CHRONIC ETHANOL CONSUMPTION AND MITOCHONDRIAL DNA DAMAGE

长期乙醇消耗与线粒体 DNA 损伤

• 批准号: 6604231
• 负责人: ALAN CAHILL
• 金额: $ 22.08万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-19 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6604231
• 关键词: DNA damage; adduct; age difference; alcoholic beverage consumption; alcoholism /alcohol abuse; ethanol; laboratory rat; mitochondrial DNA; oxidative stress; pathologic process; phosphorylation

DESCRIPTION: (Adapted from the Investigator's Abstract) It is proposed to investigate the hypothesis that chronic ethanol consumption results in increased oxidative damage to mtDNA and that aging may increase the susceptibility of liver mitochondria to ethanol-elicited defects in mtDNA homeostasis. Published data show that long-term ethanol feeding has a profound effect on the metabolic functioning of rat liver mitochondria. Ethanol intake results in decreased oxidative phosphorylation, structurally abnormal mitochondria and elevated levels of mitochondrially-produced reactive oxygen species. Previous studies by the investigator have established that long term exposure causes increased oxidative damage to mtDNA, as reflected by increased levels of 8-hydroxydeoxyguanosine (8-OHdG) adducts. These studies have been extended to show that 2 month old animals maintained on the Lieber-DeCarli diet for one year exhibit a 40% depletion in mtDNA content and a 3-fold increase in 8-OHdG adduct formation. In addition, increases in single strand breaks and deletions of mtDNA are also observed. Recently, a short term, chronic ethanol feeding regimen was developed where 1 year old rats are fed the Lieber-DeCarli diet for 2 months, a feeding period that is not associated with alterations in mtDNA structure in young animals. Preliminary results show that these animals exhibit a greater mtDNA depletion (greater than 60%) than that seen in young animals fed ethanol for 1 year. This suggests that aging increases the susceptibility of hepatic mitochondria to ethanol-induced alterations in mtDNA homeostasis. The proposed studies will (a) fully characterize the new feeding model with regard to mtDNA content, levels of oxidative damage and the activities of respiratory chain complexes; (b) investigate the effect of oxidative damage on the processes of mtDNA degradation and repair in old animals, in order to elucidate the biochemical mechanism(s) behind the ethanol-elicited mtDNA depletion; (c) investigate the role of ethanol and reactive oxygen species in the formation of mtDNA deletions; (d) investigate the effect of decreased mtDNA content on the production of mitochondrial transcripts and the activities of electron transport chain complexes; (e) investigate the role of mtDNA structural alterations in the formation of pathological lesions associated with alcoholic liver disease (ALD); and (f) investigate the effects of ethanol consumption on hepatic mtDNA structure in human alcoholics. Our understanding of the role of mtDNA in the pathogenesis of alcoholic liver disease will be enhanced by these in-depth analyses.

描述：（根据调查人员的摘要进行了改编） 研究慢性乙醇消耗导致的假设 增加对mtDNA的氧化损伤，并且衰老可能会增加 肝线粒体对mtDNA中乙醇的缺陷的敏感性 稳态。已发表的数据表明，长期乙醇喂养具有深刻的 对大鼠肝线粒体代谢功能的影响。乙醇摄入量 导致氧化磷酸化降低，结构异常 线粒体和线粒体生产的活性氧的水平升高 物种。研究者先前的研究已经确定 暴露会导致对mtDNA的氧化损伤增加，如增加而反映 8-羟基氧鸟苷（8-OHDG）加合物的水平。这些研究已经 扩展以表明在Lieber-Decarli饮食上维持2个月大的动物 一年的mtDNA含量耗尽了40％，增加了3倍 8-OHDG加合物形成。另外，单链断裂的增加和 还观察到mtDNA的缺失。最近，短期，慢性乙醇 喂养方案是开发出1岁大鼠喂食lieber-decarli的开发方案 饮食2个月，一个与改变有关的喂养期 年轻动物中的mtDNA结构。初步结果表明这些动物 表现出比Young的mtDNA耗竭（大于60％） 动物喂乙醇1年。这表明衰老增加了 肝线粒体对乙醇诱导的mtDNA改变的敏感性 稳态。拟议的研究将（a）完全表征新的喂养 关于mtDNA含量，氧化损伤水平和 呼吸链复合物的活动； （b）研究 MtDNA降解和修复过程中的氧化损伤 动物，为了阐明后面的生化机制 乙醇吸收的mtDNA耗竭； （c）研究乙醇和 在mtDNA缺失形成中的活性氧； （d）调查 mtDNA含量降低对线粒体产生的影响 转录本和电子传输链复合物的活性； （E） 研究mtDNA结构改变在形成中的作用 与酒精性肝病（ALD）相关的病理病变； （f） 研究乙醇消耗对肝mtDNA结构中的影响 人类酗酒者。我们对mtDNA在发病机理中的作用的理解 这些深入的分析将增强酒精性肝病。