RNA trafficking in mitochondria

线粒体中的RNA运输

基本信息

批准号：
8541028
负责人：
Carla M Koehler
金额：
$ 28.47万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-01-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8541028
关键词：
Abbreviations Address Adenine Nucleotide Translocase Albumins Area Binding Biochemical Bioenergetics Biogenesis Biological Models Biology Cardiomyopathies Cell Energetics Cell Nucleus Cells Cessation of life Code Collaborations Complement Complex Cytomegalovirus Cytosol DNA biosynthesis Defect Development Disease Disease model Electron Transport Embryo Energy Metabolism Enterobacteria phage P1 Cre recombinase Enzymes Eukaryota Eukaryotic Cell Exonuclease Fibroblasts Free Radicals Gene Expression Genes Genetic Genetic Transcription Genome Glycolysis Goals Health Hepatocyte Human In Vitro Inherited Knock-out Knockout Mice Knowledge Laboratories Lead Letters Life Link Liver Mammalian Cell Mammalian Genetics Mammals Mediating Membrane Membrane Potentials Metabolic Metabolism Methods MicroRNAs Mitochondria Mitochondrial DNA Mitochondrial Diseases Mitochondrial Myopathies Mitochondrial Proteins Mitochondrial RNA Modeling Mus Mutation Natural regeneration Nature Nerve Degeneration Nervous System Heredodegenerative Disorders Neurodegenerative Disorders Neuropathy Nuclear Organelles Organism Oxidative Phosphorylation Pathology Pathway interactions Peptide Hydrolases Phosphate Carriers Physiological Play Point Mutation Polyribonucleotide Nucleotidyltransferase Process Production Progress Reports Protein Import Proteins Public Health RNA RNA Binding RNA Interference RNA Sequence Analysis RNA primers RNA, Ribosomal, 5S RNase P Reverse Transcriptase Polymerase Chain Reaction Ribonucleases Ribosomes Role Serum Signal Transduction Starvation Structure System TOM translocase Therapeutic Time Tissues Transfer RNA Translations Universities Yeasts disease-causing mutation fly in vivo insight knock-down loss of function mitochondrial dysfunction mitochondrial processing peptidase mouse model public health relevance receptor research study tool trafficking transcriptome sequencing translation factor translocase viral RNA

项目摘要

DESCRIPTION (provided by applicant): Mitochondria are essential organelles found in most eukaryotic cells and provide for diverse metabolic functions including the production of energy and specialized metabolites. Mitochondria require proteins and RNAs coded both by the mitochondrial and nuclear genomes. In humans, at least 1000 nuclear encoded proteins are imported into mitochondria, whereas 13 proteins are coded by mitochondrial genes. The translation of this limited number of mitochondrial coded proteins requires mitochondrial ribosomes, translation factors, and transfer RNAs. Recent studies in evolutionarily diverse organisms have shown that various RNA components are coded in the nucleus and imported from the cytosol into mitochondria. Whereas the understanding of import pathways for mitochondrial proteins is very detailed, very little is understood about the mechanism of RNA import, let alone the specific RNA substrates that are imported. The overall goal of this proposal is to dissect the pathway of RNA import into mitochondria, identify the RNA species that are imported, and determine pathological consequences when RNA import is inhibited. The RNA-binding enzyme PNPase localizes to the mitochondrial intermembrane space and seems to function as a receptor for RNAs that are imported from the cytosol. In addition, PNPase is only present in organisms such as flies, worms, and mammals, suggesting it functions in higher eukaryotes. To accomplish the proposed goals, the following specific aims are planned: In Aim 1, the biochemical role of PNPase in the import and biogenesis of RNA in the mitochondrion will be determined. In Aim 2, a conditional mouse model in which PNPase can be knocked down in a controlled manner will be characterized to determine the physiologic function of PNPase and the consequences of PNPase loss in mitochondrial function. Finally, in Specific Aim 3, the role of PNPase in RNA import in vivo will be investigated. A mutation in PNPase has been linked to a neurodegenerative disease, suggesting PNPase plays an important role in health and disease. In addition to the fundamental knowledge, characterization of the RNA import pathway can open a new door to develop methods for treating severe pathological diseases associated with mutations in mitochondrial tRNAs or mitochondrial genes. This application has a broader impact in public health because mutations in PNPase have been linked to neurodegeneration. PUBLIC HEALTH RELEVANCE: This proposal is relevant to public health because mutations in the gene PNPase have been linked to a hereditary neurodegenerative disease. Characterization of this disease will provide insight into how mitochondrial dysfunction contributes to neurodegeneration.

描述（由申请人提供）：线粒体是大多数真核细胞中发现的重要细胞器，提供多种代谢功能，包括产生能量和专门代谢物。线粒体需要由线粒体和核基因组编码的蛋白质和 RNA。在人类中，至少有 1000 种核编码蛋白被输入线粒体，而 13 种蛋白是由线粒体基因编码的。有限数量的线粒体编码蛋白的翻译需要线粒体核糖体、翻译因子和转移 RNA。最近对进化多样化生物体的研究表明，各种 RNA 成分在细胞核中编码，并从细胞质导入线粒体。尽管对线粒体蛋白输入途径的了解非常详细，但对 RNA 输入的机制了解甚少，更不用说输入的特定 RNA 底物了。该提案的总体目标是剖析 RNA 输入到线粒体的途径，识别输入的 RNA 种类，并确定 RNA 输入受到抑制时的病理后果。 RNA 结合酶 PNPase 定位于线粒体膜间隙，似乎充当从胞质溶胶输入的 RNA 的受体。此外，PNPase 仅存在于苍蝇、蠕虫和哺乳动物等生物体中，表明它在高等真核生物中发挥作用。为了实现所提出的目标，计划了以下具体目标：在目标 1 中，将确定 PNPase 在线粒体中 RNA 的输入和生物合成中的生化作用。在目标 2 中，将表征 PNPase 可以以受控方式被敲低的条件小鼠模型，以确定 PNPase 的生理功能以及 PNPase 丧失对线粒体功能的影响。最后，在具体目标 3 中，将研究 PNPase 在体内 RNA 输入中的作用。 PNPase 的突变与神经退行性疾病有关，表明 PNPase 在健康和疾病中发挥着重要作用。除了基础知识之外，RNA 输入途径的表征还可以为开发治疗与线粒体 tRNA 或线粒体基因突变相关的严重病理疾病的方法打开一扇新的大门。该应用对公共健康具有更广泛的影响，因为 PNPase 突变与神经退行性疾病有关。公共健康相关性：该提案与公共健康相关，因为 PNPase 基因的突变与遗传性神经退行性疾病有关。这种疾病的特征将有助于了解线粒体功能障碍如何导致神经变性。