Biogenesis of mitochondrial apoptotic proteins

线粒体凋亡蛋白的生物发生

• 批准号: 7544524
• 负责人: Carla M Koehler
• 金额: $ 27.92万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2010-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7544524
• 关键词: Abbreviations; Animal Model; Apoptosis; Apoptosis Inhibitor; Apoptotic; Binding Proteins; Biochemical; Biogenesis; Caspase; Categories; Cell Culture Techniques; Cell Death; Cell Line; Cells; Cessation of life; Collaborations; Coupled; Cultured Cells; DNA; Data; Defect; Development; Disease; Event; Exonuclease; Family; Free Radicals; Genetic; Goals; Home environment; Housing; Individual; Investigation; Knockout Mice; Laboratories; Life; Link; Lipids; Liver Mitochondria; Maintenance; Malignant Neoplasms; Mammals; Mediating; Membrane; Membrane Potentials; Metabolism; Mitochondria; Modeling; Molecular; Mus; Neurodegenerative Disorders; Omi serine protease; Organelles; Outer Mitochondrial Membrane; Oxidative Phosphorylation; Pathology; Pathway interactions; Peptide Hydrolases; Permeability; Phosphate Carriers; Play; Polypyrimidine Tract-Binding Protein; Polyribonucleotide Nucleotidyltransferase; Process; Production; Protein Import; Proteins; Proteolytic Processing; Public Health; RNA; RNA Degradation; RNA Helicase; RNA Interference; Research Personnel; Respiration; Role; Saccharomyces cerevisiae; Serum; Starvation; Structure; System; TOM translocase; Time; Work; Yeasts; apoptosis inducing factor; base; cytochrome c; dicarboxylate-binding protein; endonuclease G; falls; insight; knock-down; member; mitochondrial dysfunction; mitochondrial processing peptidase; novel; novel strategies; outer space; pro-apoptotic protein; programs; protein degradation; release factor; research study; translocase

In addition to a central role in metabolism, mitochondria play a critical role in apoptosis/programmed cell death. The mitochondrial intermembrane space is home to several apoptotic components that mediate the degradation of proteins (cytochrome c, Smac/DIABLO, HtrA2/OMI), DNA (apoptosis inducing factor (AIF), and Endonuclease G), and, from our current studies, RNA (PNPase). Many pro- and anti-apoptotic proteins of the Bcl-2/Bax family are targeted to the mitochondrial outer membrane. Additionally, proteins normally resident to other subcellular compartments, such as Nur77 and Mud /are also targeted to mitochondria during apoptosis. Resident proteins of the mitochondrion follow very specific pathways for import and assembly in the organelle. Presumably, these apoptotic proteins utilize specific pathways for biogenesis that are important for their highly regulated role in apoptosis. The goal of this proposal is to use a combined genetic and biochemical approach in isolated mitochondria, S. cerevisiae, cell culture, and animal models to characterize the biogenesis of the mitochondrial intermembrane space apoptotic proteins. The first objective of this proposal is to characterize the import pathway of representatives in the various categories, based on the target of degradation (ie., DNA, protein, or RNA), beginning with PNPase. The second objective is to investigate the assembly and release of PNPase from the intermembrane space. The final objective is to investigate the role of PNPase in maintaining respiration and its link to apoptosis because loss of PNPase disrupts oxidative phosphorylation and lowers the membrane potential. In contrast to previous studies that have focused primarily on the individual components, this proposal will focus specifically on the events related to the biogenesis of apoptotic proteins in the mitochondrial intermembrane space and thus provide novel insights into the role of this compartment in programmed cell death. We will determine if the different apoptotic proteins might share conserved biogenesis pathways, which could be an ideal target for the development of new approaches to modulate several apoptotic pathways at one time. This application has a broader impact in public health because the mitochondrial events linked to apoptosis contribute to cancer and neurodegenerative diseases.

除了新陈代谢中的核心作用外，线粒体在凋亡/程序性细胞中起关键作用 死亡。线粒体膜间空间是几个介导的凋亡成分的家园 蛋白质（细胞色素C，SMAC/Diablo，Htra2/Omi）的降解，DNA（凋亡诱导因子（AIF），，，，， 核酸内切酶g），以及我们目前的RNA（PNPase）。许多促凋亡蛋白 Bcl-2/Bax家族的靶向线粒体外膜。另外，蛋白质通常 居民居住在其他亚细胞室，例如Nur77和Mud /也针对线粒体 在凋亡期间。线粒体的居民蛋白质遵循非常具体的进口途径 在细胞器中的组装。据推测，这些凋亡蛋白利用特定途径进行生物发生 对于它们在凋亡中高度调节的作用非常重要。该提议的目的是结合使用 分离的线粒体，酿酒酵母，细胞培养和动物模型的遗传和生化方法 表征线粒体间膜间空间凋亡蛋白的生物发生。第一个目标 该建议的是根据基于各个类别的代表的进口途径的表征 从PNPase开始的降解靶标（即DNA，蛋白质或RNA）。第二个目标是 研究PNPase从膜间空间的组装和释放。最终目标是 研究PNPase在维持呼吸中的作用及其与凋亡的联系，因为丧失PNPase 破坏氧化磷酸化并降低膜电位。与以前的研究相比 该提案主要集中在单个组件上，将专门针对事件 与线粒体膜间空间中凋亡蛋白的生物发生有关，因此提供 新的见解对该隔室在程序性细胞死亡中的作用。我们将确定是否不同 凋亡蛋白可能共享保守的生物发生途径，这可能是 开发新方法一次调节几种凋亡途径。该应用程序具有 对公共卫生的更广泛影响，因为与凋亡有关的线粒体事件有助于癌症 和神经退行性疾病。