scholarly journals Autophagy-dependent survival is controlled with a unique regulatory network upon various cellular stress events

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Orsolya Kapuy ◽  
Marianna Holczer ◽  
Margita Márton ◽  
Tamás Korcsmáros
Keyword(s):  
Cellular Stress ◽  
Control Network ◽  
Autophagy Induction ◽  
Controlling Elements ◽  
Dynamical Features ◽  
Internal Stimulus ◽  
And Oxidative Stress ◽  
Tolerable Level ◽  
Robust Response ◽  
Kinetic Features

AbstractAlthough autophagy is a type of programmed cell death, it is also essential for cell survival upon tolerable level of various stress events. For the cell to respond adequately to an external and/or internal stimulus induced by cellular stress, autophagy must be controlled in a highly regulated manner. By using systems biology techniques, here we explore the dynamical features of autophagy induction. We propose that the switch-like characteristic of autophagy induction is achieved by a control network, containing essential feedback loops of four components, so-called autophagy inducer, autophagy controller, mTORC1 and autophagy executor, respectively. We show how an autophagy inducer is capable to turn on autophagy in a cellular stress-specific way. The autophagy controller acts as a molecular switch and not only promotes autophagy but also blocks the permanent hyperactivation of the process via downregulating the autophagy inducer. In this theoretical analysis, we explore in detail the properties of all four proposed controlling elements and their connections. Here we also prove that the kinetic features of this control network can be considered accurate in various stress processes (such as starvation, endoplasmic reticulum stress and oxidative stress), even if the exact components may be different. The robust response of the resulting control network is essential during cellular stress.

scholarly journals The Role of MicroRNAs in Diabetes-Related Oxidative Stress

2019 ◽  
Vol 20 (21) ◽  
pp. 5423 ◽  
Author(s):  
Mirza Muhammad Fahd Qadir ◽  
Dagmar Klein ◽  
Silvia Álvarez-Cubela ◽  
Juan Domínguez-Bendala ◽  
Ricardo Luis Pastori
Keyword(s):  
Oxidative Stress ◽  
Target Gene ◽  
Cellular Stress ◽  
Cellular Damage ◽  
Oxygen Species ◽  
Non Coding Rnas ◽  
And Oxidative Stress

Cellular stress, combined with dysfunctional, inadequate mitochondrial phosphorylation, produces an excessive amount of reactive oxygen species (ROS) and an increased level of ROS in cells, which leads to oxidation and subsequent cellular damage. Because of its cell damaging action, an association between anomalous ROS production and disease such as Type 1 (T1D) and Type 2 (T2D) diabetes, as well as their complications, has been well established. However, there is a lack of understanding about genome-driven responses to ROS-mediated cellular stress. Over the last decade, multiple studies have suggested a link between oxidative stress and microRNAs (miRNAs). The miRNAs are small non-coding RNAs that mostly suppress expression of the target gene by interaction with its 3’untranslated region (3′UTR). In this paper, we review the recent progress in the field, focusing on the association between miRNAs and oxidative stress during the progression of diabetes.

scholarly journals Cellular stress mechanisms of prenatal maternal stress: Heat shock factors and oxidative stress

2019 ◽  
Vol 709 ◽  
pp. 134368 ◽  
Author(s):  
Jonathan Dowell ◽  
Benjamin A. Elser ◽  
Rachel E. Schroeder ◽  
Hanna E. Stevens
Keyword(s):  
Oxidative Stress ◽  
Heat Shock ◽  
Maternal Stress ◽  
Cellular Stress ◽  
Heat Shock Factors ◽  
Prenatal Maternal Stress ◽  
And Oxidative Stress

scholarly journals Oxidative Stress Plays an Important Role in Zoledronic Acid-Induced Autophagy

2014 ◽  
pp. S601-S612 ◽  
Author(s):  
V. K. M. KHANDELWAL ◽  
L. M. MITROFAN ◽  
J. M. T. HYTTINEN ◽  
K. R. CHAUDHARI ◽  
R. BUCCIONE ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Zoledronic Acid ◽  
Cancer Cells ◽  
Mevalonate Pathway ◽  
Continuous Treatment ◽  
Autophagy Induction ◽  
Anti Cancer ◽  
Dose Dependent ◽  
And Oxidative Stress ◽  
Mcf 7

Several pre-clinical and clinical studies have demonstrated zoledronic acid (Zol), which regulates the mevalonate pathway, has efficient anti-cancer effects. Zol can also induce autophagy. The aim of this study is to add new understanding to the mechanism of autophagy induction by Zol. LC3B-II, the marker for autophagy was increased by Zol treatment in breast cancer cells. Autophagosomes induced by Zol were visualized and quantified in both transient (pDendra2-hLC3) and stable MCF-7-GFP-LC3 cell lines. Acidic vesicular organelles were quantified using acridine orange. Zol induced a dose and time dependent autophagy. Treatment of Zol increased oxidative stress in MCF-7 cells, which was reversed by GGOH or anti-oxidants. On the other hand, treatment with GGOH or anti-oxidants resulted in decreased levels of LC3B-II. Further, the induced autophagy was irreversible, as the washout of Zol after 2 h or 24 h resulted in similar levels of autophagy, as induced by continuous treatment after 72 h. Thus, it can be summarized that Zol can induce a dose dependent but irreversible autophagy, by its effect on the mevalonate pathway and oxidative stress. This study adds to the understanding of the mechanism of action of Zol, and that it can induce autophagy at clinically relevant shorter exposure times in cancer cells.

scholarly journals A Comprehensive Systems Biological Study of Autophagy-Apoptosis Crosstalk during Endoplasmic Reticulum Stress

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Marianna Holczer ◽  
Margita Márton ◽  
Anita Kurucz ◽  
Gábor Bánhegyi ◽  
Orsolya Kapuy
Keyword(s):  
Endoplasmic Reticulum ◽  
Feedback Loop ◽  
Apoptotic Cell ◽  
Population Level ◽  
Living Organism ◽  
Stochastic Approach ◽  
Biological Study ◽  
Control Network ◽  
Dynamical Features ◽  
Molecular Components

One of the most important tasks of a living organism is to maintain its genetic integrity with respect to stress. Endoplasmic reticulum (ER) has a crucial role in sensing cellular homeostasis by controlling metabolism, proteostasis, and several signaling processes. ER stressors can induce autophagy-dependent survival; however excessive level of stress results in apoptotic cell death. Although many molecular components of these networks have already been discovered, the analysis of the dynamical features of the regulatory network of life-or-death decision is still lacking. Our goal was to incorporate both theoretical and molecular biological techniques to explore the autophagy-apoptosis crosstalk under ER stress. Using various levels of different ER stressors we confirmed that the control network always generated an evidently detectable autophagy-dependent threshold for apoptosis activation. We explored the features of this threshold by introducing both autophagy activators and inhibitors, and transient treatment with excessive level of ER stressor was also performed. Our experimental data were also supported by a stochastic approach. Our analysis suggests that even if the switch-like characteristic of apoptosis activation is hardly seen on population level the double negative feedback loop between autophagy and apoptosis inducers introduces bistability in the control network.

scholarly journals Cucurbitacin B Exerts Antiaging Effects in Yeast by Regulating Autophagy and Oxidative Stress

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Yanfei Lin ◽  
Yuki Kotakeyama ◽  
Jing Li ◽  
Yanjun Pan ◽  
Akira Matsuura ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Screening Program ◽  
Model Organism ◽  
Basic Mechanism ◽  
Sod Activity ◽  
Replicative Lifespan ◽  
Cucurbitacin B ◽  
Autophagy Induction ◽  
Intracellular Targets ◽  
And Oxidative Stress

The budding yeast Saccharomyces cerevisiae has been used as a model organism for the basic mechanism of aging, which provides useful assay systems for measuring both replicative and chronological lifespans. In the course of our screening program for substances that extend replicative lifespan, cucurbitacin B (CuB) was found as a hit compound from a compound library, which contains cerebrosides, phenols, sesquiterpenoid, triterpenoids, and sterols isolated from natural products by our research group. Importantly, it prolonged not only the replicative lifespan but also the chronological lifespan in yeast. CuB increased ATG32 gene expression, suggesting that CuB induces autophagy. Indeed, the GFP signal generated from the cleavage of GFP-Atg8, which is a signature of autophagy, was increased upon CuB treatment. On the other hand, CuB failed to increase the chronological lifespans when either ATG2 or ATG32, essential autophagy genes, was deleted, indicating that the lifespan extension by CuB depends on autophagy induction. Furthermore, CuB significantly increased superoxide dismutase (Sod) activity and the survival rate of yeast under oxidative stress, while it decreased the amount of reactive oxygen species (ROS) and malondialdehyde (MDA) production, indicating that CuB has activity to antagonize oxidative stress. Additionally, CuB did not affect replicative lifespans of sod1, sod2, uth1, and skn7 mutants with the K6001 background, indicating that aging-related genes including SOD1, SOD2, UTH1, and SKN7 participate in the antiaging effect of CuB. These results suggest that CuB exerts antiaging activity by regulating autophagy, ROS, antioxidative ability, and aging-related genes. Finally, we discuss the possible intracellular targets of CuB based on the phenotypic comparison between the CuB and global gene deletion databases.

scholarly journals Distinct stress-dependent signatures of cellular and extracellular tRNA-derived small RNAs (tDRs)

2021 ◽  
Author(s):  
Guoping Li ◽  
Aidan Manning ◽  
Alex Bagi ◽  
Xinyu Yang ◽  
Jonathan Howard ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stress Responses ◽  
Small Rnas ◽  
Cellular Stress ◽  
Fragmentation Pattern ◽  
Cellular Models ◽  
Nutritional Deprivation ◽  
Cellular Stress Responses ◽  
Stress Dependent ◽  
And Oxidative Stress

The cellular response to stress is an important determinant of disease pathogenesis. Uncovering the molecular fingerprints of distinct stress responses may yield novel biomarkers for different diseases, and potentially identify key signaling pathways important for disease progression. tRNAs and tRNA-derived small RNAs (tDRs) comprise one of the most abundant RNA species in cells and have been associated with cellular stress responses. The presence of RNA modifications on tDRs has been an obstacle for accurately identifying tDRs with conventional small RNA sequencing. Here, we use AlkB-facilitated methylation sequencing (ARM-seq) to uncover a comprehensive landscape of cellular and extracellular tDR expression in a variety of human and rat cells during common stress responses, including nutritional deprivation, hypoxia, and oxidative stress. We found that extracellular tDRs have a distinct fragmentation signature with a predominant length of 31-33 nts and a highly specific termination position when compared with intracellular tDRs. Importantly, we found these signatures are better discriminators of different cellular stress responses compared to extracellular miRNAs. Distinct extracellular tDR signatures for each profiled stressor are elucidated in four different types of cells. This distinct extracellular tDR fragmentation pattern is also noted in plasma extracellular RNAs from patients on cardiopulmonary bypass. The observed overlap of these patient tDR signatures with the signatures of nutritional deprivation and oxidative stress in our cellular models provides preliminary in vivo corroboration of our findings and demonstrates the potential to establish novel extracellular tDR biomarkers in human disease models.

scholarly journals The RNA helicase Ded1 regulates translation and granule formation during multiple phases of cellular stress responses

2021 ◽  
Author(s):  
Peyman P. Aryanpur ◽  
Telsa M. Mittelmeier ◽  
Timothy A. Bolger
Keyword(s):  
Oxidative Stress ◽  
Stress Responses ◽  
Cellular Stress ◽  
Low Complexity ◽  
Rna Helicase ◽  
Additional Contribution ◽  
Granule Formation ◽  
Growth Defects ◽  
Cellular Stress Responses ◽  
And Oxidative Stress

Ded1 is a conserved RNA helicase that promotes translation initiation in steady-state conditions. Ded1 has also been shown to regulate translation during cellular stress and affect the dynamics of stress granules (SGs), accumulations of RNA and protein linked to translation repression. To better understand its role in stress responses, we examined Ded1 function in two different models: DED1 overexpression and oxidative stress. DED1 overexpression inhibits growth and promotes the formation of SGs. A ded1 mutant lacking the low-complexity C-terminal region ( ded1-ΔCT ), which mediates Ded1 oligomerization and interaction with the translation factor eIF4G1, suppressed these phenotypes, consistent with other stresses. During oxidative stress, a ded1-ΔCT mutant was defective in growth and in SG formation compared to wild-type cells, although SGs were increased rather than decreased in these conditions. Unlike stress induced by direct TOR inhibition, the phenotypes in both models were only partially dependent on eIF4G1 interaction, suggesting an additional contribution from Ded1 oligomerization. Furthermore, examination of the growth defects and translational changes during oxidative stress suggested that Ded1 plays a role during recovery from stress. Integrating these disparate results, we propose that Ded1 controls multiple aspects of translation and RNP dynamics in both initial stress responses and during recovery.

scholarly journals Autophagy Induction Protects against 7-Oxysterol-induced Cell Death via Lysosomal Pathway and Oxidative Stress

2016 ◽  
Vol 9 ◽  
pp. JCD.S37841 ◽  
Author(s):  
Xi-Ming Yuan ◽  
Nargis Sultana ◽  
Nabeel Siraj ◽  
Liam J. Ward ◽  
Bijar Ghafouri ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Lipid Accumulation ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Autophagic Vacuole ◽  
Cellular Lipid ◽  
Autophagy Induction ◽  
Cellular Lipid Accumulation ◽  
And Oxidative Stress

7-Oxysterols are major toxic components in oxidized low-density lipoprotein and human atheroma lesions, which cause lysosomal membrane permeabilization (LMP) and cell death. Autophagy may function as a survival mechanism in this process. Here, we investigated whether 7-oxysterols mixed in an atheroma-relevant proportion induce autophagy, whether autophagy induction influences 7-oxysterol-mediated cell death, and the underlying mechanisms, by focusing on cellular lipid levels, oxidative stress, and LMP in 7-oxysterol-treated macrophages. We found that 7-oxysterols induced cellular lipid accumulation, autophagy dysfunction, and cell death in the form of both apoptosis and necrosis. Exposure to 7-oxysterols induced autophagic vacuole synthesis in the form of increased autophagy marker microtubule-associated protein 1A/1B-light chain 3 (LC3) and LC3-phosphatidylethanolamine conjugate (LC3-II) and autophagic vacuole formation. This led to an accumulation of p62, indicating a reduction in autophagic vacuole degradation. Importantly, autophagy induction significantly reduced 7-oxysterol-mediated cell death by diminishing LMP and oxidative stress. Moreover, autophagy induction minimized cellular lipid accumulation induced by 7-oxysterols. These findings highlight the importance of autophagy in combating cellular stress, LMP, and cell death in atherosclerosis. Therefore, activation of the autophagy pathway may be a potential therapeutic strategy for prevention of necrotic core formation in atherosclerotic lesions.

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