A Computational Model of Reactive Oxygen Species and Redox Balance in Cardiac Mitochondria
A Computational Model of Reactive Oxygen Species and Redox Balance in Cardiac Mitochondria
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DOI：
10.1016/j.bpj.2013.07.006
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发表时间：
2013-08-20
影响因子：
3.4
通讯作者：
Winslow, Raimond L.
中科院分区：
文献类型：
--
作者：
Gauthier, Laura D.;Greenstein, Joseph L.;Winslow, Raimond L.
活性氧（ROS）水平升高在健康和患病细胞中的心肌细胞信号传导中起关键作用。线粒体代表ROS的主要细胞来源，特别是复合物I和III的活性。这里提出的模型探讨了状态3和状态4呼吸的电子传递链ROS生产的调制和底物和呼吸抑制剂的作用。模型模拟显示，当处于状态4时，来自复合物III的ROS产生随膜电位（Delta Psi（m））呈指数增加。模型中的复合物I ROS释放可以在NADH和琥珀酸盐（反向电子流）存在下发生，导致高度还原的泛醌池，在状态4中显示最高的ROS产生通量。在充分的ROS清除的存在下，总的ROS产生在状态3中是中等的，并且在状态4条件下显著增加。ROS生产模型进行了扩展，将其与ROS清除的最小模型相结合。当通过增加线粒体内膜的质子渗透性来氧化线粒体氧化还原状态时，使用组合模型的模拟显示，ROS水平最初随着生产下降而下降，同时Δ Psi（m）降低，然后随着清除能力耗尽而增加。因此，这种ROS产生的机制模型证明了ROS水平是如何由线粒体氧化还原平衡控制的。
Elevated levels of reactive oxygen species (ROS) play a critical role in cardiac myocyte signaling in both healthy and diseased cells. Mitochondria represent the predominant cellular source of ROS, specifically the activity of complexes I and Ill. The model presented here explores the modulation of electron transport chain ROS production for state 3 and state 4 respiration and the role of substrates and respiratory inhibitors. Model simulations show that ROS production from complex III increases exponentially with membrane potential (Delta Psi(m)) when in state 4. Complex I ROS release in the model can occur in the presence of NADH and succinate (reverse electron flow), leading to a highly reduced ubiquinone pool, displaying the highest ROS production flux in state 4. In the presence of ample ROS scavenging, total ROS production is moderate in state 3 and increases substantially under state 4 conditions. The ROS production model was extended by combining it with a minimal model of ROS scavenging. When the mitochondrial redox status was oxidized by increasing the proton permeability of the inner mitochondrial membrane, simulations with the combined model show that ROS levels initially decline as production drops off with decreasing Delta Psi(m) and then increase as scavenging capacity is exhausted. Hence, this mechanistic model of ROS production demonstrates how ROS levels are controlled by mitochondrial redox balance.