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

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...

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Autores principales:	Vitaly A Selivanov, Tatyana V Votyakova, Jennifer A Zeak, Massimo Trucco, Josep Roca, Marta Cascante
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2009
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/b353c157fd9a43da8d0e6b4696235dca
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spelling	oai:doaj.org-article:b353c157fd9a43da8d0e6b4696235dca2021-11-25T05:42:45ZBistability of mitochondrial respiration underlies paradoxical reactive oxygen species generation induced by anoxia.1553-734X1553-735810.1371/journal.pcbi.1000619https://doaj.org/article/b353c157fd9a43da8d0e6b4696235dca2009-12-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20041200/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Increased 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.Vitaly A SelivanovTatyana V VotyakovaJennifer A ZeakMassimo TruccoJosep RocaMarta CascantePublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 5, Iss 12, p e1000619 (2009)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Vitaly A Selivanov Tatyana V Votyakova Jennifer A Zeak Massimo Trucco Josep Roca Marta Cascante Bistability of mitochondrial respiration underlies paradoxical reactive oxygen species generation induced by anoxia.
description	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.
format	article
author	Vitaly A Selivanov Tatyana V Votyakova Jennifer A Zeak Massimo Trucco Josep Roca Marta Cascante
author_facet	Vitaly A Selivanov Tatyana V Votyakova Jennifer A Zeak Massimo Trucco Josep Roca Marta Cascante
author_sort	Vitaly A Selivanov
title	Bistability of mitochondrial respiration underlies paradoxical reactive oxygen species generation induced by anoxia.
title_short	Bistability of mitochondrial respiration underlies paradoxical reactive oxygen species generation induced by anoxia.
title_full	Bistability of mitochondrial respiration underlies paradoxical reactive oxygen species generation induced by anoxia.
title_fullStr	Bistability of mitochondrial respiration underlies paradoxical reactive oxygen species generation induced by anoxia.
title_full_unstemmed	Bistability of mitochondrial respiration underlies paradoxical reactive oxygen species generation induced by anoxia.
title_sort	bistability of mitochondrial respiration underlies paradoxical reactive oxygen species generation induced by anoxia.
publisher	Public Library of Science (PLoS)
publishDate	2009
url	https://doaj.org/article/b353c157fd9a43da8d0e6b4696235dca
work_keys_str_mv	AT vitalyaselivanov bistabilityofmitochondrialrespirationunderliesparadoxicalreactiveoxygenspeciesgenerationinducedbyanoxia AT tatyanavvotyakova bistabilityofmitochondrialrespirationunderliesparadoxicalreactiveoxygenspeciesgenerationinducedbyanoxia AT jenniferazeak bistabilityofmitochondrialrespirationunderliesparadoxicalreactiveoxygenspeciesgenerationinducedbyanoxia AT massimotrucco bistabilityofmitochondrialrespirationunderliesparadoxicalreactiveoxygenspeciesgenerationinducedbyanoxia AT joseproca bistabilityofmitochondrialrespirationunderliesparadoxicalreactiveoxygenspeciesgenerationinducedbyanoxia AT martacascante bistabilityofmitochondrialrespirationunderliesparadoxicalreactiveoxygenspeciesgenerationinducedbyanoxia
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Bistability of mitochondrial respiration underlies paradoxical reactive oxygen species generation induced by anoxia.

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