Selivanov 2011 PLoS Comput Biol

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Selivanov VA, Votyakova TV, Pivtoraiko VN, Zeak J, Sukhomlin T, Trucco M, Roca J, Cascante M (2011) Reactive oxygen species production by forward and reverse electron fluxes in the mitochondrial respiratory chain. PLoS Comput Biol 7(3):e1001115. doi: 10.1371/journal.pcbi.1001115.

» PMID: 21483483 Open Access

Selivanov VA, Votyakova Tatyana V, Pivtoraiko VN, Zeak Jennifer, Sukhomlin T, Trucco M, Roca J, Cascante M (2011) PLoS Comput Biol

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.


O2k-Network Lab: US PA Pittsburgh Goetzman ES


Labels: MiParea: Respiration 

Stress:Oxidative stress;RONS  Organism: Rat  Tissue;cell: Nervous system  Preparation: Isolated mitochondria 

Regulation: mt-Membrane potential, Redox state 

Pathway:HRR: Oxygraph-2k