3.
Apoptosis pathwaysSo far, two intracellular apoptosis-signaling pathways have been identified, the
receptor pathway and the mitochondrial pathway (Figure 1).
Figure 1. Apoptosis pathways.
Two intracellular apoptosis-signaling pathways have been identified, the receptor
pathway and the mitochondrial pathway. (i) The receptor pathway is activated
through ligand binding to plasma membrane receptors (Fas/CD95, TNFα, and
TRAIL). Ligand binding induces oligomerization of the receptors and recruitment
of adapter proteins and inactive procaspases, such as caspase-8. The procaspase is
proteolytically activated at the receptor complex, and the active enzyme is released
into the cytosol, where it activates downstream executioner caspases, such as
caspase-3 or –7. (ii) The mitochondrial pathway is activated by a wide range of
stimuli, including toxins, UV and gamma irradiation, hypoxia, staurosporine, and
growth factor deprivation. All these stimuli result in the activation of pro-apoptotic
multidomain Bcl-2 proteins, such as Bax or Bak. The proteins oligomerize and
induce permeabilization of the outer mitochondrial membrane, through formation
of large high-conductance channels in the membrane. Cytochrome c and other
intermembrane proteins are released into the cytosol, where cytochrome c forms a
complex with Apaf-1, procaspase-9, and dATP, referred to as the apoptosome. In
the apoptosome, the inactive procaspase-9 is activated through proteolytic cleavage.
The active enzyme subsequently activates downstream caspases, such as caspase-3.
In some cell types, caspase-8 activated by the receptor pathway cleaves the ‘BH3-
domain-only’ protein Bid. The C-terminal fragment of Bid (tcBid) induces
activation of the multidomain proteins and activates the mitochondrial pathway.MITOCHONDRIA IN APOPTOSIS INDUCTION 123