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Apoptosis (aka programmed cell death) is a cell suicide mechanism that is activated through the mitochondria due to cell stress (intrinsic pathway) or initiated via death receptors that sense extracellular death signals through ligand binding (extrinsic pathway). Death Receptors belong to the tumor necrosis factor (TNF) super family, which include TNFR1, Fas, DR3, TRAILR1, TRAILR2, DR6, EDAR, and NGFR. When death receptors are bound by their corresponding ligands, the receptors’ intracellular death domain (DD) interacts with the signaling adaptor Fas-associated death domain (FADD) through the TNFR-associated death domain (TRADD). FADD also associates with pro-caspase 8 or 10 to form death inducing signalling complexes (DISCs) which invoke downstream signal cascades that lead to apoptosis.

Apoptosis that occurs through the intrinsic pathway is induced by injury within the cell. Examples of intracellular stresses include oncogenes, hypoxia, direct DNA damage, growth factor withdrawal, and survival factor deprivation. These intrinsic stresses are detected by p53 which triggers pro-apoptotic Bcl-2 family members that inactivate anti-apoptotic Bcl-2 proteins and cIAPs (cellular Inhibitors of Apoptosis). As a result, destabilization of the mitochondrial membrane occurs due to permeabilization. The damaged mitochondria leaks apoptotic factors, such as SMAC (Second Mitochondria-Derived Activator of Caspase) and Cytochrome c, into the cytosol and sets off the caspase proteolytic cascade which destroys the cell from within, eventually ending with cell death.

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