IMPACTING MITOCHONDRIA FUNCTION THROUGH ALTERED PROTEASE ACTIVITY

通过改变蛋白酶活性影响线粒体功能

• 批准号: 9078540
• 负责人: Rockland Luke Wiseman
• 金额: $ 42.11万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9078540
• 关键词: ATP-Dependent Proteases; Alzheimer' s Disease; Apoptotic; Attenuated; Cardiovascular Diseases; Cell Death; Cell Survival; Cells; Cellular Stress; Disease; Electron Transport; Energy Metabolism; Environmental Risk Factor; Functional disorder; Genetic; Goals; Huntington Disease; Individual; Inner mitochondrial membrane; Lead; Link; Maintenance; Malignant Neoplasms; Membrane; Metabolic; Mitochondria; Molecular; Morphology; Neurodegenerative Disorders; Neurons; Oxidative Stress; Parkinson Disease; Pathogenesis; Pathologic; Pathology; Peptide Hydrolases; Protein Import; Quality Control; Recovery; Regulation; Signal Transduction; Stress; Tubular formation; Work; human disease; meetings; mitochondrial dysfunction; mitochondrial membrane; new therapeutic target; public health relevance; response; therapeutic target

 DESCRIPTION (provided by applicant): Oxidative stress and mitochondria dysfunction are inextricably linked in the onset and pathology of human diseases including neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. Currently, the underlying molecular mechanisms that define the relationship between oxidative stress and mitochondria dysfunction in these diseases remain poorly defined. Mitochondria inner membrane (IM) proteases such as YME1L and OMA1 coordinate to regulate many aspects of mitochondrial function including energy metabolism, organellar morphology and apoptotic signaling. Imbalances in the activity of these proteases induced by genetic or environmental factors disrupt mitochondria function and predispose individuals to etiologically diverse human diseases including many neurodegenerative disorders. Despite the importance of these proteases for mitochondria function, how the activity of IM proteases is impacted by pathologic insults are poorly understood. We hypothesize that stress-induced alterations in mitochondria IM proteases directly influence mitochondrial function and dictate cell survival in response to pathologic insults. Consistent with this prediction, we have identified YME1L and OMA1 as stress-sensitive mitochondrial proteases that undergo reciprocal regulation in response to oxidative and pathologic insults. OMA1, but not YME1L, is degraded in response to cellular insults that depolarize the mitochondria membrane through a mechanism involving YME1L. In contrast, YME1L, but not OMA1, is degraded in response to cellular insults that depolarize the mitochondria membrane and induce metabolic crisis by reducing cellular ATP through a mechanism involving activated OMA1. In this proposal, we will define the impact of YME1L or OMA1 degradation on mitochondria functions including regulation of mitochondrial morphology, inner membrane proteostasis maintenance, electron transport chain activity and neuronal sensitivity to oxidative and proteotoxic insults associated with neurodegenerative disease pathology. Through these efforts, we will demonstrate that the differential stress-sensitivity of YME1L and OMA1 distinctly impacts IM proteolytic capacity and alters mitochondria function in response to oxidative insults. Thus, our work will reveal YME1L or OMA1 degradation as a new molecular mechanism involved in defining the relationship between oxidative stress, mitochondria dysfunction and cell death associated with diseases such as the neurodegenerative disorders. Additionally, our work will identify YME1L and OMA1 activity as new therapeutic targets that can be modulated to attenuate pathologic mitochondria dysfunction associated with human disease.

 描述（由适用提供）：氧化应激和线粒体功能障碍在人类疾病的发作和病理学中密不可分，包括神经退行性疾病，例如阿尔茨海默氏病，帕金森氏病和亨廷顿氏病。当前，这些疾病中氧化应激与线粒体功能障碍之间关系之间关系的潜在分子机制仍然很差。线粒体内膜（IM）蛋白酶（例如YME1L和OMA1）坐标以调节线粒体功能的许多方面，包括能量代谢，有机形态和凋亡信号传导。遗传或环境因素引起的这些蛋白酶活性的不平衡破坏了线粒体功能，并使个体倾向于病因学上多样化的人类疾病，包括许多神经退行性疾病。尽管这些蛋白酶对线粒体功能的重要性很重要，但对IM蛋白酶的活性如何受到病理损伤的影响。我们假设应激诱导的线粒体IM蛋白酶的改变直接影响线粒体功能，并决定对病理损伤的响应细胞存活。与该预测一致，我们将YME1L和OMA1确定为应激敏感的线粒体蛋白酶，对氧化和病理损伤的响应进行了相互调节。 OMA1而不是YME1L，由于响应细胞损伤而通过涉及YME1L的机制去极化线粒体膜的细胞侮辱而降解。相比之下，YME1L而不是OMA1，响应细胞损伤而降低了通过涉及活化OMA1的机制来减少细胞ATP，从而使线粒体膜去极化并诱导代谢危机。在此提案中，我们将定义YME1L或OMA1降解对线粒体功能的影响，包括调节线粒体形态，内膜内部蛋白质的维持，电子传输链活性和对氧化和蛋白质毒性感染的神经元敏感性与神经毒性疾病疾病的敏感性。通过这些努力，我们将证明YME1L和OMA1的差异应力敏感性明显影响IM蛋白水解能力，并改变线粒体对氧化感染的作用。这是我们的工作将揭示YME1L或OMA1降解，这是一种在定义氧化应激，线粒体功能障碍与与神经退行性疾病等疾病相关的细胞死亡之间的关系涉及的新分子机制。此外，我们的工作将识别YME1L和OMA1活性是新的治疗靶标，可以调节以减轻与人类疾病相关的病理线粒体功能障碍。