EFFECTS OF OXIDATIVE STRESS ON MITOCHONDRIA FUNCTION IN RELATION TO APOPTOSIS

这个子项目是许多研究子项目中的一个 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来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 线粒体不仅对细胞的能量状态起重要作用，而且是决定细胞生死的致命细胞器。线粒体通过表达促凋亡因子、从线粒体膜间隙释放细胞色素c来调节细胞死亡。 氧化应激（Oxidative stress）是线粒体在氧化磷酸化过程中产生的一种应激反应，在调节线粒体功能中起重要作用，与多种人类疾病有关，包括癌症、神经退行性疾病和心血管疾病。例如，缺血性心脏病与心脏细胞线粒体的氧化损伤有关。因此，了解氧化应激如何影响线粒体的功能至关重要。本研究拟以芽殖酵母为模型生物，研究氧化应激对线粒体功能的影响及其与细胞凋亡的关系。这项研究将集中在Mcd 1，一个亚基的cohesin复合物。我们最近报道（Yang et al.，2008），在氧化应激时，Mcd 1被半胱天冬酶样蛋白酶Eps 1切割。然后，Mcd 1的裂解的C-末端片段从细胞核易位到线粒体，引起细胞色素c的释放并增强凋亡性细胞死亡。在这个计划中，我们计划使用细胞，分子和生物化学技术来破译这种易位的分子机制及其对线粒体功能的影响。

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. Mitochondria are not only important for the energetic status of the cell, but also the fatal organelles deciding about the cellular life and death. Mitochondria regulate cell death via the expression of pro-apoptotic factors, release of cytochrome c from the mitochondrial inter-membrane space. Oxidative stress, caused in part by mitochondria during the process of oxidative phosphorylation, plays an important role in regulating the function of mitochondria.Oxidative stress has been implicated to several human diseases, including cancer, neurodegenerative disorder, and cardiovascular diseases. Ischemic heart disease, for example, has been linked to oxidative damages to mitochondria of heart cells. It is therefore critical to understand how oxidative stress affects the function of mitochondria. In this project, we propose to study the effects of oxidative stress on mitochondria function relation to apoptosis, using budding yeast as a model organism. The study will focus on Mcd1, a subunit of the cohesin complex. We recently reported (Yang et al., 2008) that upon oxidative stress, Mcd1 is cleaved by a caspase-like protease Eps1. The cleaved C-terminal fragment of Mcd1 is then translocated from nucleus to mitochondria, causing the release of cytochrome c and enhancing the apoptotic cell death. In this proposal, we plan to use cellular, molecular and biochemical techniques to decipher the molecular mechanism of this translocation and its effects on the function of mitochondria.