DISRUPTION OF MITOCHONDRIAL FUNCTION DURING APOPTOSIS

点击翻译按钮获取中文摘要

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.