Mitochondrial calcium and reactive oxygen species in neural apoptosis.

摘要

Growing evidence suggest the involvement of neural apoptosis in mediating cell loss observed in a variety of neurodegenerative conditions. Elevations in calcium and reactive oxygen species (ROS) have been implicated in mediating neural apoptosis. However the mechanism(s) by which increases in calcium and ROS occur and mediate such cell loss is unclear. Because mitochondria are involved in both calcium and ROS homeostasis these subcellular organelles are uniquely suited to play a pivotal role in neural apoptosis. For example, mitochondria have been demonstrated to be necessary for apoptosis in cell free systems. Alterations in mitochondrial physiology are early and necessary events in a variety of apoptotic settings. Lastly, mitochondrial derived factors have been shown to be required for apoptotic cell loss. Taken together, these data support a possible role for mitochondria in mediating calcium and oxyradical induced neural loss.; The present study examines the role of elevated mitochondrial calcium and mitochondrial free radical levels in neural apoptosis following a variety of apoptotic stimuli. Studies carried out in neural derived PC6 cells, a PC12 subclone, demonstrate that increases in mitochondrial calcium and free radical levels occurred early (within three hours) following administration of a variety of apoptotic insults. Cells engineered to overexpress the mitochondrial antioxidant enzyme manganese superoxide dismutase exhibited attenuated increases in mitochondrial calcium, mitochondrial ROS, and cell loss following apoptotic insults. Agents which prevented increases in mitochondrial calcium and oxyradicals attenuated cell loss in such conditions. Studies using pharmacological inhibitors demonstrate the involvement of the mitochondrial permeability transition in increased mitochondrial calcium, mitochondrial ROS, and apoptosis. Taken together, these data indicate that alterations in mitochondrial calcium and oxyradical homeostasis are early events in neural apoptosis.