Cellular and Molecular Consequences of Respiratory Chain Defects in Neurons

描述（由申请人提供）：线粒体呼吸复合体的缺陷会引起许多代谢疾病，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病症的生物学原理并开发有效的治疗方法。为了实现这些目标，我们开发了具有不同线粒体呼吸复合物缺陷的小鼠模型。我们现在建议研究与特定线粒体呼吸复合物（复合物 I、III 或 IV）缺陷相关的致病机制。我们的初步数据显示，根据受影响的复合体，表型存在一些显着差异。受不同缺陷影响的大脑代谢特征的识别将用于更好地了解致病机制。最后，根据前两个目标收集的信息，我们将测试线粒体生物合成和脂质利用的增加是否可以对某些线粒体脑病产生保护作用。

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.