Mitochondrial Integrated Stress Response in Neurological Diseases

线粒体在细胞生物学中起着至关重要的作用，因为它是大多数代谢途径的中心枢纽。他们是 不仅对能量转换是必需的，而且对几乎所有细胞的生物合成和分解代谢都是必不可少的 选民。线粒体功能障碍会在所有细胞中造成严重破坏，特别是在那些高度 依赖于线粒体的能量和代谢功能，如神经元和胶质细胞。基因的改变 线粒体蛋白质组包括1000多种蛋白质，由细胞核和 线粒体基因组，导致原发的线粒体疾病。这些疾病，目前有 没有有效的治疗方法，会导致严重的、往往是致命的神经变性。线粒体功能障碍也起到了作用 在许多与年龄相关的神经退行性疾病的发病机制中发挥作用，如阿尔茨海默氏症和帕金森病 疾病和肌萎缩侧索硬化。因此，从治疗上解决线粒体功能障碍的后果可能 对许多人类疾病的治疗产生了深远的影响。设计有效的解决方案的主要挑战 对线粒体脑病的治疗是我们对其影响的有限理解 线粒体功能障碍。传统的观点认为，这些疾病只是由能源故障引起的 这是不够的，因为越来越明显的是，线粒体功能障碍影响的不仅仅是ATP 并导致细胞新陈代谢的广泛重新布线。该领域一个令人兴奋的新发展是 观察到各种类型的线粒体功能障碍激活了转录和代谢反应， 涉及多条应激信号通路。我们和其他人发现了一种“线粒体整合应激” 在线粒体疾病的不同遗传形式中存在“反应”(MtISR)，表明mtISR是强烈的 与线粒体疾病和潜在的致病共同点有关。我们假设， 虽然在短期内，这些反应可能是补偿性的，但如果持续且未得到解决，它们将成为 适应不良，并导致关键代谢物失衡，这可能比能量缺陷更有害 它本身。虽然我们现在充分认识到外周组织中的这些适应不良机制，如肌肉和 心脏，在受线粒体脑病影响的中枢神经系统中，人们对它们知之甚少。更深一层的 需要了解中枢神经系统mtISR的特征和后果，才能理解其 致病意义和制定靶点治疗策略。我们的研究小组有一个历史悠久的 致力于研究线粒体疾病的致病机制，我们积累了 在研究线粒体脑病和线粒体机制方面有二十多年的专业知识 神经退行性变的功能障碍。在此R35应用程序中，我们重点关注以下方面的基本知识差距 通过研究重述人类疾病的疾病模型，线粒体ISR在线粒体脑病中的作用。我们会 使用一系列既有既定方法又有技术创新的方法来制定 疾病中枢神经系统的代谢重组，并确定潜在的治疗调节反应的靶点。

Mitochondria play essential roles in cell biology because are central hubs of most metabolic pathways. They are not only essential for energy conversion, but also for the biosynthesis and catabolism of virtually all cell constituents. Mitochondrial dysfunction causes havoc in all cells, but especially in those cell types that are highly dependent on mitochondrial energetic and metabolic functions, such as neurons and glia. Genetic alterations of the mitochondrial proteome, which includes more than 1000 proteins, encoded by both the nuclear and the mitochondrial genomes, result in primary mitochondrial disorders. These diseases, for which there is currently no effective treatment, result in severe and often fatal neurodegeneration. Mitochondrial dysfunction also plays a role in the pathogenesis of many age-related neurodegenerative disorders, such as Alzheimer and Parkinson disease and ALS. Therefore, addressing therapeutically the consequences of mitochondrial dysfunction could have a profound impact on the treatment of many human disorders. A major challenge in devising effective treatments for mitochondrial encephalopathies is our limited understanding of the ramifications of the effects of mitochondrial dysfunction. The conventional view that these disorders are caused simply by energy failure is inadequate, as it is becoming increasingly clear that mitochondrial dysfunction affects much more than just ATP generation and leads to an extensive rewiring of cell metabolism. An exciting new development in the field is the observation that various types of mitochondrial dysfunction activate transcriptional and metabolic responses that involve multiple stress signaling pathways. We and others have identified a “mitochondrial integrated stress response” (mtISR) in diverse genetic forms of mitochondrial disorders, suggesting that mtISR is strongly associated with mitochondrial diseases and a potential pathogenic common denominator. We postulate that, while in the short term these responses may be compensatory, if sustained and unresolved, they become maladaptive and causes imbalances of key metabolites, which may be more detrimental than the energy defect itself. While we now fully appreciate these maladaptive mechanisms in peripheral tissues, such as muscle and heart, very little is known about them in the CNS affected by mitochondrial encephalopathies. A deeper knowledge of the characteristics and the consequences of the mtISR in the CNS is needed to understand its pathogenic significance and develop targets therapeutic strategies. Our research group has a long-standing commitment to investigating the pathogenic mechanisms of mitochondrial diseases and we have accumulated over two decades of expertise in studying the mechanisms of mitochondrial encephalopathies and mitochondrial dysfunction in neurodegeneration. In this R35 application, we focus on fundamental gaps in knowledge on the mtISR in mitochondrial encephalopathies by studying disease models that recapitulate human diseases. We will use a series of approaches, both established and technologically innovative, to generate a blueprint of the metabolic rewiring in the diseased CNS and identify targets potentially responsive to therapeutic modulation.