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: 7483073
• 负责人: SHANNON MARIE BAILEY
• 金额: $ 29.14万
• 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 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7483073
• 关键词: Alcohol Hepatotoxicity; Alcoholic Liver Diseases; Alcohols; Animal Feed; Animals; Apoptosis; Cell Death; Cell physiology; Cells; Cellular Stress Response; Chronic; Complex; Condition; Cysteine; Cytokine Signaling; DNA Damage; Data; Defect; Disruption; Energy Metabolism; Ethanol; Ethanol toxicity; Event; Goals; Hepatic; Hepatocyte; Homeostasis; Hypoxia; Injury; Investigation; Knowledge; Label; Lead; Link; Liver; Liver diseases; Mediating; Membrane; Membrane Proteins; Mitochondria; Mitochondrial Proteins; Modeling; Modification; Molecular Chaperones; Molecular Target; Nitric Oxide; Nitrogen; Oxidation-Reduction; Oxidative Phosphorylation; Oxidative Stress; Oxygen; Pathway interactions; Permeability; Physiology; Post-Translational Protein Processing; Process; Production; Protein Biosynthesis; Proteins; Proteomics; Rattus; Reaction; Reagent; Regulation; Research Personnel; Respiration; Respiratory Chain; Respiratory physiology; Signal Transduction; Site; Site-Directed Mutagenesis; Source; Stress; Sulfhydryl Compounds; Supplementation; System; Testing; Therapeutic; Therapeutic Effect; Up-Regulation; alcohol exposure; alcohol response; base; chronic alcohol ingestion; concept; cytokine; design; dietary supplements; feeding; indexing; insight; mitochondrial dysfunction; novel; oxidation; prevent; programs; prohibitin; protein expression; respiratory; response

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）：长期饮酒通过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的复杂过程引起肝损伤。线粒体既是活性氧和氮物质（ROS/RNS）介导的修饰的形成来源，又是靶点，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介导的应激破坏线粒体功能。线粒体蛋白巯基氧化还原状态的变化被认为在调节几种线粒体功能中是重要的，包括呼吸、细胞因子信号传导、线粒体通透性转换和细胞凋亡。慢性酒精消耗和线粒体蛋白巯基状态变化的影响之间的相似性强烈支持线粒体中蛋白巯基氧化促进酒精诱导的细胞死亡的机制联系。最近的研究表明，S-腺苷甲硫氨酸（SAM）治疗酒精性肝损伤的作用是通过线粒体途径介导的。在该提案中，假设在慢性饮酒期间SAM给药将通过巯基依赖性机制保护肝脏线粒体功能以响应ROS/RNS的增加。因此，该项目的总体目标是确定SAM介导的保护机制，ROS/RNS对线粒体功能的影响，以响应慢性酒精。这些概念将通过在充分表征的慢性酒精消耗的大鼠模型中追求以下特定目的来测试，所述慢性酒精消耗在肝脏中产生线粒体功能障碍：（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SAM补充对慢性酒精诱导的线粒体呼吸NO依赖性控制变化的影响。(3)表征SAM给药对酒精诱导的线粒体DNA损伤、线粒体蛋白质合成缺陷以及呼吸复合物组装中抑制素/BAP 37的调节功能的影响。这些研究将产生新的信息氧化还原调节线粒体蛋白硫醇在酒精中毒的机制。还将获得SAM分子靶点的新信息，这将有助于设计有效的治疗策略来治疗肝脏疾病。

项目成果

Proteomic analysis of 4-hydroxynonenal (4-HNE) modified proteins in liver mitochondria from chronic ethanol-fed rats.

• DOI: 10.1016/j.redox.2014.09.006
• 发表时间: 2014
• 期刊: REDOX BIOLOGY
• 影响因子: 11.4
• 作者: Andringa, Kelly K.;Udoh, Uduak S.;Landar, Aimee;Bailey, Shannon M.
• 通讯作者: Bailey, Shannon M.

The methyl donor S-adenosylmethionine prevents liver hypoxia and dysregulation of mitochondrial bioenergetic function in a rat model of alcohol-induced fatty liver disease.

• DOI: 10.1016/j.redox.2016.08.005
• 发表时间: 2016-10
• 期刊: REDOX BIOLOGY
• 影响因子: 11.4
• 作者: King, Adrienne L.;Mantena, Sudheer K.;Andringa, Kelly K.;Millender-Swain, Telisha;Dunham-Snary, Kimberly J.;Oliva, Claudia R.;Griguer, Corinne E.;Bailey, Shannon M.
• 通讯作者: Bailey, Shannon M.

Mitochondrial-nuclear genome interactions in non-alcoholic fatty liver disease in mice.

• DOI: 10.1042/bj20131433
• 发表时间: 2014-07-15
• 期刊: The Biochemical journal
• 作者: Betancourt AM;King AL;Fetterman JL;Millender-Swain T;Finley RD;Oliva CR;Crowe DR;Ballinger SW;Bailey SM
• 通讯作者: Bailey SM

Betaine treatment attenuates chronic ethanol-induced hepatic steatosis and alterations to the mitochondrial respiratory chain proteome.

• DOI: 10.1155/2012/962183
• 发表时间: 2012
• 期刊: International journal of hepatology
• 影响因子: 1.8
• 作者: Kharbanda KK;Todero SL;King AL;Osna NA;McVicker BL;Tuma DJ;Wisecarver JL;Bailey SM
• 通讯作者: Bailey SM

Assessment of mitochondrial dysfunction arising from treatment with hepatotoxicants.

评估肝毒药物治疗引起的线粒体功能障碍。

• DOI: 10.1002/0471140856.tx1408s44
• 发表时间: 2010
• 期刊: Current protocols in toxicology
• 作者: King,AdrienneL;Bailey,ShannonM
• 通讯作者: Bailey,ShannonM