IMPACTING MITOCHONDRIA FUNCTION THROUGH ALTERED PROTEASE ACTIVITY

 描述（由申请人提供）：氧化应激和线粒体功能障碍在人类疾病的发病和病理学中不可分割地联系在一起，所述人类疾病包括神经退行性疾病，例如阿尔茨海默病、帕金森病和亨廷顿病。目前，定义这些疾病中氧化应激和线粒体功能障碍之间关系的潜在分子机制仍然不清楚。线粒体内膜（IM）蛋白酶如YME1L和OMA1协调调节线粒体功能的许多方面，包括能量代谢、细胞器形态和凋亡信号传导。由遗传或环境因素诱导的这些蛋白酶活性的不平衡破坏线粒体功能，并使个体易患病因多样的人类疾病，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，但对IM蛋白酶的活性如何受到病理损伤的影响知之甚少。我们推测，应激诱导的线粒体IM蛋白酶的改变直接影响线粒体功能，并决定细胞的生存在病理损伤。与这一预测一致，我们已经确定YME1L和OMA1作为应激敏感性线粒体蛋白酶，在氧化和病理损伤的反应中进行相互调节。OMA1，而不是YME1L，降解响应于细胞损伤，通过涉及YME1L的机制使线粒体膜脱钙。相比之下，YME1L而不是OMA1响应于细胞损伤而降解，所述细胞损伤通过涉及活化的OMA1的机制通过减少细胞ATP使线粒体膜脱附并诱导代谢危机。在这个提议中，我们将定义YME1L或OMA1降解对线粒体功能的影响，包括线粒体形态的调节，内膜蛋白稳态的维持，电子传递链的活性和神经元对与神经退行性疾病病理学相关的氧化和蛋白毒性损伤的敏感性。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，并改变线粒体功能，以应对氧化损伤。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活性作为新的治疗靶点，可以调节以减轻与人类疾病相关的病理性线粒体功能障碍。

 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.