Role of the mitochondrial matrix processing protease in mitochondrial biogenesis

线粒体基质加工蛋白酶在线粒体生物发生中的作用

• 批准号: 9302470
• 负责人: Eric Torres
• 金额: $ 3.69万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9302470
• 关键词: Alzheimer' s Disease; Attenuated; Biogenesis; Biological Models; Cardiovascular Diseases; Cell Line; Cells; Chemicals; Cleaved cell; Cytosol; Data; Defect; Degenerative Disorder; Development; Diabetes Mellitus; Disease; Event; Family; Friedreich Ataxia; Fumarate Hydratase; Genetic Screening; Goals; Homeostasis; Huntington Disease; Insulinase; Lead; Link; Malignant Neoplasms; Mammalian Cell; Mammals; Mediating; Membrane; Metabolism; Mitochondria; Mitochondrial Matrix; Mitochondrial Myopathies; Mitochondrial Proteins; Morphology; Mutation; Myopathy; N-terminal; Nerve Degeneration; Neurodegenerative Disorders; Neuropathy; Nuclear; PTEN-induced putative kinase; Parkinson Disease; Pathway interactions; Peptide Hydrolases; Peptides; Phosphotransferases; Play; Production; Protein Export Pathway; Protein Import; Protein translocation; Proteins; Proteolytic Processing; Public Health; Quality Control; RNA Interference; Recombinants; Recruitment Activity; Research; Role; Series; Signal Transduction; Structure; Sum; System; Testing; Work; Yeasts; base; chemical genetics; experimental study; frataxin; inhibitor/antagonist; insight; knock-down; mitochondrial dysfunction; mitochondrial processing peptidase; muscular system; neuroblastoma cell; novel; parkin gene/protein; parkin protein; public health relevance; relating to nervous system; response; small molecule; small molecule inhibitor; success; tool; trafficking; translational study

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.

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、心血管疾病以及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。线粒体对于能量的产生很重要，并且在中间代谢和信号传导等其他途径中也发挥着重要作用。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​​制也至关重要，这会影响线粒体的生物发生、形态和稳态。弗里德赖希的共济失调可能是由 frataxin 突变引起的，其中一部分会导致成熟缺陷。基质加工肽酶 (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的成熟和折叠所必需的，包括 Pink1 和细胞内双重定位的蛋白质（如延胡索酶）。本研究的目的是表征在化学遗传筛选中鉴定出的新型 MPP 小分子调节剂。该提案的目的是：（1）描述 MPP 介导蛋白质输入的机制，初步数据表明 MPP 既能切割靶向序列，又能在蛋白质易位中发挥核心作用。 (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，并且可能在模型系统中选择性诱导该通路有用。鉴于之前使用小分子调节剂来表征蛋白质易位的成功，利用这些 MPP 调节剂将为线粒体组装缺陷如何导致神经退行性疾病提供机制见解。这项研究与公共卫生相关，因为它可能会导致开发新策略来理解和治疗弗里德赖希病和帕金森病等退行性神经疾病。