The 2 main apoptotic pathways. The “intrinsic” (mitochondrial) pathway is induced by intracellular stress signals leading to translocation of bcl-2 family members into the mitochondria. This induces alterations in mitochondrial permeability and consequent release of cytochrome C, which in association with apoptotic protease-activating factor 1 (APAF-1) activates caspase-9. The “extrinsic” (death-receptor) pathway is activated by the binding of ligands to tumor necrosis factor receptor (TNF-R) or FAS, inducing activation of caspase 8. Both caspase 8 and caspase-9 subsequently activate caspases-3, -6, and -7, which cleave substrates involved in the regulation of cell death.