Determining the origins of superoxide and hydrogen peroxide in the mammalian NADH:ubiquinone oxidoreductase

Bazil, Jason N.; Pannala, Venkat R.; Dash, Ranjan K.; Beard, Daniel A.

doi:10.1016/j.freeradbiomed.2014.08.023

Cited by 35 publications

(57 citation statements)

References 33 publications

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“…Among the putative site of ROS production by CI, the reduced FMN in the N-module appears as a main one, at least in physiological conditions (Bazil et al, 2014;Birrell et al, 2009;Galkin and Brandt, 2005;Hirst et al, 2008;Kussmaul and Hirst, 2006). ROS production by FMN site is highly dependent on NADH/NAD + ratio and NAD + level (Birrell et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Assembly defects induce oxidative stress in inherited mitochondrial complex I deficiency

Leman

Guéguen

Desquiret-Dumas

et al. 2015

The International Journal of Biochemistry & Cell Biology

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Section: Discussionmentioning

confidence: 99%

Assembly defects induce oxidative stress in inherited mitochondrial complex I deficiency

Leman

Guéguen

Desquiret-Dumas

et al. 2015

The International Journal of Biochemistry & Cell Biology

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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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“…1. The modeling approach is based on our prior work [14,30]. In brief, structural and thermodynamic data are used to constrain the model, and enzyme state-transitions are governed by the law of mass action.…”

Section: Methods and Model Constructionmentioning

confidence: 99%

“…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]. In this state, it is more accurate to describe complex I as entering a near equilibrium state [14,30]. In this state, the redox centers on complex I are highly reduced and can lead to the generation of significant amounts of free radicals.…”

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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Determining the origins of superoxide and hydrogen peroxide in the mammalian NADH:ubiquinone oxidoreductase

Cited by 35 publications

References 33 publications

Assembly defects induce oxidative stress in inherited mitochondrial complex I deficiency

Assembly defects induce oxidative stress in inherited mitochondrial complex I deficiency

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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