Ethanol Hepatotoxicity and NO-Dependent Mitochondrial Dysfunction

酒精引起的低氧增加通过以下机制促进肝脏毒性 没有详细地理解。线粒体！活性氧的功能障碍及其相关形成 而氮物种(ROS/RNS)似乎是肝脏酒精暴露的结果。我们 假设乙醇依赖的低氧与一氧化氮(NO)有关 与线粒体呼吸链的相互作用，这已经得到了研究的支持 在上一次供资期间开展的活动。在这场竞争性的更新中，我们建立在这些发现的基础上 这表明a)增强了对NO依赖的线粒体呼吸抑制的敏感性 在酒精暴露早期发生b)这种反应在缺乏诱导性一氧化氮的小鼠身上被消融。 合酶异构体c)这些变化与线粒体蛋白质组的变化和 蛋白质和线粒体DNA的氧化修饰。这些数据导致了这一假设 酒精的肝毒性会通过增加线粒体功能障碍和 这些影响将通过线粒体靶向抗氧化剂得到改善。这一概念将 通过追求以下具体目标来进行测试：1.确定线粒体的影响 靶向抗氧化剂(MTA)对酒精依赖的肝毒性和低氧的发展。2： MTA对慢性酒精依赖大鼠线粒体活性变化的影响 蛋白质，对NO抑制呼吸链的敏感性和对线粒体DNA的损伤。3：确定 MTA对乙醇依赖的线粒体蛋白质组修饰的影响。这 该项目将通过定义导致肝脏的机制来促进公共健康 慢性酒精中毒所造成的损害。此外，使用新的 一类药物，针对细胞中产生能量的部分，以逆转或防止这些有毒物质 酒精的影响将被测试。

Increased hypoxia in response to ethanol contributes to hepatotoxicity through mechanisms that are not understood in detail. Mitochondria! dysfunction and the associated formation of reactive oxygen and nitrogen species (ROS/RNS) appear to be a consequence of alcohol exposure in the liver. We hypothesized that ethanol-dependent hypoxia involved a contribution from the nitric oxide (NO) interaction with the mitochondrial respiratory chain, and this has been supported by studies undertaken in the previous funding period. In this competing renewal, we build upon these findings that demonstrate a) enhanced sensitivity to the NO-dependent inhibition of mitochondrial respiration occurs early on exposure to alcohol b) this response is ablated in mice lacking the inducible NO synthase isoform c) these changes are associated with changes in the mitochondrial proteome and oxidative modification of proteins and mitochondrial DNA. These data have led to the hypothesis that alcohol hepatotoxicity is exacerbated through increased mitochondrial dysfunction and these effects will be ameliorated by mitochondrially targeted antioxidants. This concept will be tested by pursuit of the following Specific Aims: 1. Determine the effect of mitochondrially targeted antioxidants (MTA) on the development of alcohol-dependent hepatoxicity and hypoxia. 2: Determine the effects of MTA on the chronic alcohol-dependent changes in activity of mitochondrial proteins, sensitivity to inhibition of the respiratory chain by NO and damage to mtDNA. 3: Determine the effects of MTA on the ethanol dependent modifications of the mitochondrial proteome. This project will contribute to public health through defining the mechanisms that lead to the liver damage that occurs in response to chronic alcoholism. In addition, the possibility of using a new class of drugs directed to the parts of the cell that produce energy to reverse or prevent these toxic effects of alcohol will be tested.