Role of the mitochondrial matrix processing protease in mitochondrial biogenesis

描述(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Friedreich‘s共济失调和帕金森氏症、阿尔茨海默氏症和亨廷顿氏病。线粒体对能量的产生很重要，在其他途径中也扮演着重要的角色，如中间代谢和信号传递。组装途径不仅对线粒体的功能很重要，而且蛋白质分解途径对蛋白质质量控制也是必不可少的，蛋白质质量控制影响线粒体的生物发生、形态和动态平衡。Friedreich‘s共济失调可能是由Frataxin突变引起的，Frataxin突变的子集导致成熟缺陷。基质处理多肽酶(MPP)是Frataxin成熟以及大多数具有N末端靶向序列的线粒体前体成熟和折叠所必需的，包括PINK1和细胞内双重定位的延胡索酶等蛋白质。这项研究的目标是表征在化学遗传筛选中发现的针对MPP的新型小分子调节剂。这项建议的目的是：(1)表征MPP介导蛋白质输入的机制，这一机制得到了初步数据的支持，这些数据表明MPP既切割靶向序列，又在蛋白质转位中发挥中心作用。(2)确定MPP抑制PINK1裂解如何阻止外膜易位并刺激Parkin募集。初步数据支持，MPP调节剂可以激活PINK1/Parkin通路，并可能在模型系统中用于选择性地诱导该通路。鉴于以前成功地使用小分子调节器来表征蛋白质易位，利用这些MPP调节器将提供对线粒体组装缺陷如何导致神经退行性疾病的机械性洞察。这项研究与公共卫生有关，因为它可能导致开发新的策略来理解和治疗退行性神经疾病，如Friedreich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.