ABSTRACT
Aberrant processes of cell death have been positively linked to the pathogenesis of a number of diseases including disorders of the central nervous system (reviewed in references 1 and 2). Cell death can be broadly separated into two polar categories termed apoptosis and necrosis. In apoptosis, or programmed cell death, cells display chromatin condensation, internucleosomal DNA cleavage, cytoplasmic shrinking and plasma membrane blebbing, and are phagocytosed by neighboring cells. This contrasts with necrosis, where cells swell and rupture, eliciting an inflammatory response. Mitochondria play a pivotal role in the genesis and propagation of apoptosis via events such as mitochondrial calcium accumulation, generation of free radicals and, perhaps, activation of permeability transition pores3. Four mitochondrial molecules mediating downstream cell-death pathways have been identified:
cytochrome c, Smac, apoptosis-inducing factor and endonuclease G. Cytochrome c binds to Apaf-1, which, together with procaspase-9, forms apoptosomes and, in turn, causes caspase9 and caspase-3 activation. Smac binds to inhibitors of activated caspases, resulting in further caspase activation. Apoptosis-inducing factor and endonuclease G act via caspaseindependent pathways to trigger cell death4-7. A schematic diagram showing the apoptotic cascades is shown in Figure 32.1.
