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: 9113356
• 负责人: Eric Torres
• 金额: $ 3.65万
• 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/9113356
• 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; Health; 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; Parkinson Disease; Pathway interactions; Peptide Hydrolases; Peptides; Phosphotransferases; Play; Process; 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; Staging; Structure; Sum; System; Testing; Work; Yeasts; base; chemical genetics; frataxin; inhibitor/antagonist; insight; knock-down; mitochondrial dysfunction; mitochondrial processing peptidase; muscular system; neuroblastoma cell; novel; parkin gene/protein; parkin protein; relating to nervous system; research study; 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，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。线粒体不仅对能量的产生很重要，而且在中间代谢和信号传导等其他途径中也起着重要作用。不仅组装途径对线粒体功能很重要，而且蛋白质水解途径对蛋白质质量控制也很重要，蛋白质质量控制影响线粒体的生物发生、形态和稳态。弗里德赖希共济失调症可以由卵黄蛋白的突变引起，其中一个子集导致成熟缺陷。基质加工肽酶（MPP）对于frataxin的成熟以及大多数具有n端靶向序列的线粒体前体的成熟和折叠是必需的，包括Pink1和细胞内双定位的富马酸酶等蛋白质。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。本研究的目的是：(1)描述MPP介导蛋白质进口的机制，初步数据表明MPP既可以切割靶向序列，又在蛋白质易位中发挥核心作用。(2)确定MPP抑制Pink1切割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有用，以选择性地诱导该通路。鉴于之前使用小分子调节剂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，因为它可能导致开发新的策略来理解和治疗退行性神经疾病，如弗里德赖希病和帕金森病。