Catalytic Coupling of Oxidative Phosphorylation, ATP Demand, and Reactive Oxygen Species Generation

Bazil, Jason N.; Beard, Daniel A.; Vinnakota, Kalyan C.

doi:10.1016/j.bpj.2015.09.036

Cited by 63 publications

(88 citation statements)

References 78 publications

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“…Specifically, we have developed a multi-scale model of cardiovascular dynamics that integrates myocardial energetics and cross-bridge kinetics with whole-organ and whole-body models of the heart and the circulation. The model is based on previously developed and independently validated models of myocardial energy metabolism [2, 3, 14], cardiac muscle dynamics [15], and whole-organ heart mechanics and pumping [16]. Integrating these components together using a recently developed model of the cardiac cross-bridge kinetics/dynamics that accounts for the influence of [MgATP], [MgADP] and [P i ] on state transitions [15], we are able to computationally predict how metabolic state influences cardiac function and whole-body cardiovascular state.…”

Section: Introductionmentioning

confidence: 99%

Influence of metabolic dysfunction on cardiac mechanics in decompensated hypertrophy and heart failure

Tewari

Bugenhagen

Vinnakota

et al. 2016

Journal of Molecular and Cellular Cardiology

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Alterations in energetic state of the myocardium are associated with decompensated heart failure in humans and in animal models. However, the functional consequences of the observed changes in energetic state on mechanical function are not known. The primary aim of the study was to quantify mechanical/energetic coupling in the heart and to determine if energetic dysfunction can contribute to mechanical failure. A secondary aim was to apply a quantitative systems pharmacology analysis to investigate the effects of drugs that target cross-bridge cycling kinetics in heart failure-associated energetic dysfunction. Herein, a model of metabolite- and calcium-dependent myocardial mechanics was developed from calcium concentration and tension time courses in rat cardiac muscle obtained at different lengths and stimulation frequencies. The muscle dynamics model accounting for the effect of metabolites was integrated into a model of the cardiac ventricles to simulate pressure-volume dynamics in the heart. This cardiac model was integrated into a simple model of the circulation to investigate the effects of metabolic state on whole-body function. Simulations predict that reductions in metabolite pools observed in canine models of heart failure can cause systolic dysfunction, blood volume expansion, venous congestion, and ventricular dilation. Simulations also predict that myosin-activating drugs may partially counteract the effects of energetic state on cross-bridge mechanics in heart failure while increasing myocardial oxygen consumption. Our model analysis demonstrates how metabolic changes observed in heart failure are alone sufficient to cause systolic dysfunction and whole-body heart failure symptoms.

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Section: Introductionmentioning

confidence: 99%

Influence of metabolic dysfunction on cardiac mechanics in decompensated hypertrophy and heart failure

Tewari

Bugenhagen

Vinnakota

et al. 2016

Journal of Molecular and Cellular Cardiology

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“…Computational models have already been used to study mitochondrial dysfunction [22], ROS generation [23, 24] and ROS scavenging [25, 26]. However, this is the first time, that this kind of models has been used to study drug cardiotoxicity.…”

Section: Discussionmentioning

confidence: 99%

A Biophysical Systems Approach to Identifying the Pathways of Acute and Chronic Doxorubicin Mitochondrial Cardiotoxicity

Oliveira

Niederer

2016

PLoS Comput Biol

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The clinical use of the anthracycline doxorubicin is limited by its cardiotoxicity which is associated with mitochondrial dysfunction. Redox cycling, mitochondrial DNA damage and electron transport chain inhibition have been identified as potential mechanisms of toxicity. However, the relative roles of each of these proposed mechanisms are still not fully understood. The purpose of this study is to identify which of these pathways independently or in combination are responsible for doxorubicin toxicity. A state of the art mathematical model of the mitochondria including the citric acid cycle, electron transport chain and ROS production and scavenging systems was extended by incorporating a novel representation for mitochondrial DNA damage and repair. In silico experiments were performed to quantify the contributions of each of the toxicity mechanisms to mitochondrial dysfunction during the acute and chronic stages of toxicity. Simulations predict that redox cycling has a minor role in doxorubicin cardiotoxicity. Electron transport chain inhibition is the main pathway for acute toxicity for supratherapeutic doses, being lethal at mitochondrial concentrations higher than 200μM. Direct mitochondrial DNA damage is the principal pathway of chronic cardiotoxicity for therapeutic doses, leading to a progressive and irreversible long term mitochondrial dysfunction.

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“…Succinate accumulates in the surrounding tissue until either the source of fumarate is exhausted, or reperfusion begins. During reperfusion, complex II metabolizes the available succinate to produce QH2, leading to hyperpolarization of the inner mitochondrial membrane [29]. The combination of a high QH2 levels and hyperpolarized membrane potential drives complex I to enter the socalled reverse electron transport state and produces ROS at extremely high rates [29].…”

Section: Eq (1)mentioning

confidence: 99%

Analysis of Mammalian Succinate Dehydrogenase Kinetics and Reactive Oxygen Species Production

Manhas

Duong

Lee

et al. 2019

Preprint

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Succinate dehydrogenase is an inner mitochondrial membrane protein complex that links the tricarboxylic acid cycle to the electron transport system. It catalyzes the reaction between succinate and ubiquinone to produce fumarate and ubiquinol. In addition, it can produce significant amounts of superoxide and hydrogen peroxide under the right conditions. While the flavin adenine dinucleotide (FAD) is the putative site of reactive oxygen species production, free radical production from other sites are less certain. Herein, we developed a computational model to analyze free radical production data from complex II and identify the mechanism of superoxide and hydrogen peroxide production. The model includes the major redox centers consisting of the FAD, three iron-sulfur clusters, and a transiently catalytic bound semi quinone. The model consists of five-states that represent oxidation status of the enzyme complex. Each step in the reaction scheme is thermodynamically constrained, and transitions between each state involve either one-electron or two-electron redox reactions. The model parameters were simultaneously fit using data consisting of enzyme kinetics and free radical production rates under a range of conditions. In the absence of respiratory chain inhibitors, model analysis revealed that the 3Fe-4S iron-sulfur cluster is the primary source of superoxide production followed by the FAD radical. However, when the quinone reductase site of complex II is inhibited or the quinone pool is highly reduced, superoxide production from the FAD site dominates at low succinate concentrations. In addition, hydrogen peroxide formation from the complex is only significant when these one of these conditions is met and the fumarate concentrations is in the low micromolar range. From the model simulations, the redox state of the quinone pool was found to be the primary determinant of free radical production from complex II. This study highlights the importance of evaluating enzyme kinetics and associated side-reactions in a consistent, quantitative and biophysical detailed manner. By incorporating the results from a diverse set of experiments, this computational approach can be used to interpret and explain key differences among the observations from a single, unified perspective. QH SUC H O O J J J J •-= --

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Catalytic Coupling of Oxidative Phosphorylation, ATP Demand, and Reactive Oxygen Species Generation

Cited by 63 publications

References 78 publications

Influence of metabolic dysfunction on cardiac mechanics in decompensated hypertrophy and heart failure

Influence of metabolic dysfunction on cardiac mechanics in decompensated hypertrophy and heart failure

A Biophysical Systems Approach to Identifying the Pathways of Acute and Chronic Doxorubicin Mitochondrial Cardiotoxicity

Analysis of Mammalian Succinate Dehydrogenase Kinetics and Reactive Oxygen Species Production

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