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Bistability of mitochondrial respiration underlies paradoxical reactive oxygen species generation induced by anoxia

Selivanov, VA and Votyakova, TV and Zeak, JA and Trucco, M and Roca, J and Cascante, M (2009) Bistability of mitochondrial respiration underlies paradoxical reactive oxygen species generation induced by anoxia. PLoS Computational Biology, 5 (12). ISSN 1553-734X

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Increased production of reactive oxygen species (ROS) in mitochondria underlies major systemic diseases, and this clinical problem stimulates a great scientific interest in the mechanism of ROS generation. However, the mechanism of hypoxia-induced change in ROS production is not fully understood. To mathematically analyze this mechanism in details, taking into consideration all the possible redox states formed in the process of electron transport, even for respiratory complex III, a system of hundreds of differential equations must be constructed. Aimed to facilitate such tasks, we developed a new methodology of modeling, which resides in the automated construction of large sets of differential equations. The detailed modeling of electron transport in mitochondria allowed for the identification of two steady state modes of operation (bistability) of respiratory complex III at the same microenvironmental conditions. Various perturbations could induce the transition of respiratory chain from one steady state to another. While normally complex III is in a low ROS producing mode, temporal anoxia could switch it to a high ROS producing state, which persists after the return to normal oxygen supply. This prediction, which we qualitatively validated experimentally, explains the mechanism of anoxia-induced cell damage. Recognition of bistability of complex III operation may enable novel therapeutic strategies for oxidative stress and our method of modeling could be widely used in systems biology studies. © 2009 Selivanov et al.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Selivanov, VA
Votyakova, TV
Zeak, JA
Trucco, Mmnt@pitt.eduMNT
Roca, J
Cascante, M
ContributionContributors NameEmailPitt UsernameORCID
Date: 1 December 2009
Date Type: Publication
Journal or Publication Title: PLoS Computational Biology
Volume: 5
Number: 12
DOI or Unique Handle: 10.1371/journal.pcbi.1000619
Refereed: Yes
ISSN: 1553-734X
MeSH Headings: Animals; Cell Hypoxia--physiology; Computer Simulation; Electron Transport Complex III--metabolism; Humans; Mitochondria--physiology; Models, Biological; Oxygen--metabolism; Oxygen Consumption--physiology; Reactive Oxygen Species--metabolism
Other ID: NLM PMC2789320
PubMed Central ID: PMC2789320
PubMed ID: 20041200
Date Deposited: 03 Aug 2012 16:39
Last Modified: 04 Feb 2019 15:58


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