Reactive Oxygen Species Production by Forward and Reverse Electron Fluxes in the Mitochondrial Respiratory Chain
Year: 2011
Type: article
Abstract: Reactive oxygen species (ROS) produced in the mitochondrial respiratory chain (RC) are primary signals that modulate cellular adaptation to environment, and are also destructive factors that damage cells under the conditions of hypoxia/reoxygenation relevant for various systemic diseases or transplantation. The important role of ROS in cell survival requires detailed investigation of mechanism and determinants of ROS production. To perform such an investigation we extended our rule-based model of complex III in order to account for electron transport in the whole RC coupled to proton translocation, transmembrane electrochemical potential generation, TCA cycle reactions, and substrate transport to mitochondria. It fits respiratory electron fluxes measured in rat brain mitochondria fueled by succinate or pyruvate and malate, and the dynamics of NAD(+) reduction by reverse electron transport from succinate through complex I. The fitting of measured characteristics gave an insight into the mechanism of underlying processes governing the formation of free radicals that can transfer an unpaired electron to oxygen-producing superoxide and thus can initiate the generation of ROS. Our analysis revealed an association of ROS production with levels of specific radicals of individual electron transporters and their combinations in species of complexes I and III. It was found that the phenomenon of bistability, revealed previously as a property of complex III, remains valid for the whole RC. The conditions for switching to a state with a high content of free radicals in complex III were predicted based on theoretical analysis and were confirmed experimentally. These findings provide a new insight into the mechanisms of ROS production in RC.
Source: PLoS Computational Biology
Institutions: Lomonosov Moscow State University, Institut de Biomedicina de la Universitat de Barcelona, Universitat de Barcelona, University of Pittsburgh, Children's Hospital of Pittsburgh, University of Alabama at Birmingham, Institute of Theoretical and Experimental Biophysics, Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Consorci Institut D'Investigacions Biomediques August Pi I Sunyer
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,043
Funders: U.S. Department of Defense, European Commission, Generalitat de Catalunya, Ministerio de Ciencia e Innovación, National Institutes of Health, Agència de Gestió d'Ajuts Universitaris i de Recerca, Instituto de Salud Carlos III, European Regional Development Fund, National Institute on Aging, National Institute of Diabetes and Digestive and Kidney Diseases, FP7 Food, Agriculture and Fisheries, Biotechnology
Awards: G1770074201, G1952936224, Characterization and modelling of dietary effects mediated by gut microbiota on lipid metabolism, G2898191549, DIAbetes type 1 PRediction, Early Pathogenesis and Prevention, G3170664214, G3248929534, G3569961625, G4054822409, Prediction and Prevention of Type 1 Diabetes (TrialNet), G4119534169, ENDOCRINE PANCREAS REGENERATION, Control of neuronal ROS generation by membrane potential, G5714039386, G5850682332, G5932924763, Modelling and simulation environment for systems medicine\n(Chronic obstructive pulmonary disease -COPD- as a use case)
OpenAlex ID: W1984555524