Determining the origins of superoxide and hydrogen peroxide in the mammalian NADH:ubiquinone oxidoreductase
Determining the origins of superoxide and hydrogen peroxide in the mammalian NADH:ubiquinone oxidoreductase
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DOI：
10.1016/j.freeradbiomed.2014.08.023
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发表时间：
2014-12-01
影响因子：
7.4
通讯作者：
Beard, Daniel A.
中科院分区：
文献类型：
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作者：
Bazil, Jason N.;Pannala, Venkat R.;Beard, Daniel A.
NADH：泛醌氧化还原酶(复合体I)是电子传递链中的一个质子泵，可以产生大量的超氧化物和过氧化氢。虽然黄素单核苷酸(FMN)是过氧化氢产生的推测位点，但负责产生超氧化物的位点不太确定。在这里，使用计算模型分析了络合物I动力学和ROS产生的数据，以确定对超氧化物负责的位置。分析包括所有主要的氧化还原中心：FMN、铁硫簇合物N_2和半喹酮。分析表明，完全还原的FMN和半喹酮是产生超氧化物的主要来源，而铁硫簇合物N_2没有产生。FMN自由基只有在苯醌还原酶位点被阻断时才产生ROS。模型模拟表明，在反向电子传输过程中，ROS的生成量最大，FMN和半喹酮都产生类似量的超氧化物。此外，该模型还成功地预测了当膜电位较高和基质pH为碱性时ROS产生量的增加。在复合体I产生的总ROS中，大部分来自FMN。(C)2014 Elsevier Inc.保留所有权利。
NADH:ubiquinone oxidoreductase (complex I) is a proton pump in the electron transport chain that can produce a significant amounts of superoxide and hydrogen peroxide. While the flavin mononucleotide (FMN) is the putative site for hydrogen peroxide generation, sites responsible for superoxide are less certain. Here, data on complex I kinetics and ROS generation are analyzed using a computational model to determine the sites responsible for superoxide. The analysis includes all the major redox centers: the FMN, iron-sulfur cluster N2, and semiquinone. Analysis reveals that the fully reduced FMN and semiquinone are the primary sources of superoxide, and the iron-sulfur cluster N2 produces none. The FMN radical only produces ROS when the quinone reductase site is blocked. Model simulations reveal that ROS generation is maximized during reverse electron transport with both the FMN and the semiquinone producing similar amounts of superoxide. In addition, the model successfully predicts the increase in ROS generation when the membrane potential is high and matrix pH is alkaline. Of the total ROS produced by complex I, the majority originates from the FMN. (C) 2014 Elsevier Inc. All rights reserved.