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发挥着重要作用，因为它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至关重要 选民。线粒体功能障碍会对所有细胞造成严重破坏，尤其是那些高度敏感的细胞类型。 依赖于线粒体的能量和代谢功能，例如神经元和神经胶质细胞。基因改变 线粒体蛋白质组，包括 1000 多种蛋白质，由细胞核和线粒体编码 线粒体基因组，导致原发性线粒体疾病。目前针对这些疾病 没有有效的治疗，会导致严重且往往致命的神经变性。线粒体功能障碍也起作用 在许多与年龄相关的神经退行性疾病（例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，通过治疗解决线粒体功能障碍的后果可以 对许多人类疾病的治疗产生深远的影响。设计有效的解决方案是一个重大挑战 线粒体脑病的治疗方法是我们对线粒体脑病影响后果的有限了解 线粒体功能障碍。传统观点认为这些疾病只是由能量衰竭引起的 不足，因为越来越清楚的是，线粒体功能障碍不仅仅影响 ATP 产生并导致细胞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“线粒体综合压力 反应”（mtISR）在线粒体疾病的多种遗传形式中，表明 mtISR 强烈 与线粒体疾病和潜在的致病共同点有关。我们假设， 虽然在短期内这些应对措施可能是补偿性的，但如果持续存在且得不到解决，它们就会变成 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 本身。虽然我们现在充分认识到外周组织（例如肌肉和组织）中的这些适应不良机制 心脏，人们对它们在受线粒体脑病影响的中枢神经系统中知之甚少。更深层次的 需要了解 CNS 中 mtISR 的特征和后果，以了解其 致病意义并制定目标治疗策略。我们的研究小组拥有长期 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脑病机制方面拥有二十多年的专业知识 神经变性的功能障碍。在此 R35 应用程序中，我们重点关注有关 通过研究再现人类疾病的疾病模型来研究线粒体脑病中的 mtISR。我们将 使用一系列既定的和技术创新的方法来生成蓝图 患病中枢神经系统的代谢重新布线，并确定可能对治疗调节有反应的靶点。