IMPACTING MITOCHONDRIA FUNCTION THROUGH ALTERED PROTEASE ACTIVITY

通过改变蛋白酶活性影响线粒体功能

基本信息

批准号：
9915982
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
项目类别：
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/9915982
关键词：
ATP-Dependent Proteases Alzheimer&apos s Disease Apoptotic Attenuated Cardiovascular Diseases Cell Death Cell Survival Cells Cellular Stress Disease Electron Transport Energy Metabolism Environmental Risk Factor Etiology Genetic Goals Human Pathology Huntington Disease Impairment Individual Inner mitochondrial membrane Lead Link Maintenance Malignant Neoplasms Membrane Metabolic Mitochondria Mitochondrial Proteins 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 mitochondrial dysfunction mitochondrial membrane new therapeutic target proteostasis proteotoxicity public health relevance response therapeutic target

项目摘要

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（通过应用程序证明）：氧化应激和mitchondria功能障碍在人类的OND病理方面密不可分，包括神经退行性的阿尔茨海默氏病，以及亨廷顿氏病，这些机制定义了这些疾病之间的关系。定期的Mitchondrial功能的许多方面，包括能量代谢，细胞器的形态和凋亡信号传导。我们假设应激诱发的alteas直接诱发的线粒体功能，并在preption ts中与preptions yme1l和Oma1一致。 YME1L响应细胞损伤，通过涉及YME1L的机制降解了线粒体MEMRNE，而不是OMA1。在此提案中，我们将定义YME1L或OMA1降解对线粒体的影响，包括对Mitchondrial形态的调节，内膜蛋白质的维护，电子运输和神经元素的氧化和蛋白质氧化毒素，我们将证明YME1L OMA1的差异应力 - 敏感性不可能影响IM蛋白质的能力，并响应氧化性损伤而改变线粒体的功能。。