A Systems Biological Perspective of Cellular Stress-Directed Programmed Cell Death

Kapuy, Orsolya; Lizák, Beáta; Stiller, Ibolya; Bánhegyi, Gábor

doi:10.4236/cmb.2014.41003

Cited by 6 publications

(5 citation statements)

References 27 publications

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“…non-tolerable) ER stress levels were induced in the host cell ( Fig 2B and 2C ). Corresponding to our already published data [ 51 , 53 ], we further revealed here that cells survived with the help of autophagy-dependent self-degradation at low levels of ER stress, however, severe ER stress resulted in apoptotic cell death, meanwhile autophagy was switched off. According to previous experimental data [ 59 ], we confirm here that CQ/HCQ blocks the formation of autophagosomes, thereby disrupting autophagy-dependent survival even at low levels of ER stress.…”

Section: Discussionsupporting

confidence: 89%

“…Although the complexity of cellular systems makes this analysis highly challenging, a reductionist approach using a simple wiring diagram can be created containing the key components of the control network to address fundamental questions [ 47 , 49 ]. Accordingly, we have focused our research on the systems biology analysis of autophagy and its crosstalk with apoptosis with respect to ER stress [ 51 – 53 ]. Recently, we have shown by using both molecular and systems biology methods that autophagy always generates an evidently distinguishable threshold for apoptosis activation upon ER stress [ 51 , 53 ].…”

Section: Introductionmentioning

confidence: 99%

“…Accordingly, we have focused our research on the systems biology analysis of autophagy and its crosstalk with apoptosis with respect to ER stress [ 51 – 53 ]. Recently, we have shown by using both molecular and systems biology methods that autophagy always generates an evidently distinguishable threshold for apoptosis activation upon ER stress [ 51 , 53 ]. Our four-component model (i.e.…”

Section: Introductionmentioning

confidence: 99%

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Chloroquine and COVID-19—A systems biology model uncovers the drug’s detrimental effect on autophagy and explains its failure

Kapuy

Korcsmáros

2022

PLoS ONE

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The COVID-19 pandemic caused by SARS-CoV-2 has resulted in an urgent need for identifying potential therapeutic drugs. In the first half of 2020 tropic antimalarial drugs, such as chloroquine (CQ) or hydroxochloroquine (HCQ) were the focus of tremendous public attention. In the initial periods of the pandemic, many scientific results pointed out that CQ/HCQ could be very effective for patients with severe COVID. While CQ and HCQ have successfully been used against several diseases (such as malaria, autoimmune disease and rheumatic illnesses); long term use of these agents are associated with serious adverse effects (i.e. inducing acute kidney injury, among many others) due to their role in blocking autophagy-dependent self-degradation. Recent experimental and clinical trial data also confirmed that there is no sufficient evidence about the efficient usage of CQ/HCQ against COVID-19. By using systems biology techniques, here we show that the cellular effect of CQ/HCQ on autophagy during endoplasmic reticulum (ER) stress or following SARS-CoV-2 infection results in upregulation of ER stress. By presenting a simple mathematical model, we claim that although CQ/HCQ might be able to ameliorate virus infection, the permanent inhibition of autophagy by CQ/HCQ has serious negative effects on the cell. Since CQ/HCQ promotes apoptotic cell death, here we confirm that addition of CQ/HCQ cannot be really effective even in severe cases. Only a transient treatment seemed to be able to avoid apoptotic cell death, but this type of therapy could not limit virus replication in the infected host. The presented theoretical analysis clearly points out the utility and applicability of systems biology modelling to test the cellular effect of a drug targeting key major processes, such as autophagy and apoptosis. Applying these approaches could decrease the cost of pre-clinical studies and facilitate the selection of promising clinical trials in a timely fashion.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Chloroquine and COVID-19—A systems biology model uncovers the drug’s detrimental effect on autophagy and explains its failure

Kapuy

Korcsmáros

2022

PLoS ONE

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“…However, excessive level of cellular stress results in an irreversible switch-like activation of apoptosis inducer and autophagy inducer gets inactive [ 35 ]. We suggested that the effect of crosstalk element and the double negative feedback loop between autophagy and apoptosis inducers have a crucial role in guaranteeing the proper decision-making between life and death [ 36 ]. Later Xu et al confirmed experimentally that autophagy induction in response to stress is uniformly unimodal, while apoptotic process gets activated in bimodal fashion [ 37 ].…”

Section: Introductionmentioning

confidence: 99%

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

Holczer

Márton

Kurucz

et al. 2015

BioMed Research International

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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.

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“…However, excessive levels of autophagy can lead to apoptosis with increased stress levels [7, 10–13]. Apoptosis, a kind of programmed cell death, can be triggered by the proapoptotic protein Bax, which causes mitochondrial membrane permeabilization to release mitochondrial cytochrome c into the cytoplasm, further activating Caspases to induce apoptosis [14–17]. An increasing number of studies confirm that the autophagy and apoptosis networks are linked at various levels through common regulatory elements [18, 19].…”

Section: Introductionmentioning

confidence: 99%

Autophagy and apoptosis are regulated by stress on Bcl2 by AMBRA1 in the endoplasmic reticulum and mitochondria

Yang

Liu

2019

Theor Biol Med Model

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BackgroundAutophagy and apoptosis are two important physiological processes that determine cell survival or death in response to different stress signals. The regulatory mechanisms of these two processes share B-cell lymphoma-2 family proteins and AMBRA1, which are present in both the endoplasmic reticulum and mitochondria. B-cell lymphoma-2 family proteins sense different stresses and interact with AMBRA1 to regulate autophagy and apoptosis, which are respectively mediated by Beclin1 and Caspases. Therefore, we investigated how different levels of stress on B-cell lymphoma-2 family proteins that bind to AMBRA1 in the endoplasmic reticulum and mitochondria regulate the switch from autophagy to apoptosis.MethodsIn this paper, we considered the responses of B-cell lymphoma-2 family proteins, which bind to AMBRA1 in both the endoplasmic reticulum and mitochondria, to two different levels of stress in a model originally proposed by Kapuy et al. We investigated how these two stress levels affect the transition from autophagy to apoptosis and their effects on apoptosis activation over time. Additionally, we analyzed how the feedback regulation in this model affects the bifurcation diagrams of two levels of stress and cell fate decisions between autophagy and apoptosis.ResultsAutophagy is activated for minor stress in mitochondria regardless of endoplasmic reticulum stress, while apoptosis is activated for only significant stress in mitochondria. Apoptosis is only sensitive to mitochondria stress. The time duration before apoptosis activation is longer in the presence of high AMBRA1 levels with high endoplasmic reticulum and mitochondria stress. AMBRA1 can compete with B-cell lymphoma-2 family proteins to bind and activate Beclin1 and thus promote the autophagy process for a long time before apoptosis. Furthermore, apoptosis is prone to occur with increasing activation of Caspases, inactivation of Beclin1-A and the Michaelis constant of Caspases.ConclusionA novel mathematical model has been developed to understand the complex regulatory mechanisms of autophagy and apoptosis. Our model may be applied to further autophagy-apoptosis dynamic modeling experiments and simulations.

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A Systems Biological Perspective of Cellular Stress-Directed Programmed Cell Death

Cited by 6 publications

References 27 publications

Chloroquine and COVID-19—A systems biology model uncovers the drug’s detrimental effect on autophagy and explains its failure

Chloroquine and COVID-19—A systems biology model uncovers the drug’s detrimental effect on autophagy and explains its failure

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

Autophagy and apoptosis are regulated by stress on Bcl2 by AMBRA1 in the endoplasmic reticulum and mitochondria

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