Figure 1.

Programmed cell death can be executed via extrinsic and intrinsic pathways depending on the stimulus leading to apoptosis. In the intrinsic apoptotic pathway, pro-apoptotic signals (such as pro-apoptotic Bcl-2 family proteins Bax and Bak) translocate to mitochondria, resulting in mitochondrial membrane permeabilization. This in turn provides a route for release of intermembrane space proteins (such as cytochrome c (Cyt c), apoptosis inducing factor (AIF), Endo G and Smac/DIABLO (Second mitochondria-derived activator of caspase/direct inhibitor of apoptosis protein binding protein with a low pI)) into the cytosol. Once in the cytosol, cytochrome c promotes the formation of the 'apoptosome', a molecular platform for the activation of caspase-9. In turn, active caspase-9 catalyzes the proteolytic activation of caspase-3. This leads to DNA fragmentation and chromatin condensation. Caspase 3 may also serve to amplify the initial death signal by helping to promote further cytochrome c release from mitochondria. Smac/DIABLO and Omi stress-regulated endoprotease/high temperature requirement protein A2 (Omi/HtrA2) promote apoptosis indirectly by binding to and antagonizing members of the inhibitor of apoptosis protein (IAP) family. AIF and Endo G, on the other hand, translocate from the cytosol to the nuclear compartment, leading to DNA fragmentation and chromatin condensation. Extrinsic signals bind to their receptors and trigger intracellular signaling, leading to caspase-8 activation. Activation of caspase-8 by extrinsic stimuli (such as tumor necrosis factor-α, Fas ligand) involves mitochondria-dependent signaling (in type II cells) and results in cleavage of the pro-apoptotic Bcl-2 family protein Bid to t-Bid. Translocation of t-Bid to the mitochondria is believed to be one of the signals for mitochondrial events during apoptosis. In type I cells, on the other hand, execution of apoptosis occurs without significant participation of mitochondria. APAF-1, apoptosis protease activating factor 1; ER, endoplasmic reticulum.