ACTIVATION OF MITOCHONDRIAL OUTER MEMBRANE PERMEABILIZATION BY BH3-ONL

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 由于不同组织对细胞间能量的需求不同，有时必须通过在进行ATP合成的每个线粒体中创建更多的冠膜来满足对线粒体的更多能量需求。因此，线粒体脊膜的生物发生在动物的发育和衰老中都起着重要的作用。最近的证据表明，OPA1在调节眼眶连接大小和晶状体内间隙的可达性方面起着至关重要的作用。在细胞凋亡过程中，OPA1寡聚体被分解，细胞色素c在牙髓腔内的可获得性显著增加。几年前，这一观察结果导致Scorrano和他的同事提出，在细胞凋亡过程中，克里斯塔连接变得更宽，从晶体内间隙释放细胞色素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相连的晶体内间隙中，因此有人认为，在细胞色素c快速和完全释放的过程中，细胞色素c的重塑是必需的步骤。通过观察到细胞色素c与外膜反应伙伴的可及性增加，也表明N/C-Bid诱导的细胞色素c结构变化。然而，眼底重塑在细胞凋亡中的作用仍存在争议。因此，我们正在使用电子显微镜断层扫描来表征何时发生重塑，何时没有重塑，这是通过促凋亡效应和分解OPA1寡聚体的化合物进行治疗的结果。

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.