Institute for Computational Medicine, Baltimore, MD, USA.
Biophys J. 2013 Aug 20;105(4):1045-56. doi: 10.1016/j.bpj.2013.07.006.
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 III. 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 (ΔΨm) 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 ΔΨm 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.
活性氧（ROS）水平升高在健康和患病细胞中心肌细胞信号转导中起着关键作用。线粒体是 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电子传递链 ROS 产生的调制，用于状态 3 和状态 4 呼吸以及底物和呼吸抑制剂的作用。模型模拟表明，当处于状态 4 时，ROS 从复合物 III 以指数方式产生，与膜电位（ΔΨm）相关。在模型中，复合物 I 的 ROS 释放可以在 NADH 和琥珀酸（逆行电子流）存在的情况下发生，导致高度还原的泛醌池，显示出在状态 4 下最高的 ROS 产生通量。在有足够的 ROS 清除的情况下，在状态 3 下总 ROS 产生适度增加，而在状态 4 条件下则大幅增加。通过将其与 ROS 清除的最小模型相结合，扩展了 ROS 产生模型。当通过增加线粒体内膜的质子通透性来氧化线粒体的氧化还原状态时，与组合模型的模拟表明，ROS 水平最初会随着 ΔΨm 的降低而下降，因为产生减少，然后随着清除能力的耗尽而增加。因此，这种 ROS 产生的机制模型展示了 ROS 水平如何受线粒体氧化还原平衡的控制。
