Mitochondrial dynamics in alcohol-induced tissue injury

描述(申请人提供)：过量饮酒会导致许多器官系统的损伤，包括脂肪变化和肝硬变、骨骼肌肌病、心脏病、胰腺炎和认知功能的改变。虽然这些病理变化有很好的文献记载，但对其潜在的分子机制却知之甚少。许多研究表明，酒精会导致线粒体形状、超微结构和呼吸活动的严重异常。因此，线粒体动力学是未来研究的一个有前途的途径，最近被证明控制线粒体的形状、超微结构和功能。在了解介导线粒体融合和分裂的机制方面取得了快速进展，我们已经开发了小鼠模型来研究线粒体融合缺陷的后果。线粒体融合是由两个线粒体外膜GTP酶控制的，称为Mitofusin 1和2(Mfn1和Mfn2)，我们构建了这两个基因都有条件等位基因的小鼠。我们假设线粒体融合保护细胞免受酒精诱导的损伤，并将使用我们的小鼠模型在肝脏和肌肉细胞中测试这一假设。具体地说，我们将使用含有Mfn1和Mfn2条件等位基因的小鼠品系来确定线粒体融合的丢失是否会增加对酒精诱导的肝损伤的易感性。此外，我们将使用原代小鼠成肌细胞培养，来自携带条件Mfn1和Mfn2等位基因的小鼠，以确定线粒体融合是否参与骨骼肌肌病，这是长期饮酒最常见的后果之一。综上所述，这些实验将检验线粒体动力学在两个受酒精不利影响的重要组织--肝脏和骨骼肌--中的作用，并可能为开发新的治疗方法带来见解。与公共健康相关的声明：酗酒在美国是一个主要的公共健康问题。国家酒精和药物依赖委员会的估计表明，大约有1800万美国人患有过度饮酒。它是死亡的主要原因，并因医疗保健、犯罪、车祸和缺勤而造成巨大的经济成本。众所周知，酒精会损害许多组织和器官中的线粒体结构和活动，包括肝脏、骨骼肌、心脏、胰腺和大脑。然而，我们对潜在的细胞过程或涉及的途径几乎没有分子上的了解。饮酒已被证明会对线粒体造成损害，我们将测试线粒体融合是否是一个重要因素。对疾病病理生理学的基础生物医学研究传统上会带来长期的好处，并可能导致有效的治疗方法。如果这项研究揭示线粒体动力学缺陷在酒精介导的损伤中起重要作用，将有助于我们理解基本的疾病机制，并可能导致新的治疗方法。

DESCRIPTION (provided by applicant): Excessive alcohol consumption leads to injury in many organ systems, including fatty changes and cirrhosis of liver, skeletal muscle myopathy, heart disease, pancreatitis, and changes in cognitive function. Although these pathological changes are well-documented, little is understood about the underlying molecular mechanisms. Many studies have shown that alcohol causes severe abnormalities in mitochondrial shape, ultrastructure, and respiratory activity. A promising avenue of future research, therefore, is mitochondrial dynamics, which has recently been demonstrated to control mitochondrial shape, ultrastructure, and function. There has been rapid progress in understanding the machineries that mediate mitochondrial fusion and fission, and we have developed mouse models to study the consequences of defective mitochondrial fusion. Mitochondrial fusion is controlled by two mitochondrial outer membrane GTPases called Mitofusin 1 and 2 (Mfn1 and Mfn2), and we have constructed mice with conditional alleles in both. We hypothesize that mitochondrial fusion protects cells from alcohol-induced injury and will use our mouse models to test this hypothesis in liver and muscle cells. Specifically, we will use mouse strains containing conditional alleles of Mfn1 and Mfn2 to determine whether loss of mitochondrial fusion increases susceptibility to alcohol-induced liver damage. In addition, we will use primary mouse myoblast cultures, derived from mice carrying conditional Mfn1 and Mfn2 alleles, to determine whether mitochondrial fusion is involved in skeletal muscle myopathy, one of the most common consequences of chronic alcohol use. Taken together, these experiments will examine the role of mitochondrial dynamics in two important tissues affected adversely by alcohol--the liver and skeletal muscle--and may lead to insights to develop new therapies. Statement of relevance to public health: Alcohol abuse is a major public health issue in the United States. Estimates from the National Council on Alcohol and Drug Dependence indicate that approximately 18 million Americans suffer from alcohol over-consumption. It is a major cause of mortality and results in enormous economic costs due to health care, crime, car accidents, and absence from work. It is known that alcohol damages mitochondria structure and activity in many tissue and organs, including the liver, skeletal muscle, heart, pancreas, and brain. However, we have little molecular understanding of the underlying cellular processes or pathways involved. Alcohol consumption has been shown to cause damage to mitochondria, and we will test whether mitochondrial fusion is an important factor. Basic biomedical research into the pathophysiology of disease has traditionally resulted in long-term benefits and may lead to effective therapies. If this research reveals that defects in mitochondrial dynamics play an important role in alcohol-mediated damage, it will contribute to our understanding of fundamental disease mechanisms and may lead to new treatments.