Figure 9. Overview of death-signalling pathways in mammalian cells.

The death receptor pathway (left) is initiated by the binding of a ligand (Eg: FasL) to its receptor Fas, which results in the sequential recruitment of FADD and pro-caspase-8. c-FLIP can block the recruitment of pro-caspase-8 to the complex. The proximity of several pro-caspase-8 molecules results in its activation. Caspase-8 can proteolytically activate caspase-3, or it can cleave Bid to its truncated form t-Bid, which binds to Bax and gets integrated into the mitochondrial membrane to release cytochrome c. In response to various cellular stress-induced apoptotic stimuli, the intrinsic mitochondrial pathway is activated. This pathway involves the translocation of proapoptotic molecules such as Bax from the cytosol to the mitochondrial membrane. Bax can release cytochromec from the mitochondria into the cytosol. Cytochromec associates with Apaf-1 and caspase-9 to form the apoptosome and subsequent activation of caspase-3. Mitochondria also release AIF and Endo G, which may exert their effects on the nuclei. Mitochondria released Smac/Diablo and Omi/HtrA2 sequesters inhibitors of apoptosis (IAPs) to prevent them from inhibiting caspase-3. BNIP3 is a Bcl2 family member that is translocated and integrated into the mitochondria. Unlike other Bcl2 family members, BNIP3 can induce necrotic cell death in response to death stimuli. Activation of poly (ADP-ribose) polymerase (PARP) leads to NAD+ depletion and may induce mitochondrial depolarization to release AIF. ROS, reactive oxygen species. Legend and Figure from citation (320).