Role of the mitochondrial matrix processing protease in mitochondrial biogenesis

描述（由申请人提供）：线粒体功能缺陷导致多种疾病，包括癌症、心血管疾病和退行性神经和肌肉疾病，包括弗里德赖希共济失调和帕金森病、阿尔茨海默病和亨廷顿病。它对能量的产生很重要，并且在其他途径如中间代谢和信号传导中也起着重要作用。组装途径不仅对线粒体功能很重要，而且蛋白水解途径对于蛋白质质量控制也是必不可少的，其影响线粒体的生物发生、形态和稳态。弗里德赖希共济失调可以特别地由共济失调蛋白的突变引起，其中一个子集导致成熟缺陷。基质加工肽酶（MPP）是共济失调蛋白成熟以及大多数具有N-末端靶向序列的线粒体前体的成熟和折叠所必需的，包括Pink 1和在细胞内双重定位的蛋白质如胰蛋白酶。本研究的目的是表征在化学遗传筛选中鉴定的新型MPP小分子调节剂。本研究的主要目的是：（1）初步研究MPP介导蛋白质转运的机制，初步研究结果表明MPP不仅可以切割靶序列，而且在蛋白质转运中起重要作用。(2)确定如何通过MPP抑制Pink 1切割，阻止外膜易位并刺激帕金招募。初步数据支持MPP调节剂可以激活Pink 1/Parkin通路，并且可能在模型系统中用于选择性地诱导该通路。鉴于先前在使用小分子调节剂表征蛋白质易位方面的成功，利用这些MPP调节剂将提供对线粒体组装缺陷如何导致神经退行性疾病的机理性见解。这项研究与公共卫生有关，因为它可能会导致新的策略的发展，以了解和治疗退行性神经疾病，如弗里德赖希病和帕金森病。

DESCRIPTION (provided by applicant): Defects in mitochondrial function contribute to a wide range of diseases including cancer, cardiovascular disease, and degenerative neural and muscular disorders, including Friedreich's ataxia and Parkinson's, Alzheimer's, and Huntington's diseases. The mitochondrion is important for the production of energy and also plays an important role in other pathways such as intermediary metabolism and signaling. Not only are assembly pathways important for mitochondrial function, but the proteolytic pathways are essential for protein quality control, which impacts biogenesis, morphology, and homeostasis of mitochondria. Friedreich's ataxia can specifically be caused by mutations in frataxin, a subset of which result in defects in maturation. The matrix processing peptidase (MPP) is required for frataxin maturation as well as the maturation and folding of most mitochondrial precursors with an N-terminal targeting sequence, including Pink1 and proteins like fumarase that are dual-localized within the cell. The goal of this study is to characterize novel small molecule modulators for MPP that were identified in a chemical genetic screen. The aims of this proposal are: (1) Characterize the mechanism by which MPP mediates protein import, which is supported by preliminary data that indicate MPP both cleaves the targeting sequence and has a central role in protein translocation. (2) Determine how inhibiting Pink1 cleavage by MPP arrests translocation at the outer membrane and stimulates Parkin recruitment. Preliminary data supports that the MPP modulators can activate the Pink1/Parkin pathway and may be useful in model systems to selectively induce the pathway. Given the previous success in using small molecule modulators to characterize for protein translocation, exploiting these MPP modulators will provide mechanistic insight into how defects in mitochondrial assembly contribute to neurodegenerative diseases. This study is relevant to public health because it may lead to the development of new strategies to understand and treat degenerative neural diseases such as Friedreich's and Parkinson's diseases.