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Special Issue "Quantitative Modelling in Molecular System Bioenergetics"

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry, Molecular Biology and Biophysics".

Deadline for manuscript submissions: closed (15 September 2010)

Special Issue Editor

Guest Editor
Dr. Valdur Saks

Laboratory of Bioenergetics, INSERM U884, Joseph Fourier University, Grenoble, France
Phone: +33476635627
Fax: +33 4 7651 4218
Interests: bioenergetics; systems biology; biophysics; enzymology; cell physiology

Special Issue Information

Dear Colleagues,

The new Special Issue of IJMS continues description of developments in new area of the research - Molecular System Bioenergetics, which was begun by publication of a book “Molecular System Bioenergetics. Energy for Life” by Wiley-VCH in 2007 (http://www3.interscience.wiley.com/cgi-bin/bookhome/117349267) and followed by publication in 2009 of Special Issue of IJMS “Molecular System Bioenergetics” (http://www.mdpi.com/journal/ijms/special_issues/molecular_system_bioenergetics). The way of life of cells is metabolism by exchanging mass and energy with surrounding medium, and understanding its mechanisms needs knowledge of the complex interactions between cellular systems and components. Understanding of the mechanisms of regulation of metabolic and energy fluxes is one of the important aims of Molecular System Bioenergetics, a part of Systems Biology. An important tool in these investigations is the use of quantitative, mathematical models for description, analysis and prediction of the behavior of the complex, integrated systems. While there is abundant literature on quantitative aspects of Systems Biology, network theories etc, important area of metabolic research is still full of contradictions, especially regarding the mathematical description of intracellular metabolic systems and energy metabolism of the cells. Here, two opposite approaches are used with conflicting results, as it has been described in details in a recent review by Saks et al., Int. J. Mol. Sci. 2008, 9, 751-767. One part of investigators ignores the information of complex cell structure and intracellular interactions; these are not interesting for this Special Issue. The aim of this Issue is discussion of problems of modelling of real intracellular metabolic systems functioning in non-equilibrium steady state, taking into account compartmentation of metabolites and enzymes, metabolic channeling, restrictions of intracellular diffusion, direct interaction of enzymes within multienzyme complexes, formation and behavior of dissipative metabolic networks etc. This is a new challenge for Molecular System Bioenergetics.

Prof. Dr. Valdur Saks
Guest Editor

Keywords

  • mathematical modelling
  • metabolism
  • cellular bioenergetics
  • compartmentation
  • metabolic channeling
  • dissipative metabolic networks
  • non-equilibrium steady state kinetics
  • feedback regulation

Related Special Issue

Published Papers (5 papers)

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Research

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Open AccessArticle Energetics of Glucose Metabolism: A Phenomenological Approach to Metabolic Network Modeling
Int. J. Mol. Sci. 2010, 11(8), 2921-2961; doi:10.3390/ijms11082921
Received: 6 July 2010 / Revised: 5 August 2010 / Accepted: 6 August 2010 / Published: 12 August 2010
Cited by 1 | PDF Full-text (501 KB) | HTML Full-text | XML Full-text
Abstract
A new formalism to describe metabolic fluxes as well as membrane transport processes was developed. The new flux equations are comparable to other phenomenological laws. Michaelis-Menten like expressions, as well as flux equations of nonequilibrium thermodynamics, can be regarded as special cases [...] Read more.
A new formalism to describe metabolic fluxes as well as membrane transport processes was developed. The new flux equations are comparable to other phenomenological laws. Michaelis-Menten like expressions, as well as flux equations of nonequilibrium thermodynamics, can be regarded as special cases of these new equations. For metabolic network modeling, variable conductances and driving forces are required to enable pathway control and to allow a rapid response to perturbations. When applied to oxidative phosphorylation, results of simulations show that whole oxidative phosphorylation cannot be described as a two-flux-system according to nonequilibrium thermodynamics, although all coupled reactions per se fulfill the equations of this theory. Simulations show that activation of ATP-coupled load reactions plus glucose oxidation is brought about by an increase of only two different conductances: a [Ca2+] dependent increase of cytosolic load conductances, and an increase of phosphofructokinase conductance by [AMP], which in turn becomes increased through [ADP] generation by those load reactions. In ventricular myocytes, this feedback mechanism is sufficient to increase cellular power output and O2 consumption several fold, without any appreciable impairment of energetic parameters. Glucose oxidation proceeds near maximal power output, since transformed input and output conductances are nearly equal, yielding an efficiency of about 0.5. This conductance matching is fulfilled also by glucose oxidation of β-cells. But, as a price for the metabolic mechanism of glucose recognition, β-cells have only a limited capability to increase their power output. Full article
(This article belongs to the Special Issue Quantitative Modelling in Molecular System Bioenergetics)
Open AccessArticle Robustness in Regulatory Interaction Networks. A Generic Approach with Applications at Different Levels: Physiologic, Metabolic and Genetic
Int. J. Mol. Sci. 2009, 10(10), 4437-4473; doi:10.3390/ijms10104437
Received: 15 September 2009 / Revised: 2 October 2009 / Accepted: 14 October 2009 / Published: 19 October 2009
Cited by 18 | PDF Full-text (2016 KB) | HTML Full-text | XML Full-text
Abstract
Regulatory interaction networks are often studied on their dynamical side (existence of attractors, study of their stability). We focus here also on their robustness, that is their ability to offer the same spatiotemporal patterns and to resist to external perturbations such as [...] Read more.
Regulatory interaction networks are often studied on their dynamical side (existence of attractors, study of their stability). We focus here also on their robustness, that is their ability to offer the same spatiotemporal patterns and to resist to external perturbations such as losses of nodes or edges in the networks interactions architecture, changes in their environmental boundary conditions as well as changes in the update schedule (or updating mode) of the states of their elements (e.g., if these elements are genes, their synchronous coexpression mode versus their sequential expression). We define the generic notions of boundary, core, and critical vertex or edge of the underlying interaction graph of the regulatory network, whose disappearance causes dramatic changes in the number and nature of attractors (e.g., passage from a bistable behaviour to a unique periodic regime) or in the range of their basins of stability. The dynamic transition of states will be presented in the framework of threshold Boolean automata rules. A panorama of applications at different levels will be given: brain and plant morphogenesis, bulbar cardio-respiratory regulation, glycolytic/oxidative metabolic coupling, and eventually cell cycle and feather morphogenesis genetic control. Full article
(This article belongs to the Special Issue Quantitative Modelling in Molecular System Bioenergetics)

Review

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Open AccessReview Quantitative Analysis of Cellular Metabolic Dissipative, Self-Organized Structures
Int. J. Mol. Sci. 2010, 11(9), 3540-3599; doi:10.3390/ijms11093540
Received: 13 August 2010 / Revised: 11 September 2010 / Accepted: 12 September 2010 / Published: 27 September 2010
Cited by 14 | PDF Full-text (872 KB) | HTML Full-text | XML Full-text
Abstract
One of the most important goals of the postgenomic era is understanding the metabolic dynamic processes and the functional structures generated by them. Extensive studies during the last three decades have shown that the dissipative self-organization of the functional enzymatic associations, the [...] Read more.
One of the most important goals of the postgenomic era is understanding the metabolic dynamic processes and the functional structures generated by them. Extensive studies during the last three decades have shown that the dissipative self-organization of the functional enzymatic associations, the catalytic reactions produced during the metabolite channeling, the microcompartmentalization of these metabolic processes and the emergence of dissipative networks are the fundamental elements of the dynamical organization of cell metabolism. Here we present an overview of how mathematical models can be used to address the properties of dissipative metabolic structures at different organizational levels, both for individual enzymatic associations and for enzymatic networks. Recent analyses performed with dissipative metabolic networks have shown that unicellular organisms display a singular global enzymatic structure common to all living cellular organisms, which seems to be an intrinsic property of the functional metabolism as a whole. Mathematical models firmly based on experiments and their corresponding computational approaches are needed to fully grasp the molecular mechanisms of metabolic dynamical processes. They are necessary to enable the quantitative and qualitative analysis of the cellular catalytic reactions and also to help comprehend the conditions under which the structural dynamical phenomena and biological rhythms arise. Understanding the molecular mechanisms responsible for the metabolic dissipative structures is crucial for unraveling the dynamics of cellular life. Full article
(This article belongs to the Special Issue Quantitative Modelling in Molecular System Bioenergetics)
Open AccessReview The Chemical Master Equation Approach to Nonequilibrium Steady-State of Open Biochemical Systems: Linear Single-Molecule Enzyme Kinetics and Nonlinear Biochemical Reaction Networks
Int. J. Mol. Sci. 2010, 11(9), 3472-3500; doi:10.3390/ijms11093472
Received: 15 August 2010 / Accepted: 14 September 2010 / Published: 20 September 2010
Cited by 22 | PDF Full-text (481 KB) | HTML Full-text | XML Full-text
Abstract
We develop the stochastic, chemical master equation as a unifying approach to the dynamics of biochemical reaction systems in a mesoscopic volume under a living environment. A living environment provides a continuous chemical energy input that sustains the reaction system in a [...] Read more.
We develop the stochastic, chemical master equation as a unifying approach to the dynamics of biochemical reaction systems in a mesoscopic volume under a living environment. A living environment provides a continuous chemical energy input that sustains the reaction system in a nonequilibrium steady state with concentration fluctuations. We discuss the linear, unimolecular single-molecule enzyme kinetics, phosphorylation-dephosphorylation cycle (PdPC) with bistability, and network exhibiting oscillations. Emphasis is paid to the comparison between the stochastic dynamics and the prediction based on the traditional approach based on the Law of Mass Action. We introduce the difference between nonlinear bistability and stochastic bistability, the latter has no deterministic counterpart. For systems with nonlinear bistability, there are three different time scales: (a) individual biochemical reactions, (b) nonlinear network dynamics approaching to attractors, and (c) cellular evolution. For mesoscopic systems with size of a living cell, dynamics in (a) and (c) are stochastic while that with (b) is dominantly deterministic. Both (b) and (c) are emergent properties of a dynamic biochemical network; We suggest that the (c) is most relevant to major cellular biochemical processes such as epi-genetic regulation, apoptosis, and cancer immunoediting. The cellular evolution proceeds with transitions among the attractors of (b) in a “punctuated equilibrium” manner. Full article
(This article belongs to the Special Issue Quantitative Modelling in Molecular System Bioenergetics)
Open AccessReview Application of the Principles of Systems Biology and Wiener's Cybernetics for Analysis of Regulation of Energy Fluxes in Muscle Cells in Vivo
Int. J. Mol. Sci. 2010, 11(3), 982-1019; doi:10.3390/ijms11030982
Received: 30 January 2010 / Revised: 26 February 2010 / Accepted: 26 February 2010 / Published: 8 March 2010
Cited by 14 | PDF Full-text (1221 KB) | HTML Full-text | XML Full-text
Abstract
The mechanisms of regulation of respiration and energy fluxes in the cells are analyzed based on the concepts of systems biology, non-equilibrium steady state kinetics and applications of Wiener’s cybernetic principles of feedback regulation. Under physiological conditions cardiac function is governed by [...] Read more.
The mechanisms of regulation of respiration and energy fluxes in the cells are analyzed based on the concepts of systems biology, non-equilibrium steady state kinetics and applications of Wiener’s cybernetic principles of feedback regulation. Under physiological conditions cardiac function is governed by the Frank-Starling law and the main metabolic characteristic of cardiac muscle cells is metabolic homeostasis, when both workload and respiration rate can be changed manifold at constant intracellular level of phosphocreatine and ATP in the cells. This is not observed in skeletal muscles. Controversies in theoretical explanations of these observations are analyzed. Experimental studies of permeabilized fibers from human skeletal muscle vastus lateralis and adult rat cardiomyocytes showed that the respiration rate is always an apparent hyperbolic but not a sigmoid function of ADP concentration. It is our conclusion that realistic explanations of regulation of energy fluxes in muscle cells require systemic approaches including application of the feedback theory of Wiener’s cybernetics in combination with detailed experimental research. Such an analysis reveals the importance of limited permeability of mitochondrial outer membrane for ADP due to interactions of mitochondria with cytoskeleton resulting in quasi-linear dependence of respiration rate on amplitude of cyclic changes in cytoplasmic ADP concentrations. The system of compartmentalized creatine kinase (CK) isoenzymes functionally coupled to ANT and ATPases, and mitochondrial-cytoskeletal interactions separate energy fluxes (mass and energy transfer) from signalling (information transfer) within dissipative metabolic structures – intracellular energetic units (ICEU). Due to the non-equilibrium state of CK reactions, intracellular ATP utilization and mitochondrial ATP regeneration are interconnected by the PCr flux from mitochondria. The feedback regulation of respiration occurring via cyclic fluctuations of cytosolic ADP, Pi and Cr/PCr ensures metabolic stability necessary for normal function of cardiac cells. Full article
(This article belongs to the Special Issue Quantitative Modelling in Molecular System Bioenergetics)

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