Redox Modification of Thiols in Alcohol Hepatotoxicity

酒精肝毒性中硫醇的氧化还原修饰

• 批准号: 6947884
• 负责人: SHANNON MARIE BAILEY
• 金额: $ 25.38万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-15 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6947884
• 关键词: S adenosylmethionine; alcoholic beverage consumption; alcoholic liver cirrhosis; alcoholism /alcohol abuse; aminothiol; dietary supplements; free radical oxygen; genetic translation; laboratory rat; liver disorder chemotherapy; liver function; mitochondria; mitochondrial DNA; nitric oxide; nitric oxide synthase; nutrition related tag; oxidation reduction reaction; posttranslational modifications; proteomics

DESCRIPTION (provided by applicant): Chronic alcohol consumption causes liver damage by a complex process involving oxidative and nitrosative stress, hypoxia, upregulation of proinflammatory cytokines, and defects in energy metabolism. As both a source for the formation and target of modifications mediated by reactive oxygen and nitrogen species (ROS/RNS), the mitochondrion is recognized as a site critical in cellular stress responses. Emerging evidence indicates that ROS/RNS-mediated stress disrupts mitochondrial function. Changes in the thiol redox status of mitochondrial proteins is proposed to be important in regulating several mitochondrial functions including respiration, cytokine signaling, the mitochondria permeability transition, and apoptosis. The similarity between the effects of chronic alcohol consumption and changes in mitochondrial protein thiol status strongly supports a mechanistic link for the oxidation of protein thiols in mitochondria contributing to alcohol-induced cell death. Recent studies have suggested that the therapeutic effects of S-adenosylmethionine (SAM) in treating alcohol-induced liver injury are mediated though mitochondrial pathways. In this proposal it is hypothesized that SAM administration during chronic alcohol consumption will preserve hepatic mitochondrial function in response to increases in ROS/RNS through thiol-dependent mechanisms. Thus, the overall goal of this project is to identify mechanisms that link SAM-mediated protection to the effects of ROS/RNS on mitochondrial function in response to chronic alcohol. These concepts will be tested by the pursuit of the following Specific Aims in a well characterized rat model of chronic alcohol consumption which produces mitochondrial dysfunction in liver: (1) Determine the effects of SAM on chronic alcohol-mediated modulation of mitochondrial protein thiol redox status. (2) Determine the effect of SAM supplementation on chronic alcohol-induced changes in NO-dependent control of mitochondrial respiration. (3) Characterize the influence of SAM administration on alcohol-induced mtDNA damage, mitochondrial protein synthesis defects, and the regulatory function of prohibitin/BAP37 in respiratory complex assembly. These studies will generate novel information on the mechanisms of redox regulation of mitochondrial protein thiols in alcohol toxicity. New information on the molecular targets of SAM will also be achieved, which will enable the design of effective therapeutic strategies to treat liver diseases.

描述（由申请人提供）：慢性饮酒导致肝脏损伤是一个复杂的过程，涉及氧化和亚硝化应激、缺氧、促炎细胞因子上调和能量代谢缺陷。作为活性氧和活性氮（ROS/RNS）介导的修饰的形成源和靶标，线粒体被认为是细胞应激反应的关键位点。新出现的证据表明，ROS/ rns介导的应激会破坏线粒体功能。线粒体蛋白硫醇氧化还原状态的改变被认为在调节几种线粒体功能中很重要，包括呼吸、细胞因子信号传导、线粒体通透性转变和细胞凋亡。长期饮酒的影响与线粒体蛋白硫醇状态变化之间的相似性有力地支持了线粒体蛋白硫醇氧化与酒精诱导的细胞死亡之间的机制联系。最近的研究表明，s -腺苷蛋氨酸（SAM）对酒精性肝损伤的治疗作用是通过线粒体途径介导的。在这一提议中，我们假设在慢性饮酒期间服用SAM会通过硫醇依赖机制保护肝线粒体功能，以响应ROS/RNS的增加。因此，该项目的总体目标是确定在慢性酒精反应中，sam介导的保护与ROS/RNS对线粒体功能的影响之间的联系机制。这些概念将通过在一个具有良好特征的慢性酒精消耗大鼠模型中进行以下特定目标的测试，该模型会产生肝脏线粒体功能障碍：(1)确定SAM对慢性酒精介导的线粒体蛋白硫醇氧化还原状态的调节的影响。(2)确定补充SAM对慢性酒精诱导的no依赖性线粒体呼吸控制变化的影响。(3)表征SAM给药对酒精诱导的mtDNA损伤、线粒体蛋白合成缺陷以及禁止素/BAP37在呼吸复合物组装中的调节功能的影响。这些研究将为线粒体蛋白硫醇在酒精中毒中的氧化还原调控机制提供新的信息。还将获得有关SAM分子靶点的新信息，这将使设计有效的治疗肝病的治疗策略成为可能。