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(申请人提供)：氧化应激和线粒体功能障碍在人类疾病的发生和病理中有着千丝万缕的联系，包括神经退行性疾病，如阿尔茨海默病、帕金森病和亨廷顿病。目前，定义氧化应激和线粒体功能障碍之间关系的潜在分子机制在这些疾病中仍不清楚。线粒体内膜蛋白(IM)酶如YME1L和OMA1协同调节线粒体功能的多个方面，包括能量代谢、细胞器形态和细胞凋亡信号。由遗传或环境因素引起的这些蛋白水解酶活性的失衡破坏了线粒体的功能，并使个体容易患上各种人类疾病，包括许多神经退行性疾病。尽管这些蛋白水解酶对线粒体功能很重要，但病理损伤是如何影响IM蛋白水解酶活性的，目前还知之甚少。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的功能，并决定细胞对病理侮辱的反应。与这一预测一致，我们已经确定YME1L和OMA1是应激敏感的线粒体蛋白水解酶，它们在氧化和病理损伤的反应中经历相互调节。OMA1，而不是YME1L，通过涉及YME1L的一种机制，在细胞损伤使线粒体膜去极化的反应中被降解。相反，YME1L，而不是OMA1，在细胞损伤的反应中被降解，这种损伤通过激活OMA1的机制降低细胞的ATP，从而使线粒体膜去极化并引发代谢危机。在这项提案中，我们将确定YME1L或OMA1降解对线粒体功能的影响，包括线粒体形态的调节、内膜蛋白平衡的维持、电子传输链的活性以及与神经退行性疾病病理相关的氧化和蛋白毒性损伤的神经元敏感性。通过这些努力，我们将证明YME1L和OMA1的差异应激敏感性显著影响IM的蛋白分解能力，并改变线粒体功能以响应氧化损伤。因此，我们的工作将揭示YME1L或OMA1降解作为一种新的分子机制参与定义氧化应激、线粒体功能障碍和与神经退行性疾病等疾病相关的细胞死亡之间的关系。此外，我们的工作将确定YME1L和OMA1活性为新的治疗靶点，可以调节它们来减轻与人类疾病相关的病理性线粒体功能障碍。