DISRUPTION OF MITOCHONDRIAL FUNCTION DURING APOPTOSIS

这个子项目是许多利用 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。 在凋亡过程中，Bcl-2家族的促凋亡成员诱导线粒体外膜透化和细胞色素c释放，导致半胱天冬酶活化。活化的半胱天冬酶的第一个靶点是透化的线粒体本身，导致电子传递的破坏、线粒体跨膜电位的损失、ATP水平的下降、活性氧（ROS）的产生和线粒体结构完整性的损失。在2003年，我们确定了NDUFS 1，75 kDa的呼吸复合物I的亚基，作为一个主要的半胱天冬酶底物的线粒体。表达p75切割位点突变体（D255 A）的细胞在细胞凋亡期间维持ATP水平，并在响应细胞凋亡刺激时产生减少的活性氧。虽然细胞色素c的释放和DNA片段不受不可裂解的p75突变体的影响，线粒体形态保持在垂死的细胞，质膜完整性的损失被推迟。因此，半胱天冬酶切割NDUFS 1促进细胞凋亡中的线粒体变化。这项工作已提交出版。

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. During apoptosis, pro-apoptotic members of the Bcl-2 family induce mitochondrial outer membrane permeabilization and cytochrome c release resulting in caspase activation. Among the first targets of the activated caspases are the permeabilized mitochondria themselves, leading to disruption of electron transport, loss of mitochondrial transmembrane potential, decline in ATP levels, production of reactive oxygen species (ROS) and loss of mitochondrial structural integrity. In 2003, we identified NDUFS1, the 75 kDa subunit of respiratory complex I, as a major caspase substrate in the mitochondria. Cells expressing a cleavage site mutant of p75 (D255A) sustained and ATP levels during apoptosis and produced reduced ROS in response to apoptotic stimuli. While cytochrome c release and DNA fragmentation were unaffected by the uncleavable p75 mutant, mitochondrial morphology was maintained in the dying cells, and loss of plasma membrane integrity was delayed. Therefore, caspase cleavage of NDUFS1 promotes mitochondrial changes in apoptosis. This work has been submitted for publication.