Bistability of mitochondrial respiration underlies paradoxical reactive oxygen species generation induced by anoxia.
Bistability of mitochondrial respiration underlies paradoxical reactive oxygen species generation induced by anoxia.
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DOI：
10.1371/journal.pcbi.1000619
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发表时间：
2009-12
影响因子：
4.3
通讯作者：
Cascante M
中科院分区：
文献类型：
--
作者：
Selivanov VA;Votyakova TV;Zeak JA;Trucco M;Roca J;Cascante M
线粒体中活性氧（ROS）的产生增加是重大全身性疾病的基础，这一临床问题激发了对ROS产生机制的极大科学兴趣。然而，缺氧诱导的ROS生成变化的机制尚不完全清楚。为了在数学上详细分析这一机制，考虑到电子传递过程中形成的所有可能的氧化还原状态，即使是呼吸复合物III，也必须构建一个由数百个微分方程组成的系统。为了方便这些任务，我们开发了一种新的建模方法，它存在于大型微分方程集的自动构建中。线粒体中电子传递的详细建模允许在相同的微环境条件下识别呼吸复合体III的两种稳态操作模式（双稳态）。各种扰动可诱导呼吸链从一种稳态向另一种稳态过渡。正常情况下复合物III处于低ROS生成模式，但短暂缺氧可将其切换到高ROS生成状态，并在恢复正常供氧后持续。这一预测，我们定性验证了实验，解释了缺氧诱导细胞损伤的机制。对复合体III操作双稳定性的认识可能为氧化应激提供新的治疗策略，我们的建模方法可以广泛应用于系统生物学研究。活性氧（ROS）是线粒体呼吸电子传递的副产物，其水平在很大程度上决定了活细胞中氧化应激的程度。在电子传递过程中形成的自由基，如亚双醌，可以将其不配对的电子直接传递给氧，从而产生超氧自由基，产生各种ROS。在临床实践中众所周知，缺氧后重新供氧的组织产生的ROS比缺氧前多得多，并且高ROS生成的状态是稳定的。时间缺氧从低到高ROS产生的转换机制尚不清楚，部分原因是缺乏对电子传递过程中形成的呼吸复合物的数百种氧化还原状态的详细数学描述。一种新的自动构建大型微分方程系统的方法使我们能够详细地描述该系统，并预测了线粒体呼吸链复合体III的性质可以定义缺氧-再氧化悖论效应的机制。我们的实验证实，缺氧-再氧化的影响是受线粒体内过程限制的，因为它是在分离的线粒体中观察到的。
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. The levels of reactive oxygen species (ROS) that are generated as a side product of mitochondrial respiratory electron transport largely define the extent of oxidative stress in living cells. Free radicals formed in electron transport, such as ubisemiquinone, could pass their non-paired electron directly to oxygen, thus producing superoxide radical that gives rise to a variety of ROS. It is well known in clinical practice that upon recommencing oxygen supply after anoxia a tissue produces much more ROS than before the anoxia, and the state of high ROS production is stable. The mechanism of switching from low to high ROS production by temporal anoxia was unknown, in part because of the lack of detailed mathematical description of hundreds of redox states of respiratory complexes, which are formed in the process of electron transport. A new methodology of automated construction of large systems of differential equations allowed us to describe the system in detail and predicts that the mechanism of paradoxical effect of anoxia-reoxygenation could be defined by the properties of complex III of mitochondrial respiratory chain. Our experiments confirmed that the effect of hypoxia-reoxygenation is confined by intramitochondrial processes since it is observed in isolated mitochondria.
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DOI：
10.1111/j.1432-1033.1992.tb17235.x
发表时间：
1992-09-15
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
LINK, TA;HAGEN, WR;VONJAGOW, G
通讯作者：
VONJAGOW, G
影响因子：
5.3
作者：
Bell, Eric L.;Klimova, Tatyana A.;Chandel, Navdeep S.
通讯作者：
Chandel, Navdeep S.
影响因子：
3
作者：
Cai, JY;Jones, DP
通讯作者：
Jones, DP
影响因子：
3.9
作者：
CINO, M;DELMAESTRO, RF
通讯作者：
DELMAESTRO, RF
影响因子：
2.9
作者：
Cooley, JW;Ohnishi, T;Daldal, F
通讯作者：
Daldal, F