Partial loss of complex I due to NDUFS4 deficiency augments myocardial reperfusion damage by increasing mitochondrial superoxide/hydrogen peroxide production
Partial loss of complex I due to NDUFS4 deficiency augments myocardial reperfusion damage by increasing mitochondrial superoxide/hydrogen peroxide production
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DOI：
10.1016/j.bbrc.2018.02.208
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发表时间：
2018-03-25
影响因子：
3.1
通讯作者：
Mailloux, Ryan J.
中科院分区：
文献类型：
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作者：
Kuksal, Nidhi;Gardiner, Danielle;Mailloux, Ryan J.
最近的研究发现，复合物 I 是心肌缺血再灌注 (IR) 损伤期间活性氧 (ROS) 的唯一来源。然而，也有报道称，心脏线粒体也可以从呼吸链和克雷布斯循环中的其他来源产生ROS。本研究探讨了由于 Ndufs4 基因选择性缺失导致的复合物 I 部分缺乏对心脏组织 IR 损伤的影响。与野生型 (WT) 同窝小鼠相比，NDUFS4 杂合子 (NDUFS4+/-) 小鼠的整体体重或器官重量没有表现出任何显着变化。从 NDUFS4 小鼠分离的心脏或肝脏线粒体中释放的超氧化物 (O-2(中心点-))/过氧化氢 (H2O2) 没有变化。使用选择性 ROS 释放抑制剂，我们发现复合物 III 是 WT 和 NDUFS4 +/- 心脏线粒体在状态 4 条件下呼吸的 ROS 的主要来源。对 NDUFS4 +/- 小鼠的心脏进行再灌注损伤表明，复合物 I 的部分丢失会降低收缩恢复并增加心肌梗塞面积。这些结果与从接受 IR 攻击的 NDUFS4 +/- 心脏分离的线粒体中 O-2（中心点-）/H2O2 释放率显着增加相关。综上所述，这些结果表明，复合物 I 的部分缺失使心肌对 IR 损伤敏感，并且再灌注后 ROS 的主要来源是复合物 III。 (C) 2018 Elsevier Inc. 保留所有权利。
Recent work has found that complex I is the sole source of reactive oxygen species (ROS) during myocardial ischemia-reperfusion (IR) injury. However, it has also been reported that heart mitochondria can also generate ROS from other sources in the respiratory chain and Krebs cycle. This study examined the impact of partial complex I deficiency due to selective loss of the Ndufs4 gene on IR injury to heart tissue. Mice heterozygous for NDUFS4 (NDUFS4+/-) did not display any significant changes in overall body or organ weight when compared to wild-type (WT) littermates. There were no changes in superoxide (O-2(center dot-))/hydrogen peroxide (H2O2) release from cardiac or liver mitochondria isolated from NDUFS4 mice. Using selective ROS release inhibitors, we found that complex III is a major source of ROS in WT and NDUFS4 +/- cardiac mitochondria respiring under state 4 conditions. Subjecting hearts from NDUFS4 +/- mice to reperfusion injury revealed that the partial loss of complex I decreases contractile recovery and increases myocardial infarct size. These results correlated with a significant increase in O-2(center dot-)/H2O2 release rates in mitochondria isolated from NDUFS4 +/- hearts subjected to an IR challenge. Taken together, these results demonstrate that the partial absence of complex I sensitizes the myocardium towards IR injury and that the main source of ROS following reperfusion is complex III. (C) 2018 Elsevier Inc. All rights reserved.