ROLE OF MTDNA DAMAGE IN ALCOHOL- AND CYP2E1-DEPENDENT TOXICITY

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 在美国，酒精性肝病是导致死亡和残疾的重要原因。急性和慢性酒精摄入会增加肝脏的氧化应激，有可能导致氧化损伤。氧化应激的特征是活性氧物种(ROS)的稳态浓度增加，ROS是由于分子氧的部分还原而产生的氧化离子或分子。乙醇产生氧化应激状态的一个中心途径是诱导细胞色素P450亚型2E1(CYP2E1)，它代谢酒精并在此过程中产生ROS。乙醇会导致肝脏线粒体DNA(MtDNA)氧化损伤和耗尽，以及线粒体功能障碍。此外，长期饮酒会导致线粒体DNA复制基因的代偿性上调。然而，乙醇诱导线粒体DNA损伤和失衡的机制以及线粒体DNA损伤对线粒体功能的损害程度目前尚不清楚。 我们的长期目标是破译影响线粒体的分子事件，这些事件导致酒精诱导的肝损伤。我们的目的是确定线粒体DNA损伤在酒精性肝细胞损伤中的机制和作用。这一建议的中心假设是，由于CYP2E1活性和酒精摄入而产生的高水平ROS会导致急性氧化性肝线粒体DNA损伤，继而导致线粒体功能障碍和肝损伤。持续的氧化应激可能导致线粒体DNA复制的代偿性增加，这可能有助于体内慢性暴露后对乙醇的适应。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Alcoholic liver disease represents an important cause of death and disability in the United States. Acute and chronic ethanol consumption enhances oxidative stress in the liver, potentially leading to oxidative damage. Oxidative stress is characterized by an increased steady-state concentration of reactive oxygen species (ROS), which are oxidizing ions or molecules derived from the partial reduction of molecular oxygen. A central pathway by which ethanol generates a state of oxidative stress is the induction of the cytochrome P450 isoform 2E1 (CYP2E1), which metabolizes alcohol and generates ROS in the process. Ethanol causes liver mitochondrial DNA (mtDNA) oxidative damage and depletion, as well as mitochondrial dysfunction. In addition, prolonged alcohol administration induces a compensatory upregulation of mtDNA replication genes. However, the mechanisms of ethanol-induced mtDNA damage and imbalance and the extent to which mtDNA damage impairs mitochondrial function are currently unknown. Our long-term goal is to decipher the molecular events affecting mitochondria that result in alcohol-induced liver injury. Our objective is to identify the mechanisms and effects of mtDNA damage in alcohol-induced hepatocyte injury. The central hypothesis of this proposal is that high levels of ROS produced as a result of CYP2E1 activity and alcohol administration result in acute oxidative liver mtDNA damage followed by mitochondrial dysfunction and liver injury. Prolonged CYP2E1-dependent oxidative stress may result in compensatory increases in mtDNA replication, which may contribute to adaptation to ethanol after chronic exposure in vivo.