Figure 3.

 Mitochondria mediated (intrinsic) pathway of apoptosis. Various stimuli, including ultraviolet (UV) and γ-irradiation, endoplasmic reticulum (ER) stress, growth factor deprivation, and oxidative stress with production of reactive oxygen species (ROS) trigger the intrinsic pathway via activation of proapoptotic members of the Bcl-2 family of protein (that is, Bax, Bak), which oligomerise on the outer mitochondrial membrane and cause mitochondrial dysfunction. The proapoptotic action of Bax and Bak can be antagonised by the antiapoptotic members of the same family Bcl-2 or Bcl-X_L. Following mitochondrial dysfunction, several apoptogenic factors, including cytochrome c and second mitochondria derived activator of caspases/direct IAP binding protein with low pI (SMAC/DIABLO), are released from the mitochondrial intermembrane space into the cytosol. Cytochrome c binds to the adaptor apoptosis associated factor 1 (Apaf-1) and recruits procaspase-9 to form a complex named apoptosome which, in an APT requiring reaction, results in activation of the initiator caspase-9. Caspase-9, in turn, activates the effector caspases (caspase-3, -6, and -7) responsible for degradation of cellular substrates. SMAC/DIABLO contributes to caspase activation by binding and inactivating the endogenous inhibitor of caspases IAPs.