Mitochondrial Dynamics in Alcohol-induced Tissue Injury

描述(申请人提供)：慢性酒精滥用与许多器官的疾病有关，但这些疾病的发病机制仍不清楚。对动物模型的研究表明，长期摄入酒精会导致线粒体结构和功能的紊乱。线粒体生物能量学的损伤和线粒体的凋亡调节功能被认为是酒精性心脏病和肝病细胞死亡增加的中心原因。新出现的研究表明，调控线粒体形态和功能的因素之间存在相互依赖关系。线粒体融合-裂变或马达蛋白的表达或突变改变会导致细胞/组织损伤。我们的研究提供了慢性酒精暴露改变线粒体形态和融合-裂变动力学的证据。我们的假设是，线粒体形态的变化是决定复杂的细胞和组织对乙醇的反应的关键事件，导致组织损伤。该研究计划整合了遗传学、先进的成像和生物化学方法，以揭示乙醇诱导的组织损伤过程中线粒体形状变化的机制、调节和后果。我们已经开发了一系列活细胞成像方法来可视化和定量线粒体融合-裂变和运动性，这是一个工具包，使我们能够揭示酒精暴露下线粒体动力学的机制、调节和损伤。这些研究将重点放在心脏和肝脏的组织损伤上，那里的细胞功能依赖于可以根据需要进行调节的高能力线粒体新陈代谢。实验模型将跨越从细胞系到原代培养细胞再到完整器官的范围。这些实验分为以下三个目的：(1)确定长期酒精摄入对线粒体动力学的影响并分析其潜在机制；(2)建立对照和酒精暴露组织中线粒体生物能量学和融合-裂变动力学之间的关系；(3)确定线粒体形态和动力学的改变是否有助于酒精诱导的细胞损伤。了解线粒体动力学在慢性酒精滥用诱导的组织损伤中的作用将有助于深入了解酒精性肝病和心肌病的发病机制，并可能为开发诊断、预后和治疗工具开辟新的途径。叙述：慢性酒精中毒与多种组织中线粒体功能障碍和线粒体形态改变有关。线粒体动力学被认为是酒精作用的目标，这是线粒体形态变化的基础，而线粒体形态的变化反过来又导致线粒体功能障碍。最近对活细胞线粒体结构和功能的研究进展将使我们能够确定线粒体动力学在酒精性肝和心肌损伤中的机制和意义。

DESCRIPTION (provided by applicant): Chronic alcohol abuse is associated with diseases of many organs, but the pathogenesis of these conditions still remains obscure. Studies on animal models have demonstrated that chronic ethanol feeding causes structural and functional derangements of mitochondria. Impairments of mitochondrial bioenergetics and the apoptosis-regulating function of mitochondria are considered to be central for the increased cell death in both alcoholic heart and liver disease. Emerging research indicates the interdependence between the factors that regulate mitochondrial morphology and function. Altered expression or mutation of the mitochondrial fusion- fission or motor proteins leads to cell/tissue injury. Our studies provide evidence that chronic ethanol exposure alters the mitochondrial morphology and fusion-fission dynamics. Our hypothesis is that the changes in mitochondrial morphology are crucial events in determining complex cellular and tissue responses to ethanol contributing to tissue injury. The research plan integrates genetics, advanced imaging and biochemistry approaches to unravel mechanisms, regulation and consequences of mitochondrial shape changes during ethanol-induced tissue injury. We have developed an array of live cell imaging approaches to visualize and quantitate both mitochondrial fusion-fission and motility, a toolkit that enables us to uncover the mechanisms, the regulation and impairment of mitochondrial dynamics upon alcohol exposure. The studies will focus on the tissue injury in heart and liver, where cell function relies on a high capacity of mitochondrial metabolism that can be regulated on demand. The experimental models will span the range from cell lines, through primary cultured cells to the intact organ. The experiments are organized into three aims as follows: (1) To determine the effects of chronic alcohol feeding on mitochondrial dynamics and analyze the underlying mechanisms; (2) To establish the relationship between mitochondrial bioenergetics and fusion-fission dynamics in control and alcohol-exposed tissue; (3) To determine whether the alterations in mitochondrial morphology and dynamics contribute to alcohol-induced cell injury. Understanding the role of mitochondrial dynamics in the chronic alcohol abuse-induced tissue injury will afford insights into the pathogenesis of alcoholic liver disease and cardiomyopathy and may open new avenues for developing diagnostic, prognostic and therapeutic tools. Narrative: Chronic alcoholism is associated with mitochondrial dysfunction and changes in mitochondrial morphology in multiple tissues. Mitochondrial dynamics is envisioned as a target of the alcohol's effect, which underlies changes in mitochondrial morphology which, in turn, lead to mitochondrial dysfunction. Recent progress in the study of mitochondrial structure and function in live cells will enable us to establish the mechanisms and significance of mitochondrial dynamics in the alcoholic liver and cardiac muscle injury.