scholarly journals Conserved Actin Cysteine Residues Are Oxidative Stress Sensors That Can Regulate Cell Death in Yeast

2007 ◽  
Vol 18 (4) ◽  
pp. 1359-1365 ◽  
Author(s):  
Michelle E. Farah ◽  
David C. Amberg
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Cellular Response ◽  
Yeast Cells ◽  
Nuclear Fragmentation ◽  
Actin Isoforms ◽  
Chronological Aging ◽  
Stress Sensors ◽  
Universal Mechanism ◽  
Regulate Cell Death

Actin's functional complexity makes it a likely target of oxidative stress but also places it in a prime position to coordinate the response to oxidative stress. We have previously shown that the NADPH oxidoreductase Oye2p protects the actin cytoskeleton from oxidative stress. Here we demonstrate that the physiological consequence of actin oxidation is to accelerate cell death in yeast. Loss of Oye2p leads to reactive oxygen species accumulation, activation of the oxidative stress response, nuclear fragmentation and DNA degradation, and premature chronological aging of yeast cells. The oye2Δ phenotype can be completely suppressed by removing the potential for formation of the actin C285-C374 disulfide bond, the likely substrate of the Oye2p enzyme or by treating the cells with the clinically important reductant N-acetylcysteine. Because these two cysteines are coconserved in all actin isoforms, we theorize that we have uncovered a universal mechanism whereby actin helps to coordinate the cellular response to oxidative stress by both sensing and responding to oxidative load.

scholarly journals Hydrogen peroxide induced loss of heterozygosity correlates with replicative lifespan and mitotic asymmetry inSaccharomyces cerevisiae

PeerJ ◽  
2016 ◽  
Vol 4 ◽  
pp. e2671 ◽  
Author(s):  
Emine Güven ◽  
Lindsay A. Parnell ◽  
Erin D. Jackson ◽  
Meighan C. Parker ◽  
Nilin Gupta ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Genomic Instability ◽  
Loss Of Heterozygosity ◽  
Population Level ◽  
Cellular Aging ◽  
Yeast Cells ◽  
Replicative Lifespan ◽  
Chronological Aging ◽  
Transition Points

Cellular aging inSaccharomyces cerevisiaecan lead to genomic instability and impaired mitotic asymmetry. To investigate the role of oxidative stress in cellular aging, we examined the effect of exogenous hydrogen peroxide on genomic instability and mitotic asymmetry in a collection of yeast strains with diverse backgrounds. We treated yeast cells with hydrogen peroxide and monitored the changes of viability and the frequencies of loss of heterozygosity (LOH) in response to hydrogen peroxide doses. The mid-transition points of viability and LOH were quantified using sigmoid mathematical functions. We found that the increase of hydrogen peroxide dependent genomic instability often occurs before a drop in viability. We previously observed that elevation of genomic instability generally lags behind the drop in viability during chronological aging. Hence, onset of genomic instability induced by exogenous hydrogen peroxide treatment is opposite to that induced by endogenous oxidative stress during chronological aging, with regards to the midpoint of viability. This contrast argues that the effect of endogenous oxidative stress on genome integrity is well suppressed up to the dying-off phase during chronological aging. We found that the leadoff of exogenous hydrogen peroxide induced genomic instability to viability significantly correlated with replicative lifespan (RLS), indicating that yeast cells’ ability to counter oxidative stress contributes to their replicative longevity. Surprisingly, this leadoff is positively correlated with an inverse measure of endogenous mitotic asymmetry, indicating a trade-off between mitotic asymmetry and cell’s ability to fend off hydrogen peroxide induced oxidative stress. Overall, our results demonstrate strong associations of oxidative stress to genomic instability and mitotic asymmetry at the population level of budding yeast.

scholarly journals Calcium and cell death signaling in neurodegeneration and aging

2009 ◽  
Vol 81 (3) ◽  
pp. 467-475 ◽  
Author(s):  
Soraya Smaili ◽  
Hanako Hirata ◽  
Rodrigo Ureshino ◽  
Priscila T. Monteforte ◽  
Ana P. Morales ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Apoptotic Cell ◽  
Essential Elements ◽  
Apoptotic Cell Death ◽  
Nuclear Fragmentation ◽  
Physiological Processes ◽  
Cell Death Signaling ◽  
Lines Of Evidence

Transient increase in cytosolic (Cac2+) and mitochondrial Ca2+ (Ca m2+) are essential elements in the control of many physiological processes. However, sustained increases in Ca c2+ and Ca m2+ may contribute to oxidative stress and cell death. Several events are related to the increase in Ca m2+, including regulation and activation of a number of Ca2+ dependent enzymes, such as phospholipases, proteases and nucleases. Mitochondria and endoplasmic reticulum (ER) play pivotal roles in the maintenance of intracellular Ca2+ homeostasis and regulation of cell death. Several lines of evidence have shown that, in the presence of some apoptotic stimuli, the activation of mitochondrial processes maylead to the release of cytochrome c followed by the activation of caspases, nuclear fragmentation and apoptotic cell death. The aim of this review was to show how changes in calcium signaling can be related to the apoptotic cell death induction. Calcium homeostasis was also shown to be an important mechanism involved in neurodegenerative and aging processes.

scholarly journals Old Yellow Enzymes, Highly Homologous FMN Oxidoreductases with Modulating Roles in Oxidative Stress and Programmed Cell Death in Yeast

2007 ◽  
Vol 282 (49) ◽  
pp. 36010-36023 ◽  
Author(s):  
Osama Odat ◽  
Samer Matta ◽  
Hadi Khalil ◽  
Sotirios C. Kampranis ◽  
Raymond Pfau ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Antioxidant Activities ◽  
Ros Generation ◽  
Oxidized Glutathione ◽  
Wild Type ◽  
Antioxidant Genes ◽  
Knock Out ◽  
Chronological Aging

In a genetic screen to identify modifiers of Bax-dependent lethality in yeast, the C terminus of OYE2 was isolated based on its capacity to restore sensitivity to a Bax-resistant yeast mutant strain. Overexpression of full-length OYE2 suppresses Bax lethality in yeast, lowers endogenous reactive oxygen species (ROS), increases resistance to H2O2-induced programmed cell death (PCD), and significantly lowers ROS levels generated by organic prooxidants. Reciprocally, Δoye2 yeast strains are sensitive to prooxidant-induced PCD. Overexpression and knock-out analysis indicate these OYE2 antioxidant activities are opposed by OYE3, a highly homologous heterodimerizing protein, which functions as a prooxidant promoting H2O2-induced PCD in wild type yeast. To exert its effect OYE3 requires the presence of OYE2. Deletion of the 12 C-terminal amino acids and catalytic inactivation of OYE2 by a Y197F mutation enhance significantly survival upon H2O2-induced PCD in wild type cells, but accelerate PCD in Δoye3 cells, implicating the oye2p-oye3p heterodimer for promoting cell death upon oxidative stress. Unexpectedly, a strain with a double knock-out of these genes (Δoye2 oye3) is highly resistant to H2O2-induced PCD, exhibits increased respiratory capacity, and undergoes less cell death during the adaptive response in chronological aging. Simultaneous deletion of OYE2 and other antioxidant genes hyperinduces endogenous levels of ROS, promoting H2O2-induced cell death: in Δoye2 glr1 yeast high levels of oxidized glutathione elicited gross morphological aberrations involving the actin cytoskeleton and defects in organelle partitioning. Altering the ratio of reduced to oxidized glutathione by exogenous addition of GSH fully reversed these alterations. Based on this work, OYE proteins are firmly placed in the signaling network connecting ROS generation, PCD modulation, and cytoskeletal dynamics in yeast.

scholarly journals Redox sensitive E2 Rad6 controls cellular response to oxidative stress via K63 ubiquitination of ribosomes.

2021 ◽  
Author(s):  
Vanessa Simoes ◽  
Lana Harley ◽  
Blanche K. Cizubu ◽  
Ye Zhou ◽  
Joshua Pajak ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cellular Response ◽  
Antioxidant Defense ◽  
Dynamic Environments ◽  
Translation Initiation Factor ◽  
Yeast Cells ◽  
Initiation Factor ◽  
Deubiquitinating Enzyme ◽  
Protein Ubiquitination ◽  
Ubiquitin Conjugating Enzymes

Protein ubiquitination is an essential process that rapidly regulates protein synthesis, function, and fate in dynamic environments. Among its non-proteolytic functions, K63 ubiquitin accumulates in yeast cells exposed to oxidative stress, stalling ribosomes at elongation. K63 ubiquitin conjugates accumulate because of redox inhibition of the deubiquitinating enzyme Ubp2, however, the role and regulation of ubiquitin conjugating enzymes in this pathway remained unclear. Here we found that the E2 Rad6 binds and modifies elongating ribosomes during oxidative stress. We elucidated a mechanism by which Rad6 and its human homolog UBE2A are redox-regulated by forming reversible disulfides with the E1 activating enzyme, Uba1. We further showed that Rad6 activity is necessary to regulate translation, antioxidant defense, and adaptation to stress. Finally, we showed that Rad6 is required to induce phosphorylation of the translation initiation factor eIF2α, providing a novel link for K63 ubiquitin, elongation stalling, and the integrated stress response.

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.

Metal-based superoxide dismutase and catalase mimics reduce oxidative stress biomarkers and extend life span of Saccharomyces cerevisiae

2017 ◽  
Vol 474 (2) ◽  
pp. 301-315 ◽  
Author(s):  
Thales de P. Ribeiro ◽  
Fernanda L. Fonseca ◽  
Mariana D.C. de Carvalho ◽  
Rodrigo M. da C. Godinho ◽  
Fernando Pereira de Almeida ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Saccharomyces Cerevisiae ◽  
Superoxide Dismutase ◽  
Life Span ◽  
Yeast Cells ◽  
Cell Integrity ◽  
Oxidative Stress Biomarkers ◽  
Chronological Aging ◽  
Stress Biomarkers

Aging is a natural process characterized by several biological changes. In this context, oxidative stress appears as a key factor that leads cells and organisms to severe dysfunctions and diseases. To cope with reactive oxygen species and oxidative-related damage, there has been increased use of superoxide dismutase (SOD)/catalase (CAT) biomimetic compounds. Recently, we have shown that three metal-based compounds {[Fe(HPClNOL)Cl2]NO3, [Cu(HPClNOL)(CH3CN)](ClO4)2 and Mn(HPClNOL)(Cl)2}, harboring in vitro SOD and/or CAT activities, were critical for protection of yeast cells against oxidative stress. In this work, treating Saccharomyces cerevisiae with these SOD/CAT mimics (25.0 µM/1 h), we highlight the pivotal role of these compounds to extend the life span of yeast during chronological aging. Evaluating lipid and protein oxidation of aged cells, it becomes evident that these mimics extend the life expectancy of yeast mainly due to the reduction in oxidative stress biomarkers. In addition, the treatment of yeast cells with these mimics regulated the amounts of lipid droplet occurrence, consistent with the requirement and protection of lipids for cell integrity during aging. Concerning SOD/CAT mimics uptake, using inductively coupled plasma mass spectrometry, we add new evidence that these complexes, besides being bioabsorbed by S. cerevisiae cells, can also affect metal homeostasis. Finally, our work presents a new application for these SOD/CAT mimics, which demonstrate a great potential to be employed as antiaging agents. Taken together, these promising results prompt future studies concerning the relevance of administration of these molecules against the emerging aging-related diseases such as Parkinson's, Alzheimer's and Huntington's.

S-Dimethylarsinoglutathione (SGLU/ZIO101) Is a Novel Active Organic Arsenical That Displays a Unique Gene Expression Profile in Myeloma Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5043-5043
Author(s):  
Lawrence H. Boise ◽  
Alejo A. Morales ◽  
Claire R. Croutch ◽  
Delia Gutman ◽  
Robert Peter Gale ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Cell Death ◽  
Phase I ◽  
Cell Lines ◽  
Stress Responses ◽  
Cellular Response ◽  
Differential Sensitivity ◽  
Myeloma Cells ◽  
Rpmi 8226

Abstract Arsenic Trioxide (ATO) is highly active in acute promyelocytic leukemia (APL) and has activity in several other diseases including multiple myeloma. Since arsenicals are active and it is known that organic arsenicals are less toxic than ATO, the testing of new organic arsenicals is warranted. One such compound, ZIO-101 is in phase I/II studies. Therefore we previously compared the ability of ZIO-101 and ATO to kill four myeloma cell lines (RPMI 8226, U266, KMS11, MM.1s) that display differential sensitivity to ATO. Sensitivity to ATO and ZIO-101 did not correlate, as the most ATO resistant line (RPMI 8226) was highly sensitive to ZIO-101. We and others have reported that glutathione (GSH) is a critical regulator of ATO-induced cell death and we have utilized ascorbic acid (AA) as a GSH depleting agent both in vitro as well as clinically. We therefore also tested the effects of GSH depletion on ZIO-101-induced cell death in MM cell lines. BSO was much more effective at sensitizing cells to ATO than to ZIO-101. Moreover while AA could sensitize cells to ATO, it actually protected cells from cell death induced by ZIO-101. Taken together these data suggest ZIO-101 is active against myeloma cells although factors that determine the potency of this compound are different than those for ATO. To better characterize these differences gene expression profiling of the cellular response to ZIO-101 was performed. RNA was isolated from the 4 cell lines treated with ZIO-101 for 0, 6 and 24 h and profiling performed using Affymetrix Hu133 plus 2 arrays. We initially focused on genes that demonstrated similar changes in all four cell lines. 320 probes demonstrated an increase of 1.5 or greater at 6 h while only 58 increased at 24 h. Additionally 265 genes were decreased by at least 1.5 fold at 6 h while only 12 genes were down regulated 1.5 or greater at 24 h. Interestingly the pattern of gene expression was distinct from that observed in similar experiments with ATO. Most notably genes associated with metal responses (MT-1, ZnT-1) and oxidative stress responses (increased expression of HO-1, NQO-1, malic enzyme, GSH synthesis pathway, ferritin) were either absent or only transiently increased. In contrast there was increased expression of the pro-apoptotic gene Noxa compared to ATO treatment in the 4 cell lines. Taken together these data indicate the cellular response to ZIO-101 does not include the up regulation of protective pathways and suggest that ZIO-101 does not initiate cell death through the induction of oxidative stress. This may reflect differences in either metabolism or mechanism of action. Thus resistance to one form of arsenic does not preclude use of another. A phase I/II study of ZIO-101 in myeloma is underway.

scholarly journals Cytosolic aspartate aminotransferase moonlights as a ribosome binding modulator of Gcn2 activity during oxidative stress

2021 ◽  
Author(s):  
Robert A. Crawford ◽  
Mark P. Ashe ◽  
Simon J. Hubbard ◽  
Graham D. Pavitt
Keyword(s):  
Oxidative Stress ◽  
Translational Control ◽  
Aspartate Aminotransferase ◽  
Ribosomal Proteins ◽  
Translational Regulation ◽  
Cellular Response ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Stress Sensitivity ◽  
Yeast Cells

AbstractRegulation of translation is a fundamental facet of the cellular response to rapidly changing external conditions. Specific RNA-binding proteins (RBPs) co-ordinate the translational regulation of distinct mRNA cohorts during stress. To identify RBPs with previously under-appreciated roles in translational control, we used polysome profiling and mass spectrometry to identify and quantify proteins associated with translating ribosomes in unstressed yeast cells and during oxidative stress and amino acid starvation, which both induce the integrated stress response (ISR). Over 800 proteins were identified across polysome gradient fractions, including ribosomal proteins, translation factors and many others without previously described translation-related roles, including numerous metabolic enzymes. We identified variations in patterns of polysome enrichment in both unstressed and stressed cells and identified proteins enriched in heavy polysomes during stress. Genetic screening of polysome-enriched RBPs identified the cytosolic aspartate aminotransferase, Aat2, as a ribosome-associated protein whose deletion conferred growth sensitivity to oxidative stress. Loss of Aat2 caused aberrantly high activation of the ISR via enhanced eIF2α phosphorylation and GCN4 activation. Importantly, non-catalytic AAT2 mutants retained polysome association and did not show heightened stress sensitivity. Aat2 therefore has a separate ribosome-associated translational regulatory or ‘moonlighting’ function that modulates the ISR independent of its aspartate aminotransferase activity.

scholarly journals Protectors or Traitors: The Roles of PON2 and PON3 in Atherosclerosis and Cancer

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Ines Witte ◽  
Ulrich Foerstermann ◽  
Asokan Devarajan ◽  
Srinivasa T. Reddy ◽  
Sven Horke
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Molecular Mechanisms ◽  
Significant Contribution ◽  
Cell Death Pathways ◽  
Plaque Development ◽  
Inflammatory Processes ◽  
Antioxidative Effects ◽  
And Oxidative Stress ◽  
Regulate Cell Death

Cancer and atherosclerosis are major causes of death in western societies. Deregulated cell death is common to both diseases, with significant contribution of inflammatory processes and oxidative stress. These two form a vicious cycle and regulate cell death pathways in either direction. This raises interest in antioxidative systems. The human enzymes paraoxonase-2 (PON2) and PON3 are intracellular enzymes with established antioxidative effects and protective functions against atherosclerosis. Underlying molecular mechanisms, however, remained elusive until recently. Novel findings revealed that both enzymes locate to mitochondrial membranes where they interact with coenzyme Q10 and diminish oxidative stress. As a result, ROS-triggered mitochondrial apoptosis and cell death are reduced. From a cardiovascular standpoint, this is beneficial given that enhanced loss of vascular cells and macrophage death forms the basis for atherosclerotic plaque development. However, the same function has now been shown to raise chemotherapeutic resistance in several cancer cells. Intriguingly, PON2 as well as PON3 are frequently found upregulated in tumor samples. Here we review studies reporting PON2/PON3 deregulations in cancer, summarize most recent findings on their anti-oxidative and antiapoptotic mechanisms, and discuss how this could be used in putative future therapies to target atherosclerosis and cancer.

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