scholarly journals Yeast chronological lifespan and proteotoxic stress: is autophagy good or bad?

2011 ◽  
Vol 39 (5) ◽  
pp. 1466-1470 ◽  
Author(s):  
Belém Sampaio-Marques ◽  
Carolina Felgueiras ◽  
Alexandra Silva ◽  
Fernando Rodrigues ◽  
Paula Ludovico
Keyword(s):  
Cell Death ◽  
Cellular Response ◽  
Molecular Mechanisms ◽  
Nutrient Sensing ◽  
Signalling Pathways ◽  
Aging Effects ◽  
Tor Pathway ◽  
Chronological Lifespan ◽  
Proteotoxic Stress ◽  
Response To Stress

Autophagy, a highly conserved proteolytic mechanism of quality control, is essential for the maintenance of metabolic and cellular homoeostasis and for an efficient cellular response to stress. Autophagy declines with aging and is believed to contribute to different aspects of the aging phenotype. The nutrient-sensing pathways PKA (protein kinase A), Sch9 and TOR (target of rapamycin), involved in the regulation of yeast lifespan, also converge on a common targeted process: autophagy. The molecular mechanisms underlying the regulation of autophagy and aging by these signalling pathways in yeast, with special attention to the TOR pathway, are discussed in the present paper. The question of whether or not autophagy could contribute to yeast cell death occurring during CLS (chronological lifespan) is discussed in the light of our findings obtained after autophagy activation promoted by proteotoxic stress. Autophagy progressively increases in cells expressing the aggregation-prone protein α-synuclein and seems to participate in the early cell death and shortening of CLS under these conditions, highlighting that autophagic activity should be maintained below physiological levels to exert its promising anti-aging effects.

scholarly journals Impact of Carcinogenic Chromium on the Cellular Response to Proteotoxic Stress

2019 ◽  
Vol 20 (19) ◽  
pp. 4901 ◽  
Author(s):  
Leonardo M. R. Ferreira ◽  
Teresa Cunha-Oliveira ◽  
Margarida C. Sobral ◽  
Patrícia L. Abreu ◽  
Maria Carmen Alpoim ◽  
...  
Keyword(s):  
Stress Response ◽  
Health Effects ◽  
Cellular Response ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Chemical Properties ◽  
Adverse Health Effects ◽  
Proteotoxic Stress ◽  
Adverse Health ◽  
The Impact

Worldwide, several million workers are employed in the various chromium (Cr) industries. These workers may suffer from a variety of adverse health effects produced by dusts, mists and fumes containing Cr in the hexavalent oxidation state, Cr(VI). Of major importance, occupational exposure to Cr(VI) compounds has been firmly associated with the development of lung cancer. Counterintuitively, Cr(VI) is mostly unreactive towards most biomolecules, including nucleic acids. However, its intracellular reduction produces several species that react extensively with biomolecules. The diversity and chemical versatility of these species add great complexity to the study of the molecular mechanisms underlying Cr(VI) toxicity and carcinogenicity. As a consequence, these mechanisms are still poorly understood, in spite of intensive research efforts. Here, we discuss the impact of Cr(VI) on the stress response—an intricate cellular system against proteotoxic stress which is increasingly viewed as playing a critical role in carcinogenesis. This discussion is preceded by information regarding applications, chemical properties and adverse health effects of Cr(VI). A summary of our current understanding of cancer initiation, promotion and progression is also provided, followed by a brief description of the stress response and its links to cancer and by an overview of potential molecular mechanisms of Cr(VI) carcinogenicity.

scholarly journals Long-term depression: a cell biological view

2014 ◽  
Vol 369 (1633) ◽  
pp. 20130138 ◽  
Author(s):  
Morgan Sheng ◽  
Ali Ertürk
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Dendritic Spines ◽  
Crucial Role ◽  
Molecular Mechanisms ◽  
Signalling Pathways ◽  
Long Term Depression ◽  
A Cell ◽  
Biological Programme

Recent studies of the molecular mechanisms of long-term depression (LTD) suggest a crucial role for the signalling pathways of apoptosis (programmed cell death) in the weakening and elimination of synapses and dendritic spines. With this backdrop, we suggest that LTD can be considered as the electrophysiological aspect of a larger cell biological programme of synapse involution, which uses localized apoptotic mechanisms to sculpt synapses and circuits without causing cell death.

scholarly journals Die Another Way: Interplay between Influenza A Virus, Inflammation and Cell Death

Viruses ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 401 ◽  
Author(s):  
Gabriel Laghlali ◽  
Kate E. Lawlor ◽  
Michelle D. Tate
Keyword(s):  
Cell Death ◽  
Influenza A Virus ◽  
Tissue Damage ◽  
Influenza A ◽  
Molecular Mechanisms ◽  
Host Defence ◽  
Signalling Pathways ◽  
Fatal Disease ◽  
Global Threat ◽  
New Treatments

Influenza A virus (IAV) is a major concern to human health due to the ongoing global threat of a pandemic. Inflammatory and cell death signalling pathways play important roles in host defence against IAV infection. However, severe IAV infections in humans are characterised by excessive inflammation and tissue damage, often leading to fatal disease. While the molecular mechanisms involved in the induction of inflammation during IAV infection have been well studied, the pathways involved in IAV-induced cell death and their impact on immunopathology have not been fully elucidated. There is increasing evidence of significant crosstalk between cell death and inflammatory pathways and a greater understanding of their role in host defence and disease may facilitate the design of new treatments for IAV infection.

scholarly journals Importance of the bioenergetic reserve capacity in response to cardiomyocyte stress induced by 4-hydroxynonenal

2009 ◽  
Vol 424 (1) ◽  
pp. 99-107 ◽  
Author(s):  
Bradford G. Hill ◽  
Brian P. Dranka ◽  
Luyun Zou ◽  
John C. Chatham ◽  
Victor M. Darley-Usmar
Keyword(s):  
Cell Death ◽  
Cellular Response ◽  
Protein Modification ◽  
Ventricular Myocytes ◽  
Critical Role ◽  
Reserve Capacity ◽  
Energy Demands ◽  
Lipid Species ◽  
Cellular Context ◽  
Response To Stress

Mitochondria play a critical role in mediating the cellular response to oxidants formed during acute and chronic cardiac dysfunction. It is widely assumed that, as cells are subjected to stress, mitochondria are capable of drawing upon a ‘reserve capacity’ which is available to serve the increased energy demands for maintenance of organ function, cellular repair or detoxification of reactive species. This hypothesis further implies that impairment or depletion of this putative reserve capacity ultimately leads to excessive protein damage and cell death. However, it has been difficult to fully evaluate this hypothesis since much of our information about the response of the mitochondrion to oxidative stress derives from studies on mitochondria isolated from their cellular context. Therefore the goal of the present study was to determine whether ‘bioenergetic reserve capacity’ does indeed exist in the intact myocyte and whether it is utilized in response to stress induced by the pathologically relevant reactive lipid species HNE (4-hydroxynonenal). We found that intact rat neonatal ventricular myocytes exhibit a substantial bioenergetic reserve capacity under basal conditions; however, on exposure to pathologically relevant concentrations of HNE, oxygen consumption was increased until this reserve capacity was depleted. Exhaustion of the reserve capacity by HNE treatment resulted in inhibition of respiration concomitant with protein modification and cell death. These data suggest that oxidized lipids could contribute to myocyte injury by decreasing the bioenergetic reserve capacity. Furthermore, these studies demonstrate the utility of measuring the bioenergetic reserve capacity for assessing or predicting the response of cells to stress.

scholarly journals Cell fate determined by the activation balance between PKR and SPHK1

2020 ◽  
Vol 28 (1) ◽  
pp. 401-418
Author(s):  
Han Qiao ◽  
Tianqing Jiang ◽  
Peiqiang Mu ◽  
Xiaoxuan Chen ◽  
Xianhui Wen ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Fate ◽  
Cellular Response ◽  
Cellular Stress Response ◽  
Protein Kinase R ◽  
Survival Pathways ◽  
Stress Signal ◽  
Dependent Protein ◽  
Response To Stress ◽  
Simultaneous Activation

AbstractDouble-stranded RNA (dsRNA)-dependent protein kinase R (PKR) activation via autophosphorylation is the central cellular response to stress that promotes cell death or apoptosis. However, the key factors and mechanisms behind the simultaneous activation of pro-survival signaling pathways remain unknown. We have discovered a novel regulatory mechanism for the maintenance of cellular homeostasis that relies on the phosphorylation interplay between sphingosine kinase 1 (SPHK1) and PKR during exogenous stress. We identified SPHK1 as a previously unrecognized PKR substrate. Phosphorylated SPHK1, a central kinase, mediates the activation of PKR-induced pro-survival pathways by the S1P/S1PR1/MAPKs/IKKα signal axis, and antagonizes PKR-mediated endoplasmic reticulum (ER) stress signal transduction under stress conditions. Otherwise, phosphorylated SPHK1 also acts as the negative feedback factor, preferentially binding to the latent form of PKR at the C-terminal kinase motif, inhibiting the homodimerization of PKR, suppressing PKR autophosphorylation, and reducing the signaling strength for cell death and apoptosis. Our results suggest that the balance of the activation levels between PKR and SPHK1, a probable hallmark of homeostasis maintenance, determines cell fate during cellular stress response.

scholarly journals How the Other Half Lives: What p53 Does When It Is Not Being a Transcription Factor

2019 ◽  
Vol 21 (1) ◽  
pp. 13 ◽  
Author(s):  
Teresa Ho ◽  
Ban Xiong Tan ◽  
David Lane
Keyword(s):  
Cell Death ◽  
Transcription Factor ◽  
Genomic Instability ◽  
Cellular Response ◽  
Molecular Mechanisms ◽  
Human Cancer ◽  
Context Dependency ◽  
The Other ◽  
Independent Functions ◽  
Shed Light

It has been four decades since the discovery of p53, the designated ‘Guardian of the Genome’. P53 is primarily known as a master transcription factor and critical tumor suppressor, with countless studies detailing the mechanisms by which it regulates a host of gene targets and their consequent signaling pathways. However, transcription-independent functions of p53 also strongly define its tumor-suppressive capabilities and recent findings shed light on the molecular mechanisms hinted at by earlier efforts. This review highlights the transcription-independent mechanisms by which p53 influences the cellular response to genomic instability (in the form of replication stress, centrosome homeostasis, and transposition) and cell death. We also pinpoint areas for further investigation in order to better understand the context dependency of p53 transcription-independent functions and how these are perturbed when TP53 is mutated in human cancer.

scholarly journals The RNase Rny1p cleaves tRNAs and promotes cell death during oxidative stress in Saccharomyces cerevisiae

2009 ◽  
Vol 185 (1) ◽  
pp. 43-50 ◽  
Author(s):  
Debrah M. Thompson ◽  
Roy Parker
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Cell Survival ◽  
Cellular Response ◽  
Cellular Damage ◽  
Transfer Rnas ◽  
Endonucleolytic Cleavage ◽  
Response To Stress ◽  
Rnase T2

The cellular response to stress conditions involves a decision between survival or cell death when damage is severe. A conserved stress response in eukaryotes involves endonucleolytic cleavage of transfer RNAs (tRNAs). The mechanism and significance of such tRNA cleavage is unknown. We show that in yeast, tRNAs are cleaved by the RNase T2 family member Rny1p, which is released from the vacuole into the cytosol during oxidative stress. Rny1p modulates yeast cell survival during oxidative stress independently of its catalytic ability. This suggests that upon release to the cytosol, Rny1p promotes cell death by direct interactions with downstream components. Thus, detection of Rny1p, and possibly its orthologues, in the cytosol may be a conserved mechanism for assessing cellular damage and determining cell survival, analogous to the role of cytochrome c as a marker for mitochondrial damage.

Uteroplacental insufficiency decreases p53 serine-15 phosphorylation in term IUGR rat lungs

2007 ◽  
Vol 293 (1) ◽  
pp. R314-R322 ◽  
Author(s):  
E. A. O'Brien ◽  
V. Barnes ◽  
L. Zhao ◽  
R. A. McKnight ◽  
X. Yu ◽  
...  
Keyword(s):  
Cellular Response ◽  
Molecular Mechanisms ◽  
Active Form ◽  
Artery Ligation ◽  
Pregnant Rats ◽  
P53 Expression ◽  
Rat Lungs ◽  
Response To Stress ◽  
Induced Changes ◽  
Cycle Regulation

Intrauterine growth restriction (IUGR) increases the incidence of chronic lung disease (CLD). The molecular mechanisms responsible for IUGR-induced acute lung injury that predispose the IUGR infant to CLD are unknown. p53, a transcription factor, plays a pivotal role in determining cellular response to stress by affecting apoptosis, cell cycle regulation, and angiogenesis, processes required for thinning of lung mesenchyme. Because thickened lung mesenchyme is characteristic of CLD, we hypothesized that IUGR-induced changes in lung growth are associated with alterations in p53 expression and/or modification. We induced IUGR through bilateral uterine artery ligation of pregnant rats. Uteroplacental insufficiency significantly decreased serine-15-phosphorylated (serine-15P) p53, an active form of p53, in IUGR rat lung. Moreover, we found that decreased phosphorylation of lung p53 serine-15 localized to thickened distal air space mesenchyme. We also found that IUGR significantly decreased mRNA for targets downstream of p53, specifically, proapoptotic Bax and Apaf, as well as Gadd45, involved in growth arrest, and Tsp-1, involved in angiogenesis. Furthermore, we found that IUGR significantly increased mRNA for Bcl-2, an antiapoptotic gene downregulated by p53. We conclude that in IUGR rats, uteroplacental insufficiency induces decreased lung mesenchymal p53 serine-15P in association with distal lung mesenchymal thickening. We speculate that decreased p53 serine-15P in IUGR rat lungs alters lung phenotype, making the IUGR lung more susceptible to subsequent injury.

scholarly journals Mechanism of Antifungal Activity of Terpenoid Phenols Resembles Calcium Stress and Inhibition of the TOR Pathway

2010 ◽  
Vol 54 (12) ◽  
pp. 5062-5069 ◽  
Author(s):  
Anjana Rao ◽  
Yongqiang Zhang ◽  
Sabina Muend ◽  
Rajini Rao
Keyword(s):  
Antifungal Activity ◽  
Cellular Response ◽  
Ribosome Biogenesis ◽  
Ion Homeostasis ◽  
Model Organism ◽  
Nutrient Sensing ◽  
Cellular Interaction ◽  
Tor Pathway ◽  
Calcium Stress ◽  
Wide Range

ABSTRACT Terpenoid phenols, including carvacrol, are components of oregano and other plant essential oils that exhibit potent antifungal activity against a wide range of pathogens, including Candida albicans, Staphylococcus aureus, and Pseudomonas aeruginosa. To gain a mechanistic view of the cellular response to terpenoid phenols, we used Saccharomyces cerevisiae as a model organism and monitored temporal changes in metabolic activity, cytosolic and vacuolar pH, and Ca2+ transients. Using a panel of related compounds, we observed dose-dependent Ca2+ bursts that correlated with antifungal efficacy. Changes in pH were long lasting and followed the Ca2+ transients. A vma mutant lacking functional vacuolar H+-ATPase (V-ATPase) and defective in ion homeostasis was hypersensitive to carvacrol toxicity, consistent with a role for ionic disruptions in mediating cell death. Genomic profiling within 15 min of exposure revealed a robust transcriptional response to carvacrol, closely resembling that of calcium stress. Genes involved in alternate metabolic and energy pathways, stress response, autophagy, and drug efflux were prominently upregulated, whereas repressed genes mediated ribosome biogenesis and RNA metabolism. These responses were strongly reminiscent of the effects of rapamycin, the inhibitor of the TOR pathway of nutrient sensing. The results point to the activation of specific signaling pathways downstream of cellular interaction with carvacrol rather than a nonspecific lesion of membranes, as has been previously proposed.

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