ACTIVATION OF MITOCHONDRIAL OUTER MEMBRANE PERMEABILIZATION BY BH3-ONL

BH3-ONL 激活线粒体外膜透化

• 批准号: 7957616
• 负责人: DONALD DAVID NEWMEYER
• 金额: $ 0.94万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-15 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7957616
• 关键词: ATP Synthesis Pathway; Aging; Animals; Apoptosis; Biogenesis; Computer Retrieval of Information on Scientific Projects Database; Crista ampullaris; Development; Electron Microscope; Funding; Grant; Image Analysis; Institution; Membrane; Mitochondria; Outer Mitochondrial Membrane; Play; Reaction; Research; Research Personnel; Resources; Role; Source; Tissues; United States National Institutes of Health; crista membrane; cytochrome c; meetings; tomography

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Since the intercellular energy needs are different from tissue to tissue, sometimes demands made on mitochondria for more energy must be met by creating more cristae membrane in each mitochondrion where ATP synthesis take place. Thus the biogenesis of mitochondrial cristal membrane plays an important role both in development and in aging of animals. Recent evidence suggests that Opa1 is critical in regulating the crista junction size and the accessibility of the intracristal space. During apoptosis, Opa1 oligomers are disassembled and accessibility of cytochrome c in the intracristal space increases dramatically. Several years ago, this observation led Scorrano and colleagues to suggest that crista junctions become wider during apoptosis, releasing cytochrome c from intracristal spaces. As roughly 85% of total mitochondrial cytochrome c resides within intracristal spaces that are connected to the IMS by relatively narrow crista junctions, it has been suggested that the remodeling of cristae and crista junctions is a required step in the rapid and complete release of cytochrome c. N/C-Bid-induced structural changes in cristae and crista junctions are also suggested by observations of increased accessibility of cytochrome c to reaction partners at the outer membrane. However, the role of crista remodeling in apoptosis is controversial. Hence we are using electron microscope tomography to characterize when remodeling occurs and when it doesn't as a function of treatment with proapoptotic effectors and compounds that disassemble Opa1 oligomers.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 由于不同组织的细胞间能量需求不同，有时必须通过在发生 ATP 合成的每个线粒体中创建更多嵴膜来满足线粒体对更多能量的需求。因此，线粒体晶膜的生物发生在动物的发育和衰老中起着重要作用。最近的证据表明，Opa1 对于调节嵴连接处的大小和嵴内空间的可及性至关重要。在细胞凋亡过程中，Opa1 寡聚体被分解，晶体内细胞色素 c 的可及性急剧增加。几年前，Scorrano 及其同事根据这一观察结果提出，细胞凋亡过程中嵴连接处变宽，从嵴内空间释放细胞色素 c。由于大约 85% 的线粒体细胞色素 c 存在于通过相对狭窄的嵴连接与 IMS 连接的嵴内空间内，因此有人认为，嵴和嵴连接的重塑是细胞色素 c 快速、完全释放的必要步骤。观察到细胞色素 c 与外膜反应伙伴的可及性增加，也表明 N/C-Bid 诱导的嵴和嵴连接处的结构变化。然而，嵴重塑在细胞凋亡中的作用存在争议。因此，我们使用电子显微镜断层扫描来表征重塑何时发生以及何时不发生，作为促凋亡效应物和分解 Opa1 寡聚物的化合物治疗的函数。