ACTIVATION OF MITOCHONDRIAL OUTER MEMBRANE PERMEABILIZATION BY BH3-ONL

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH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 中心，不一定是研究者的机构。 由于细胞间的能量需求因组织而异，有时对线粒体的更多能量需求必须通过在每个线粒体中产生更多的嵴膜来满足，其中ATP合成发生。因此，线粒体嵴膜的生物发生在动物的发育和衰老中起着重要的作用。最近的证据表明，Opa 1是至关重要的，在调节嵴交界处的大小和可及性的嵴内空间。在细胞凋亡过程中，Opa 1寡聚体被分解，细胞色素c在嵴内空间的可及性急剧增加。几年前，这一观察结果使斯科拉诺和同事们提出，细胞凋亡过程中嵴连接变宽，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连接的嵴内空间中，因此已经表明嵴和嵴连接的重塑是细胞色素c快速和完全释放的必要步骤。N/C-Bid诱导的嵴和嵴连接处的结构变化也建议通过观察细胞色素c对外膜反应伴侣的可及性增加。然而，嵴重塑在细胞凋亡中的作用是有争议的。因此，我们正在使用电子显微镜断层扫描来表征重构何时发生，何时不作为促凋亡效应物和分解Opa 1寡聚体的化合物治疗的函数。

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.