Reactive Oxygen Species Production by Forward and Reverse Electron Fluxes in the Mitochondrial Respiratory Chain

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.

African eggplant (Solanum anguivi Lam.) fruit with bioactive polyphenolic compounds exerts in vitro antioxidant properties and inhibits Ca2+-induced mitochondrial swelling

“…They are unique organelles, accounting for about 85%-90% of oxygen consumed by the cell. The incomplete processing of oxygen and/or release of free electron in the mitochondria results in the production of reactive oxygen species (ROS) [2] . ROS released by the mitochondrial respiratory chain are a family of active molecules containing free radicals and are involved in the modulation of biological cell functions.…”

Redox regulation of mitochondrial functional activity by quinones

“…The potential values from −320 mV (for NADH) to −36 mV (for ubiquinone) correspond to Complex I, whereas the E 1/2 of DTBBQ (E 1/2 = −260 mV) corresponds to the potential of the NADH: ubiquinone reductase initial site, while the E 1/2 of juglone (E 1/2 = −99 mV) is close to the Q-reduction site of Complex I. It is known that rotenone interrupts electron transfer in Complex I, which causes a decrease of ROS generation by Complex III and an increase of ROS generation by Complex I (3,12,30,32,33,48,54). Then, the ROS production by quinones, which are reduced in ETC before rotenone binding site of Complex I, would increase after Complex I inhibition and, vice versa, the ROS production by quinones, which are reduced at the Complex I ubiquinonebinding site that is located higher than the rotenone-binding site in ETC would be suppressed during rotenone treatment.…”

Компьютерный Анализ Гистерезиса И Бистабильности В Дыхательной Цепи Митохондрий

“…For instance, inhibition of the electron transport chain and accompanying alterations in ROS production during hypoxia, especially, if it is followed by reoxygenation can initiate ROS-related cellular hypoxia-reoxygenation injury [7]. Selivanov and colleagues [8,9] discovered recently bistability in operation of the respiratory chain and showed computationally that bistability can be a reason of a drastic increase in ROS production during anoxia-reoxygenation. Computational analysis of bistability and an increase in ROS production during anoxia-reoxygenation was made [8,9] with the help of the rule-based model on the assumption that electron transfer between any redox pair of carriers does not depend on the redox state of the remaining electron carriers in the respiratory chain.…”

“…Selivanov and colleagues [8,9] discovered recently bistability in operation of the respiratory chain and showed computationally that bistability can be a reason of a drastic increase in ROS production during anoxia-reoxygenation. Computational analysis of bistability and an increase in ROS production during anoxia-reoxygenation was made [8,9] with the help of the rule-based model on the assumption that electron transfer between any redox pair of carriers does not depend on the redox state of the remaining electron carriers in the respiratory chain. Using this simplifying suggestion and describing explicitly the electron transfer between any two transporters that involves a few tens of reactions for the entire respiratory chain, authors were able to develop algorithms (rules) to automatically construct an implicit computational model consisting of a few hundreds differential equations and computing the probability (concentration) of all possible micro-states in Complexes I and III of the respiratory chain.…”

“…This study aims to find values of rate constants and protein concentration in the model which favorable for bistability in the respiratory chain and check with the help of this model the mechanism of a drastic increase in ROS production during hypoxiareoxygenation suggested earlier by Selivanov and colleagues [8,9]. …”