Increased reactive oxygen species production during reductive stress: The roles of mitochondrial glutathione and thioredoxin reductases.
Increased reactive oxygen species production during reductive stress: The roles of mitochondrial glutathione and thioredoxin reductases.
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DOI：
10.1016/j.bbabio.2015.02.012
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发表时间：
2015-06
影响因子：
4.3
通讯作者：
Weiss, James N.
中科院分区：
文献类型：
--
作者：
Korge, Paavo;Calmettes, Guillaume;Weiss, James N.
已知氧化还原平衡的两个极端都会导致心脏损伤，越来越多的证据表明氧化和还原应激诱导的损伤本质上是氧化性的。在还原应激期间，当电子受体预计将被大部分还原时，一些氧化还原蛋白可以将电子提供给O2，这增加了活性氧（ROS）的产生。然而，高水平的还原当量也同时增强涉及氧化还原对如NADPH/NADP+和GSH/GSSG的ROS清除系统。在这里，我们的目标是探索如何还原应力矛盾地增加净线粒体ROS的生产，尽管随之而来的增强ROS清除系统。使用重组酶和分离的透性心脏线粒体，我们表明，两个正常的抗氧化剂基质NADPH还原酶，谷胱甘肽还原酶和硫氧还蛋白还原酶，产生H2 O2通过泄漏电子从他们的还原黄素蛋白O2时，电子流受到抑制剂或由于其天然电子受体，GSSG和氧化硫氧还蛋白的有限可用性受损。在这些条件下，H2 O2的溢出取决于H2 O2通过过氧化物氧还蛋白活性的还原，其可以调节响应于内源性或外源性因素的氧化还原信号。这些发现可能解释了还原性应激过程中ROS的产生如何破坏ROS清除能力，产生线粒体ROS净溢出，导致氧化损伤。这些酶可以潜在地靶向增加癌细胞死亡或调节H2 O2诱导的氧化还原信号，以保护心脏免受缺血/再灌注损伤。
Both extremes of redox balance are known to cause cardiac injury, with mounting evidence revealing that the injury induced by both oxidative and reductive stress is oxidative in nature. During reductive stress, when electron acceptors are expected to be mostly reduced, some redox proteins can donate electrons to O2 instead, which increases reactive oxygen species (ROS) production. However, the high level of reducing equivalents also concomitantly enhances ROS scavenging systems involving redox couples such as NADPH/NADP+ and GSH/GSSG. Here our objective was to explore how reductive stress paradoxically increases net mitochondrial ROS production despite the concomitant enhancement of ROS scavenging systems. Using recombinant enzymes and isolated permeabilized cardiac mitochondria, we show that two normally antioxidant matrix NADPH reductases, glutathione reductase and thioredoxin reductase, generate H2O2 by leaking electrons from their reduced flavoprotein to O2 when electron flow is impaired by inhibitors or because of limited availability of their natural electron acceptors, GSSG and oxidized thioredoxin. The spillover of H2O2 under these conditions depends on H2O2 reduction by peroxiredoxin activity, which may regulate redox signaling in response to endogenous or exogenous factors. These findings may explain how ROS production during reductive stress overwhelms ROS scavenging capability, generating the net mitochondrial ROS spillover causing oxidative injury. These enzymes could potentially targeted to increase cancer cell death or modulate H2O2-induced redox signaling to protect the heart against ischemia/reperfusion damage.
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影响因子：
4.3
作者：
Kareyeva, Alexandra V.;Grivennikova, Vera G.;Vinogradov, Andrei D.
通讯作者：
Vinogradov, Andrei D.
影响因子：
3.9
作者：
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通讯作者：
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影响因子：
4.8
作者：
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通讯作者：
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DOI：
10.1073/pnas.1002178107
发表时间：
2010-08-31
影响因子：
11.1
作者：
Kuroda, Junya;Ago, Tetsuro;Sadoshima, Junichi
通讯作者：
Sadoshima, Junichi
DOI：
10.1073/pnas.0510977103
发表时间：
2006-05-16
影响因子：
11.1
作者：
Kussmaul, Lothar;Hirst, Judy
通讯作者：
Hirst, Judy