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; 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）：线粒体功能的缺陷有助于多种疾病，包括癌症，心血管疾病以及退化性神经和肌肉疾病，包括弗里德里希的共济失调和帕金森氏症，阿尔茨海默氏症和亨廷顿的疾病。线粒体对于能量的产生很重要，并且在其他途径中也起着重要作用，例如中介代谢和信号传导。组件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​​制至关重要，这会影响线粒体的生物发生，形态和稳态。 Friedreich的共济失调可能是由Frataxin突变引起的，Frataxin的突变会导致成熟缺陷。基质加工肽酶（MPP）是Frataxin成熟以及具有N末端靶向序列的大多数线粒体前体的成熟和折叠所必需的，包括粉红色1和蛋白质（如富马酶）在细胞内双重定位。这项研究的目的是表征在化学遗传筛选中鉴定出的新型MPP的新型小分子调节剂。该提案的目的是：（1）表征MPP介导蛋白质进口的机制，该机制由初步数据支持，这表明MPP既裂解靶向序列又在蛋白质转移中具有核心作用。 （2）确定如何通过MPP抑制PINK1裂解如何在外膜上易位并刺激Parkin的募集。初步数据支持MPP调节器可以激活Pink1/Parkin途径，并且在模型系统中可能有用以选择性诱导该途径。鉴于先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调节剂将提供机械性的见解，以了解线粒体组件中的缺陷如何有助于神经退行性疾病。这项研究与公共卫生有关，因为它可能导致发展新策略，以理解和治疗弗里德里希（Friedreich's）和帕金森（Parkinson）的疾病等退化性神经疾病。