diseases. KEYWORDS: Adult neurogenesis; Apoptosis; Autophagy; Necrosis; Neural stem cells; Neuroblasts; Programmed cell death

PMID 27098178

Autophagy: a decisive process for stemness

Oncotarget. 2016 Mar 15;7(11):12286-8. doi: 10.18632/oncotarget.7766.

García-Prat L1, Martínez-Vicente M2, Muñoz-Cánoves P1,3.

Abstract

Mature skeletal muscle is a stable tissue imposing low homeostatic demand on its stem cells, which remain in a quiescent state in their niche over time. We have shown that these long-lived resting stem cells attenuate proteotoxicity and avoid senescence through basal autophagy. This protective "clean-up" system is lost during aging, resulting in stem cell regenerative decline. Thus, autophagy is required for muscle stem cell homeostasis maintenance. KEYWORDS: aging; autophagy; muscle; senescence; stem cells

PMID 26934325

2015

Essential versus accessory aspects of cell death: recommendations of the NCCD 2015

Cell Death Differ. 2015 Jan;22(1):58-73. doi: 10.1038/cdd.2014.137. Epub 2014 Sep 19.

Galluzzi L, Bravo-San Pedro JM, Vitale I, Aaronson SA, Abrams JM, Adam D, Alnemri ES, Altucci L, Andrews D, Annicchiarico-Petruzzelli M, Baehrecke EH, Bazan NG, Bertrand MJ, Bianchi K, Blagosklonny MV, Blomgren K, Borner C, Bredesen DE, Brenner C, Campanella M, Candi E, Cecconi F, Chan FK, Chandel NS, Cheng EH, Chipuk JE, Cidlowski JA, Ciechanover A, Dawson TM, Dawson VL, De Laurenzi V, De Maria R, Debatin KM, Di Daniele N, Dixit VM, Dynlacht BD, El-Deiry WS, Fimia GM, Flavell RA, Fulda S, Garrido C, Gougeon ML, Green DR, Gronemeyer H, Hajnoczky G, Hardwick JM, Hengartner MO, Ichijo H, Joseph B, Jost PJ, Kaufmann T, Kepp O, Klionsky DJ, Knight RA, Kumar S, Lemasters JJ, Levine B, Linkermann A, Lipton SA, Lockshin RA, López-Otín C, Lugli E, Madeo F, Malorni W, Marine JC, Martin SJ, Martinou JC, Medema JP, Meier P, Melino S, Mizushima N, Moll U, Muñoz-Pinedo C, Nuñez G, Oberst A, Panaretakis T, Penninger JM, Peter ME, Piacentini M, Pinton P, Prehn JH, Puthalakath H, Rabinovich GA, Ravichandran KS, Rizzuto R, Rodrigues CM, Rubinsztein DC, Rudel T, Shi Y, Simon HU, Stockwell BR, Szabadkai G, Tait SW, Tang HL, Tavernarakis N, Tsujimoto Y, Vanden Berghe T, Vandenabeele P, Villunger A, Wagner EF, Walczak H, White E, Wood WG, Yuan J, Zakeri Z, Zhivotovsky B, Melino G, Kroemer G.

Abstract

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as 'accidental cell death' (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. 'Regulated cell death' (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death.

PMID 25236395

2014

Biomarkers distinguish apoptotic and necrotic cell death during hepatic ischemia/reperfusion injury in mice

Liver Transpl. 2014 Nov;20(11):1372-82. doi: 10.1002/lt.23958.

Yang M1, Antoine DJ, Weemhoff JL, Jenkins RE, Farhood A, Park BK, Jaeschke H.

Abstract

Hepatic ischemia/reperfusion (IRP) injury is a significant clinical problem during tumor-resection surgery (Pringle maneuver) and liver transplantation. However, the relative contribution of necrotic and apoptotic cell death to the overall liver injury is still controversial. To address this important issue with a standard murine model of hepatic IRP injury, plasma biomarkers of necrotic cell death such as micro-RNA 122, full-length cytokeratin 18 (FK18), and high-mobility group box 1 (HMGB1) protein and plasma biomarkers of apoptosis such as plasma caspase-3 activity and caspase-cleaved fragment of cytokeratin 18 (CK18) coupled with markers of inflammation (hyperacetylated HMGB1) were compared by histological features in hematoxylin and eosin-stained and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL)-stained liver sections. After 45 minutes of hepatic ischemia and 1 to 24 hours of reperfusion, all necrosis markers increased dramatically in plasma by 40- to >10,000-fold over the baseline with a time course similar to that of alanine aminotransferase. These data correlated well with histological characteristics of necrosis. Within the area of necrosis, most cells were TUNEL positive; initially (≤3 hours of reperfusion), the staining was restricted to nuclei, but it later spread to the cytosol, and this is characteristic of karyorrhexis during necrotic cell death. In contrast, the lack of morphological evidence of apoptotic cell death and relevant caspase-3 activity in the postischemic liver correlated well with the absence of caspase-3 activity and CK18 (except for a minor increase at 3 hours of reperfusion) in plasma. A quantitative comparison of FK18 (necrosis) and CK18 (apoptosis) release indicated dominant cell death by necrosis during IRP and only a temporary and very minor degree of apoptosis. These data suggest that the focus of future research should be the elucidation of necrotic signaling mechanisms to identify relevant targets, which may be used to attenuate hepatic IRP injury. © 2014 American Association for the Study of Liver Diseases. PMID 25046819


2012

Unfolded protein stress in the endoplasmic reticulum and mitochondria: a role in neurodegeneration

Front Aging Neurosci. 2012;4:5. Epub 2012 Apr 25.

Bernales S, Soto MM, McCullagh E. Source Fundación Ciencia y Vida Santiago, Chile.

Abstract

Protein-folding occurs in several intracellular locations including the endoplasmic reticulum and mitochondria. In normal conditions there is a balance between the levels of unfolded proteins and protein folding machinery. Disruption of homeostasis and an accumulation of unfolded proteins trigger stress responses, or unfolded protein responses (UPR), in these organelles. These pathways signal to increase the folding capacity, inhibit protein import or expression, increase protein degradation, and potentially trigger cell death. Many aging-related neurodegenerative diseases involve the accumulation of misfolded proteins in both the endoplasmic reticulum and mitochondria. The exact participation of the UPRs in the onset of neurodegeneration is unclear, but there is significant evidence for the alteration of these pathways in the endoplasmic reticulum and mitochondria. Here we will discuss the involvement of endoplasmic reticulum and mitochondrial stress and the possible contributions of the UPR in these organelles to the development of two neurodegenerative diseases, Parkinson's disease (PD) and Alzheimer's disease (AD).

PMID 22539924

Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling

Biochem J. 2012 Jan 15;441(2):523-40.

Lee J, Giordano S, Zhang J. Source Center for Free Radical Biology, University of Alabama at Birmingham, 901 19th Street South, Birmingham, AL 35294, USA.

Abstract

Reactive oxygen and nitrogen species change cellular responses through diverse mechanisms that are now being defined. At low levels, they are signalling molecules, and at high levels, they damage organelles, particularly the mitochondria. Oxidative damage and the associated mitochondrial dysfunction may result in energy depletion, accumulation of cytotoxic mediators and cell death. Understanding the interface between stress adaptation and cell death then is important for understanding redox biology and disease pathogenesis. Recent studies have found that one major sensor of redox signalling at this switch in cellular responses is autophagy. Autophagic activities are mediated by a complex molecular machinery including more than 30 Atg (AuTophaGy-related) proteins and 50 lysosomal hydrolases. Autophagosomes form membrane structures, sequester damaged, oxidized or dysfunctional intracellular components and organelles, and direct them to the lysosomes for degradation. This autophagic process is the sole known mechanism for mitochondrial turnover. It has been speculated that dysfunction of autophagy may result in abnormal mitochondrial function and oxidative or nitrative stress. Emerging investigations have provided new understanding of how autophagy of mitochondria (also known as mitophagy) is controlled, and the impact of autophagic dysfunction on cellular oxidative stress. The present review highlights recent studies on redox signalling in the regulation of autophagy, in the context of the basic mechanisms of mitophagy. Furthermore, we discuss the impact of autophagy on mitochondrial function and accumulation of reactive species. This is particularly relevant to degenerative diseases in which oxidative stress occurs over time, and dysfunction in both the mitochondrial and autophagic pathways play a role.

PMID 22187934

© 2012 The Author(s) The author(s) has paid for this article to be freely available under the terms of the Creative Commons Attribution Non-Commercial Licence (http://creativecommons.org/licenses/by-nc/2.5/) which permits unrestricted non-commercial use, distribution and reproduction in any medium, provided the original work is properly cited.

2008

Autophagic cell death: the story of a misnomer

Nat Rev Mol Cell Biol. 2008 Dec;9(12):1004-10. doi: 10.1038/nrm2529. Epub 2008 Oct 30.

Kroemer G1, Levine B.

Abstract

Dying cells often display a large-scale accumulation of autophagosomes and hence adopt a morphology called autophagic cell death. In many cases, it is agreed that this autophagic cell death is cell death with autophagy rather than cell death by autophagy. Here, we evaluate the accumulating body of literature that argues that cell death occurs by autophagy. We also list the caveats that must be considered when deciding whether or not autophagy is an important effector mechanism of cell death.

PMID 18971948

http://www.nature.com/nrm/journal/v9/n12/full/nrm2529.html

Autophagy fights disease through cellular self-digestion

Nature. 2008 Feb 28;451(7182):1069-75. doi: 10.1038/nature06639.

Mizushima N1, Levine B, Cuervo AM, Klionsky DJ.

Abstract

Autophagy, or cellular self-digestion, is a cellular pathway involved in protein and organelle degradation, with an astonishing number of connections to human disease and physiology. For example, autophagic dysfunction is associated with cancer, neurodegeneration, microbial infection and ageing. Paradoxically, although autophagy is primarily a protective process for the cell, it can also play a role in cell death. Understanding autophagy may ultimately allow scientists and clinicians to harness this process for the purpose of improving human health.

PMID 18305538

2006

Autophagy Counterbalances Endoplasmic Reticulum Expansion during the Unfolded Protein Response

The protein folding capacity of the endoplasmic reticulum (ER) is regulated by the unfolded protein response (UPR). The UPR senses unfolded proteins in the ER lumen and transmits that information to the cell nucleus, where it drives a transcriptional program that is tailored to re-establish homeostasis. Using thin section electron microscopy, we found that yeast cells expand their ER volume at least 5-fold under UPR-inducing conditions. Surprisingly, we discovered that ER proliferation is accompanied by the formation of autophagosome-like structures that are densely and selectively packed with membrane stacks derived from the UPR-expanded ER. In analogy to pexophagy and mitophagy, which are autophagic processes that selectively sequester and degrade peroxisomes and mitochondria, the ER-specific autophagic process described utilizes several autophagy genes: they are induced by the UPR and are essential for the survival of cells subjected to severe ER stress. Intriguingly, cell survival does not require vacuolar proteases, indicating that ER sequestration into autophagosome-like structures, rather than their degradation, is the important step. Selective ER sequestration may help cells to maintain a new steady-state level of ER abundance even in the face of continuously accumulating unfolded proteins.

Citation: Bernales S, McDonald KL, Walter P (2006) Autophagy Counterbalances Endoplasmic Reticulum Expansion during the Unfolded Protein Response. PLoS Biol 4(12): e423. doi:10.1371/journal.pbio.0040423

http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.0040423

Academic Editor: Hidde Ploegh, Massachusetts Institute of Technology, United States of America

Received: May 25, 2006; Accepted: October 11, 2006; Published: November 28, 2006

Copyright: © 2006 Bernales et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This work was supported by an American Heart Predoctoral Fellowship to SB and by grants from the National Institutes of Health to PW. PW is an Investigator of the Howard Hughes Medical Institute.

Competing interests: The authors have declared that no competing interests exist.

Abbreviations: A1PiZ, Z variant of human α-1 proteinase inhibitor; Cvt, cytoplasm-to-vacuole targeting; EM, electron microscopy; ER, endoplasmic reticulum; ERA, ER-containing autophagosome; ERAD, ER-associated protein degradation; ER-phagy, ER-selective branch of autophagy; GFP, green fluorescent protein; NE, nuclear envelope; PAS, pre-autophagosomal structure; S-UPR, Super-unfolded protein response; UPR, unfolded protein response

Other Cell Death Terms

Anoikis

  • (Greek, anoikis = "homelessness")
  • probably death by apoptosis
  • A form of programmed cell death that occurs when cells loose contact with the extracellular matrix (ECM)
  • Integrin regulation of cell viability through their interaction with extracellular matrix
  • Protein kinase and apoptosis-related signals can control anoikis both positively and negatively
  • tumorogenesis protection

Oncosis

  • (Greek, onkos = 'swelling')
  • the process occurring in early necrosis

Pyroptosis

  • Greek, pyro = fire or fever; ptosis = falling
  • proinflammatory pathway
  • cell death mediated by the activation of Caspase-1
  • also activates inflammatory cytokines, IL-1ß, and IL-18