Cellular and Molecular Consequences of Respiratory Chain Defects in Neurons

描述(申请人提供)：线粒体呼吸复合体缺陷会导致许多代谢性疾病，并被认为在与年龄相关的神经退行性疾病的发病机制中发挥关键作用。我们实验室的长期目标是了解这些疾病的生物学原理，并开发有效的治疗方法。为了实现这些目标，我们建立了不同线粒体呼吸复合体缺陷的小鼠模型。我们现在建议研究与特定线粒体呼吸复合体(复合体I、III或IV)缺陷相关的致病机制。我们的初步数据显示，受影响的复合体在表型上有一些显着的差异。识别受不同缺陷影响的大脑的代谢特征将被用来更好地理解致病机制。最后，基于前两个目标收集的信息，我们将测试线粒体生物发生和脂质利用的增加是否可以对某些线粒体脑病起到保护作用。 公共卫生相关性：线粒体呼吸复合体缺陷与许多代谢性疾病有关。这些缺陷的临床表现有很大的差异，但原因尚不清楚。我们建议研究呼吸复合体I、III和IV有缺陷的小鼠模型，以更好地确定导致不同临床表现的机制。我们将定义缺陷大脑的代谢特征，并使用这些信息来微调基于线粒体生物发生增加的治疗方法。

DESCRIPTION (provided by applicant): Defects in the mitochondrial respiratory complexes cause a number of metabolic diseases and are believed to play pivotal roles in the pathogenesis of age-related neurodegenerative disorders. Our laboratory's long term goal is to understand the biology of these conditions and develop effective treatments. To achieve these goals we have developed mouse models with defects in different mitochondrial respiratory complexes. We now propose to study the pathogenic mechanisms associated with defects in specific mitochondrial respiratory complexes (complexes I, III or IV). Our preliminary data showed some remarkable differences in the phenotypes depending on the complex affected. The identification of metabolic signatures of brains affected by the different defects will be used to better understand the pathogenic mechanisms. Finally, based on the information gathered in the first two aims, we will test whether increases in mitochondrial biogenesis and lipid utilization can have a protective effect for certain mitochondrial encephalopathies. PUBLIC HEALTH RELEVANCE: Defects in mitochondrial respiratory complexes have been associated with many metabolic diseases. There is a great deal of variation in the clinical manifestations of these defects, but the reason for this is not known. We propose to study mouse models with defects in the respiratory complexes I, III and IV to better define the mechanisms responsible for the different clinical presentations. We will define metabolic signatures of deficient brains and use this information to fine tune therapeutic approaches based on an increase in mitochondrial biogenesis.