The role of mitochondrial reactive oxygen species in apoptosis
Reactive oxygen species (ROS) are a family of small but highly reactive molecules. Although it has been widely believed that ROS played important roles in apoptosis, the signaling role of ROS in apoptosis is still elusive. In addition, the enzymatic source of ROS in most apoptotic systems is currently not clear. The mitochondrion is one of the most important ROS producing sites in eukaryotic cells. By estimation, about 1–2% of the oxygen consumed by the respiratory chain can be converted to ROS in the mitochondria. Although tremendous progress has been achieved in our knowledge of the role of mitochondria in apoptosis, few studies have been conducted on the role of mitochondrial ROS in mitochondrial-initiated apoptosis. In the present investigation, mitochondrial respiratory chain complex I inhibitor-mediated mitochondrial ROS production was used as a model to study the roles of mitochondrial ROS in apoptosis. Several mitochondrial respiratory chain complex I inhibitors were used in this study. Mitochondrial ROS production induced by mitochondrial complex I inhibitors was characterized both at the mitochondrial level and the cell level. The effect of mitochondrial ROS on mitochondrial apoptotic pathways were studied. The possible involvement of cytosolic signaling pathways in mitochondrial ROS induced apoptosis was also investigated. A direct relationship between mitochondrial ROS and mitochondrial apoptotic pathway was demonstrated in several cell lines. Mitochondrial complex I inhibitors mediated mitochondrial ROS induced mitochondrial permeability transition, mitochondrial membrane potential, cytochrome c release, caspase 3 activation, and finally DNA fragmentation in the cells. Furthermore, we also showed that mitochondrial ROS could activate JNK and p38 MAPKs in the cytosol. The activation of JNK and p38 MAPKs by mitochondrial ROS is required in mitochondrial ROS-induced apoptosis.
Robinson, Purdue University.
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