Inhibition of NADH-linked mitochondrial respiration by 4-hydroxy-2-nonenal
Inhibition of NADH-linked mitochondrial respiration by 4-hydroxy-2-nonenal
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DOI：
10.1021/bi971958i
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发表时间：
1998-01-13
期刊：
影响因子：
2.9
通讯作者：
Szweda, LI
中科院分区：
文献类型：
--
作者：
Humphries, KM;Yoo, Y;Szweda, LI
在包括心肌缺血-再灌注损伤在内的某些退行性条件的进展过程中，线粒体是自由基生成增加的来源，并表现出呼吸功能的下降(S)。因此，有人认为线粒体成分的氧化损伤在这些过程的病理中起着关键作用。膜脂多不饱和脂肪酸是自由基损伤的主要分子靶点。脂质过氧化的主要产物4-羟基-2-壬烯醛(WNE)具有高度的细胞毒性，很容易与蛋白质反应并损伤蛋白质。在这项研究中，研究了HNE对完整的心肌线粒体的影响，以深入了解自由基介导线粒体功能障碍的潜在机制。线粒体暴露于微摩尔浓度的HNE导致NADH连接但不是琥珀酸连接的状态3和非耦合呼吸迅速下降。在本实验条件下，化合物I的活性不受HNE的影响。呼吸活性的丧失反映了HNE处理的线粒体在最大氧耗率期间无法满足NADH需求。HNE通过失活α-酮戊二酸脱氢酶对完整线粒体发挥作用。因此，这些结果确定了自由基导致线粒体呼吸功能下降的一个潜在的重要机制。
During the progression of certain degenerative conditional including myocardial ischemia-reperfusion injury, mitochondria are a source of increased free-radical generation and exhibit declines in respiratory function(s). It has therefore been suggested that oxidative damage to mitochondrial components plays a critical role in the pathology of these processes. Polyunsaturated fatty acids of membrane lipids are prime molecular targets of free-radical damage. A major product of lipid peroxidation, 4-hydroxy-2-nonenal (WNE), is highly cytotoxic and can readily react with and damage protein. In this study, the effects of HNE on intact cardiac mitochondria were investigated to gain insight into potential mechanisms by which free radicals mediate mitochondrial dysfunction. Exposure of mitochondria to micromolar concentrations of HNE caused rapid declines in NADH-linked but not succinate-linked state 3 and uncoupled respiration. The activity of complex I was unaffected by HNE under the conditions of our experiments. Loss of respiratory activity reflected the inability of HNE-treated mitochondria to meet NADH demand during maximum rates of O-2 consumption. HNE exerted its effects on intact mitochondria by inactivating alpha-ketoglutarate dehydrogenase. These results therefore identify a potentially important mechanism by which free radicals bring about declines in mitochondrial respiration.