scholarly journals Interactive Multiresolution Visualization of Cellular Network Processes

2019 ◽  
Author(s):  
Oscar O. Ortega ◽  
Carlos F. Lopez
Keyword(s):  
Computational Models ◽  
Dynamic Network ◽  
Cellular Systems ◽  
Biochemical Network ◽  
Mitochondrial Outer Membrane ◽  
Cellular Processes ◽  
Detection Algorithms ◽  
Mitochondrial Outer Membrane Permeabilization ◽  
Extrinsic Apoptosis ◽  
Dynamic Execution

AbstractComputational models of network-driven processes have become a standard to explain cellular systems-level behavior and predict cellular responses to perturbations. Modern models can span a broad range of biochemical reactions and species that, in principle, comprise the complexity of dynamic cellular processes. Visualization plays a central role in the analysis of biochemical network processes to identify patterns that arise from model dynamics and perform model exploratory analysis. However, most existing visualization tools are limited in their capabilities to facilitate mechanism exploration of large, dynamic, and complex models. Here, we present PyViPR, a visualization tool that provides researchers static and dynamic representations of biochemical network processes within a Python-based Literate Programming environment. PyViPR embeds network visualizations on Jupyter notebooks, thus facilitating integration with Python modeling, simulation, and analysis workflows. To present the capabilities of PyViPR, we explore execution mechanisms of extrinsic apoptosis in HeLa cells. We show how community-detection algorithms can identify groups of molecular species that represent key biological regulatory functions and simplify the apoptosis network by placing those groups into interactively collapsible nodes. We then show how dynamic execution of a signal, under different kinetic parameter sets that fit the experimental data equally well, exhibit significantly different signal-execution modes in mitochondrial outer-membrane permeabilization – the point of no return in extrinsic apoptosis execution. Therefore, PyViPR aids the conceptual understanding of dynamic network processes and accelerates hypothesis generation for further testing and validation.

scholarly journals Probability-based mechanisms in biological networks with parameter uncertainty

2021 ◽  
Author(s):  
Oscar O. Ortega ◽  
Blake A. Wilson ◽  
James C. Pino ◽  
Michael W. Irvin ◽  
Geena V. Ildefonso ◽  
...  
Keyword(s):  
Biological Networks ◽  
Parameter Uncertainty ◽  
Mechanistic Model ◽  
Dynamic Network ◽  
Parameter Inference ◽  
Signal Flow ◽  
Cellular Processes ◽  
Biomolecular Networks ◽  
Extrinsic Apoptosis ◽  
Modulate Signal

AbstractMathematical models of biomolecular networks are commonly used to study mechanisms of cellular processes, but their usefulness is often questioned due to parameter uncertainty. Here, we employ Bayesian parameter inference and dynamic network analysis to study dominant reaction fluxes in models of extrinsic apoptosis. Although a simplified model yields thousands of parameter vectors with equally good fits to data, execution modes based on reaction fluxes clusters to three dominant execution modes. A larger model with increased parameter uncertainty shows that signal flow is constrained to eleven execution modes that use 53 out of 2067 possible signal subnetworks. Each execution mode exhibits different behaviors to in silico perturbations, due to different signal execution mechanisms. Machine learning identifies informative parameters to guide experimental validation. Our work introduces a probability-based paradigm of signaling mechanisms, highlights systems-level interactions that modulate signal flow, and provides a methodology to understand mechanistic model predictions with uncertain parameters.

scholarly journals Mitochondrial Outer Membrane Proteins Assist Bid in Bax-mediated Lipidic Pore Formation

2009 ◽  
Vol 20 (8) ◽  
pp. 2276-2285 ◽  
Author(s):  
Blanca Schafer ◽  
Joel Quispe ◽  
Vineet Choudhary ◽  
Jerry E. Chipuk ◽  
Teddy G. Ajero ◽  
...  
Keyword(s):  
Outer Membrane ◽  
Pore Formation ◽  
Outer Membrane Proteins ◽  
Mitochondrial Outer Membrane ◽  
Outer Membranes ◽  
Mitochondrial Outer Membrane Permeabilization ◽  
In Vitro Systems ◽  
Large Round ◽  
Key Features

Mitochondrial outer membrane permeabilization (MOMP) is a critical step in apoptosis and is regulated by Bcl-2 family proteins. In vitro systems using cardiolipin-containing liposomes have demonstrated the key features of MOMP induced by Bax and cleaved Bid; however, the nature of the “pores” and how they are formed remain obscure. We found that mitochondrial outer membranes contained very little cardiolipin, far less than that required for liposome permeabilization, despite their responsiveness to Bcl-2 family proteins. Strikingly, the incorporation of isolated mitochondrial outer membrane (MOM) proteins into liposomes lacking cardiolipin conferred responsiveness to cleaved Bid and Bax. Cardiolipin dependence was observed only when permeabilization was induced with cleaved Bid but not with Bid or Bim BH3 peptide or oligomerized Bax. Therefore, we conclude that MOM proteins specifically assist cleaved Bid in Bax-mediated permeabilization. Cryoelectron microscopy of cardiolipin-liposomes revealed that cleaved Bid and Bax produced large round holes with diameters of 25–100 nm, suggestive of lipidic pores. In sum, we propose that activated Bax induces lipidic pore formation and that MOM proteins assist cleaved Bid in this process in the absence of cardiolipin.

scholarly journals The structure and function of centriolar rootlets

2021 ◽  
Vol 134 (16) ◽  
Author(s):  
Robert Mahen
Keyword(s):  
Cellular Function ◽  
Structure And Function ◽  
Cellular Systems ◽  
Macromolecular Assemblies ◽  
Cellular Processes ◽  
Holistic Understanding ◽  
Eukaryotic Organisms ◽  
And Function ◽  
Knockout Animals

ABSTRACT To gain a holistic understanding of cellular function, we must understand not just the role of individual organelles, but also how multiple macromolecular assemblies function collectively. Centrioles produce fundamental cellular processes through their ability to organise cytoskeletal fibres. In addition to nucleating microtubules, centrioles form lesser-known polymers, termed rootlets. Rootlets were identified over a 100 years ago and have been documented morphologically since by electron microscopy in different eukaryotic organisms. Rootlet-knockout animals have been created in various systems, providing insight into their physiological functions. However, the precise structure and function of rootlets is still enigmatic. Here, I consider common themes of rootlet function and assembly across diverse cellular systems. I suggest that the capability of rootlets to form physical links from centrioles to other cellular structures is a general principle unifying their functions in diverse cells and serves as an example of how cellular function arises from collective organellar activity.

scholarly journals A Septin Cytoskeleton-Targeting Small Molecule, Forchlorfenuron, Inhibits Epithelial Migration via Septin-Independent Perturbation of Cellular Signaling

Cells ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 84 ◽  
Author(s):  
Lei Sun ◽  
Xuelei Cao ◽  
Susana Lechuga ◽  
Alex Feygin ◽  
Nayden G. Naydenov ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Cellular Systems ◽  
Model Organisms ◽  
Cellular Functions ◽  
Epithelial Migration ◽  
Cellular Processes ◽  
Dependent Inhibition ◽  
Erk Activity ◽  
Ht 29 ◽  
Target Effects

Septins are GTP-binding proteins that self-assemble into high-order cytoskeletal structures, filaments, and rings. The septin cytoskeleton has a number of cellular functions, including regulation of cytokinesis, cell migration, vesicle trafficking, and receptor signaling. A plant cytokinin, forchlorfenuron (FCF), interacts with septin subunits, resulting in the altered organization of the septin cytoskeleton. Although FCF has been extensively used to examine the roles of septins in various cellular processes, its specificity, and possible off-target effects in vertebrate systems, has not been investigated. In the present study, we demonstrate that FCF inhibits spontaneous, as well as hepatocyte growth factor-induced, migration of HT-29 and DU145 human epithelial cells. Additionally, FCF increases paracellular permeability of HT-29 cell monolayers. These inhibitory effects of FCF persist in epithelial cells where the septin cytoskeleton has been disassembled by either CRISPR/Cas9-mediated knockout or siRNA-mediated knockdown of septin 7, insinuating off-target effects of FCF. Biochemical analysis reveals that FCF-dependent inhibition of the motility of control and septin-depleted cells is accompanied by decreased expression of the c-Jun transcription factor and inhibited ERK activity. The described off-target effects of FCF strongly suggests that caution is warranted while using this compound to examine the biological functions of septins in cellular systems and model organisms.

scholarly journals Modulation of Mitochondrial Outer Membrane Permeabilization and Apoptosis by Ceramide Metabolism

PLoS ONE ◽  
2012 ◽  
Vol 7 (11) ◽  
pp. e48571 ◽  
Author(s):  
António Rego ◽  
Margarida Costa ◽  
Susana Rodrigues Chaves ◽  
Nabil Matmati ◽  
Helena Pereira ◽  
...  
Keyword(s):  
Outer Membrane ◽  
Membrane Permeabilization ◽  
Mitochondrial Outer Membrane ◽  
Mitochondrial Outer Membrane Permeabilization

Mitochondria in cell death

2010 ◽  
Vol 47 ◽  
pp. 99-114 ◽  
Author(s):  
Melissa J. Parsons ◽  
Douglas R. Green
Keyword(s):  
Cell Death ◽  
Neurological Diseases ◽  
Mitochondrial Outer Membrane ◽  
Intermembrane Space ◽  
Apoptotic Pathway ◽  
Life And Death ◽  
Mitochondrial Outer Membrane Permeabilization ◽  
Mitochondrial Functions ◽  
A Cell ◽  
Signalling Cascade

Apoptosis can be thought of as a signalling cascade that results in the death of the cell. Properly executed apoptosis is critically important for both development and homoeostasis of most animals. Accordingly, defects in apoptosis can contribute to the development of autoimmune disorders, neurological diseases and cancer. Broadly speaking, there are two main pathways by which a cell can engage apoptosis: the extrinsic apoptotic pathway and the intrinsic apoptotic pathway. At the centre of the intrinsic apoptotic signalling pathway lies the mitochondrion, which, in addition to its role as the bioenergetic centre of the cell, is also the cell’s reservoir of pro-death factors which reside in the mitochondrial IMS (intermembrane space). During intrinsic apoptosis, pores are formed in the OMM (outer mitochondrial membrane) of the mitochondria in a process termed MOMP (mitochondrial outer membrane permeabilization). This allows for the release of IMS proteins; once released during MOMP, some IMS proteins, notably cytochrome c and Smac/DIABLO (Second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low pI), promote caspase activation and subsequent cleavage of structural and regulatory proteins in the cytoplasm and the nucleus, leading to the demise of the cell. MOMP is achieved through the co-ordinated actions of pro-apoptotic members and inhibited by anti-apoptotic members of the Bcl-2 family of proteins. Other aspects of mitochondrial physiology, such as mitochondrial bioenergetics and dynamics, are also involved in processes of cell death that proceed through the mitochondria. Proper regulation of these mitochondrial functions is vitally important for the life and death of the cell and for the organism as a whole.

scholarly journals Poliovirus Induces Bax-Dependent Cell Death Mediated by c-Jun NH2-Terminal Kinase

2007 ◽  
Vol 81 (14) ◽  
pp. 7504-7516 ◽  
Author(s):  
Arnaud Autret ◽  
Sandra Martin-Latil ◽  
Laurence Mousson ◽  
Aurélie Wirotius ◽  
Frédéric Petit ◽  
...  
Keyword(s):  
Cell Death ◽  
Outer Membrane ◽  
Motor Neurons ◽  
Cell Receptor ◽  
Cellular Level ◽  
Membrane Permeabilization ◽  
Paralytic Poliomyelitis ◽  
Receptor Interaction ◽  
Mitochondrial Outer Membrane ◽  
Mitochondrial Outer Membrane Permeabilization

ABSTRACT Poliovirus (PV) is the causal agent of paralytic poliomyelitis, a disease that involves the destruction of motor neurons associated with PV replication. In PV-infected mice, motor neurons die through an apoptotic process. However, mechanisms by which PV induces cell death in neuronal cells remain unclear. Here, we demonstrate that PV infection of neuronal IMR5 cells induces cytochrome c release from mitochondria and loss of mitochondrial transmembrane potential, both of which are evidence of mitochondrial outer membrane permeabilization. PV infection also activates Bax, a proapoptotic member of the Bcl-2 family; this activation involves its conformational change and its redistribution from the cytosol to mitochondria. Neutralization of Bax by vMIA protein expression prevents cytochrome c release, consistent with a contribution of PV-induced Bax activation to mitochondrial outer membrane permeabilization. Interestingly, we also found that c-Jun NH2-terminal kinase (JNK) is activated soon after PV infection and that the PV-cell receptor interaction alone is sufficient to induce JNK activation. Moreover, the pharmacological inhibition of JNK by SP600125 inhibits Bax activation and cytochrome c release. This is, to our knowledge, the first demonstration of JNK-mediated Bax-dependent apoptosis in PV-infected cells. Our findings contribute to our understanding of poliomyelitis pathogenesis at the cellular level.

Therapeutic Targeting of the Bcl2 Family

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. SCI-42-SCI-42
Author(s):  
Anthony Letai ◽  
Matthew S. Davids ◽  
Triona Ni Chonghaile ◽  
Jing Deng ◽  
Luv Patel
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Lymphoblastic Leukemia ◽  
Lymphocytic Leukemia ◽  
Mitochondrial Outer Membrane ◽  
Short Term ◽  
Provocative Test ◽  
Mitochondrial Outer Membrane Permeabilization

Abstract Many, perhaps most, cancer chemotherapy agents kill cancer cells via the mitochondrial pathway of apoptosis that is controlled by the Bcl-2 family of proteins. Bcl-2 family proteins regulate commitment to cell death by controlling mitochondrial outer membrane permeabilization (MOMP). To better understand how cancer cells commit to apoptosis, and what drugs might make them commit to apoptosis, we have studied perturbing mitochondria with BH3 peptides that are derived from pro-death Bcl-2 family proteins. Using this provocative test, which we call BH3 profiling, we are able to measure how close a cell is to the threshold of apoptosis, a property we call “priming”. Priming corresponds to sensitivity to chemotherapy. Moreover, BH3 profiling can be used to detect dependence on Bcl-2 and Bcl-xL for survival, which predicts cytotoxic response to small molecule antagonists such as ABT-199 and ABT-263. In acute lymphoblastic leukemia, we find that dependence on either Bcl-2 or Bcl-xL varies from case to case, with very important consequences for sensitivity to ABT-199 and ABT-263. In chronic lymphocytic leukemia, ABT-199 has already demonstrated significant clinical activity that corresponds to its on-target activity in mitochondria in vitro. We have been testing how this in vitro mitochondrial activity in BH3 profiling assays might be translated into a useful clinical predictive biomarker. Finally, we can measure how short term incubation with many kinds of drugs, including targeted pathway inhibitors, can increase cancer cell priming, including for primary lymphoid malignancy cells. This short term increase in priming predicts subsequent cancer cell death, including in clinical treatment. We call this method “Dynamic BH3 Profiling” and are exploring how it might best be utilized in the clinic. Disclosures: Letai: Dana-Farber Cancer Institute: Patents & Royalties; AbbVie: Consultancy.

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