Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore Maryland, USA.
Biophys J. 2013 Jan 22;104(2):332-43. doi: 10.1016/j.bpj.2012.11.3808.
To understand the mechanisms involved in the control and regulation of mitochondrial reactive oxygen species (ROS) levels, a two-compartment computational mitochondrial energetic-redox (ME-R) model accounting for energetic, redox, and ROS metabolisms is presented. The ME-R model incorporates four main redox couples (NADH/NAD(+), NADPH/NADP(+), GSH/GSSG, Trx(SH)(2)/TrxSS). Scavenging systems-glutathione, thioredoxin, superoxide dismutase, catalase-are distributed in mitochondrial matrix and extra-matrix compartments, and transport between compartments of ROS species (superoxide: O(2)(⋅-), hydrogen peroxide: H(2)O(2)), and GSH is also taken into account. Model simulations are compared with experimental data obtained from isolated heart mitochondria. The ME-R model is able to simulate: i), the shape and order of magnitude of H(2)O(2) emission and dose-response kinetics observed after treatment with inhibitors of the GSH or Trx scavenging systems and ii), steady and transient behavior of ΔΨ(m) and NADH after single or repetitive pulses of substrate- or uncoupler-elicited energetic-redox transitions. The dynamics of the redox environment in both compartments is analyzed with the model following substrate addition. The ME-R model represents a useful computational tool for exploring ROS dynamics, the role of compartmentation in the modulation of the redox environment, and how redox regulation participates in the control of mitochondrial function.
为了理解线粒体活性氧(ROS)水平控制和调节的机制,提出了一个包含能量代谢、氧化还原代谢和 ROS 代谢的两室计算线粒体能量-氧化还原(ME-R)模型。ME-R 模型纳入了四个主要的氧化还原偶(NADH/NAD(+)、NADPH/NADP(+)、GSH/GSSG、Trx(SH)(2)/TrxSS)。清除系统-谷胱甘肽、硫氧还蛋白、超氧化物歧化酶、过氧化氢酶-分布在线粒体基质和细胞外基质隔间中,并且 ROS 物质(超氧化物:O(2)(⋅-)、过氧化氢:H(2)O(2))和 GSH 在隔间之间的运输也被考虑在内。模型模拟与从分离的心肌线粒体获得的实验数据进行了比较。ME-R 模型能够模拟:i),在用 GSH 或硫氧还蛋白清除系统的抑制剂处理后观察到的 H(2)O(2)发射的形状和量级以及剂量反应动力学;ii),在单个或重复的底物或解偶联剂引发的能量-氧化还原转换脉冲后,ΔΨ(m)和 NADH 的稳态和瞬态行为。模型在添加底物后分析两个隔间中氧化还原环境的动力学。ME-R 模型代表了一种用于探索 ROS 动力学、隔室化在调节氧化还原环境中的作用以及氧化还原调节如何参与线粒体功能控制的有用计算工具。