Mitochondrial Integrated Stress Response in Neurological Diseases

神经系统疾病中的线粒体综合应激反应

• 批准号: 10616130
• 负责人: Giovanni Manfredi
• 金额: $ 8.74万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-15 至 2029-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10616130
• 关键词: Address; Affect; Alzheimer' s Disease; Anabolism; Brain; Catabolism; Cells; Cellular Metabolic Process; Cellular Stress Response; Cellular biology; Central Nervous System Diseases; Cessation of life; Characteristics; Defect; Development; Disease; Disease model; Encephalopathies; Event; Failure; Generations; Genetic; Genetic Transcription; Heart; Human; Inherited; Knowledge; Metabolic; Metabolic Pathway; Metabolism; Mission; Mitochondria; Mitochondrial Diseases; Muscle; Mutation; Nerve Degeneration; Neuroglia; Neurons; Nuclear; Organelles; Parkinson Disease; Pathogenesis; Pathogenicity; Pathologic; Peripheral; Play; Proteins; Proteome; Research; Role; Series; Signal Pathway; Stress; Therapeutic; Tissues; age related neurodegeneration; biological adaptation to stress; cell type; effective therapy; human disease; improved; innovation; mitochondrial dysfunction; mitochondrial genome; nervous system disorder; premature; response; targeted treatment; virtual

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.

线粒体在细胞生物学中起着重要的作用，因为是大多数代谢途径的中心枢纽。他们是 不仅对于能量转换至关重要，而且对于几乎所有细胞的生物合成和分解代谢也必不可少 构成。线粒体功能障碍在所有细胞中造成严重破坏，尤其是在那些高度的细胞类型中 取决于线粒体能量和代谢功能，例如神经元和神经胶质。遗传改变 线粒体蛋白质组，其中包括1000多个蛋白质，由核和核编码 线粒体基因组，导致原发性线粒体疾病。这些疾病，目前有 没有有效的治疗，导致严重且经常致命的神经退行性。线粒体功能障碍也发挥 在许多与年龄相关的神经退行性疾病的发病机理中的作用，例如阿尔茨海默氏症和帕金森氏症 疾病和ALS。因此，从理论上讲线粒体功能障碍的后果可能 对许多人类疾病的治疗有深远的影响。设计有效的主要挑战 线粒体脑病的治疗方法是我们对对影响的影响的有限理解 线粒体功能障碍。这些疾病仅由能量失败引起的常规观点是 不足，因为线粒体功能障碍的影响越来越多，而不仅仅是ATP 产生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 观察各种类型的线粒体功能障碍激活转录和代谢反应， 涉及多个应力信号通路。我们和其他人已经确定了“线粒体整合应力 反应”（MTISR）线粒体疾病的潜水遗传形式，表明MTISR强烈 与线粒体疾病和潜在的致病性共同点相关。我们假设， 虽然在短期内这些回应可能是补偿性的，但如果持续和未解决，它们成为 适应不良并导致关键代谢产物的失衡，这可能比能量缺陷更有害 本身。虽然我们现在充分理解外周组织中的这些不良适应性机制，例如肌肉和 心脏在受线粒体脑病影响的中枢神经系统中知之甚少。更深 需要了解中枢神经系统中MTISR的特征和后果以了解其特征和后果 致病意义并发展目标的治疗策略。我们的研究小组有一个长期的 致力于研究线粒体疾病的致病机制，我们已经积累了 在研究线粒体脑病和线粒体的机制方面的专业知识超过二十年 神经退行性的功能障碍。在此R35应用中，我们专注于知识的基本差距 通过研究概括人类疾病的疾病模型，MTISR在线粒体脑病中。我们将 使用一系列建立和技术创新的方法来产生蓝图 在解散的中枢神经系统中重新布线并确定对治疗调节有可能响应的靶标。