Mechanisms of apoptotic cell death. Cell death via apoptosis can be triggered in defective or unwanted cells via extrinsic or intrinsic means. Ligation of death receptors (extrinsic pathway) leads to the activation of caspase 8, which in turn activates the executioner caspase, caspase 3. Activation of caspase 3 is either direct, or mediated via ‘activation’ of BH3-only proteins. These latter proteins bind to prosurvival Bcl-2 family proteins, releasing their hold on proapoptotic Bcl-2 proteins (Bak/Bax) and allowing them to form pores within the outer mitochondrial membrane, thus causing mitochondrial outer membrane permeabilization (MOMP). The release of cytochrome c (CytC) from the mitochondrial intermembrane space leads to assembly of the apoptosome, leading to caspase 3 activation and substrate proteolysis. Subsequent exposure of phosphatidylserine (PS) provides a major clearance signal for phagocytes. Activation of the intrinsic apoptotic pathway through exposure to radiation, hypoxia, DNA damage or reactive oxygen species (ROS) results in direct activation of BH3-only proteins, with eventual caspase 3 activation. Note: Underlined are the elements of the apoptotic machinery identified in platelets thus far.