Mitochondrial Integrated Stress Response in Neurological Diseases

线粒体在细胞生物学中起着重要作用，因为它是大多数代谢途径的中心枢纽。他们是 它不仅是能量转换所必需的，而且也是几乎所有细胞的生物合成和催化剂所必需的。 选民。线粒体功能障碍在所有细胞中引起破坏，但特别是在那些高度分化的细胞类型中。 依赖于线粒体能量和代谢功能，如神经元和神经胶质。基因突变 线粒体蛋白质组包括1000多种蛋白质，由细胞核和线粒体编码。 线粒体基因组，导致原发性线粒体疾病。这些疾病，目前 没有有效的治疗，导致严重的，往往是致命的神经变性。线粒体功能障碍也起着 在许多与年龄相关的神经退行性疾病（如阿尔茨海默病和帕金森病）的发病机制中发挥作用 疾病和ALS。因此，在治疗上解决线粒体功能障碍的后果， 对治疗许多人类疾病有着深远的影响。制定有效的 线粒体脑病的治疗是我们有限的理解的影响， 线粒体功能障碍传统的观点认为，这些疾病是由能量衰竭引起的， 这是不够的，因为越来越清楚的是，线粒体功能障碍影响的不仅仅是ATP 并导致细胞代谢的广泛重新布线。该领域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转录和代谢反应， 涉及多种应激信号通路。我们和其他人已经确定了一种“线粒体整合应激 在不同遗传形式的线粒体疾病中，mtISR是一种“线粒体反应”（mtISR），这表明mtISR是一种强烈的 与线粒体疾病相关，并且是潜在的致病共同点。我们假设， 虽然在短期内，这些反应可能是补偿性的，但如果持续下去并得不到解决， 适应不良并导致关键代谢物的不平衡，这可能比能量缺陷更有害 本身虽然我们现在完全理解外周组织中的这些适应不良机制，例如肌肉和 心脏，很少有人知道他们在中枢神经系统受线粒体脑病。更深 要了解中枢神经系统中的远程ISR的特点和后果，就需要了解它的 致病意义及制定靶点治疗策略。我们的研究小组长期以来 致力于研究线粒体疾病的致病机制，我们积累了 二十多年来，他在研究线粒体脑病和线粒体 神经退行性疾病中的功能障碍在这个R35应用程序中，我们关注的是 通过研究重现人类疾病的疾病模型，研究线粒体脑病中的mtISR。我们将 使用一系列的方法，既有既定的，也有技术创新的，来制定一个蓝图， 在患病的中枢神经系统中的代谢重新布线，并确定潜在地响应于治疗调节的靶点。

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.