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.
Highlights
Reactive oxygen species (ROS) are side products of electron transport in the mitochondrial respiratory chain, the principal component of energy transformation in mitochondria
Respiration at the level of mitochondria is considered as delivery of electrons and protons from NADH or succinate to oxygen through a set of transporters constituting the respiratory chain (RC)
The production of ROS, normally low, can increase under stress to the levels incompatible with cell survival; understanding the ways of ROS production in the RC represents a vital task in research
Summary
Reactive oxygen species (ROS) are side products of electron transport in the mitochondrial respiratory chain, the principal component of energy transformation in mitochondria. ROS generation starts with the formation of a superoxide radical (O22) as a result of interaction between molecular oxygen and free radicals, e.g. semiquinone (Q2): O2+Q2RO22+Q [1]. This extremely active compound can be deactivated in cells, mainly through superoxide dismutase [2]. When released in excess under certain stress conditions such as hypoxia/reoxygenation, ROS can directly damage cells [6] This destructive function of the electron transport chain represents the main problem in organ transplantation [7] and in many systemic diseases, as diverse as Parkinson disease [8] and diabetes [9]. The problem can be so great that in some organisms disruption of the electron transport chain can be a positive factor in increasing lifetime [10]
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