Figure 1. The Extrinsic and the Intrinsic (Mitochondrial) Pathways of Apoptosis.

The extrinsic apoptotic pathway involves the activation of death receptors at the cell surface, followed by a caspase cascade that eventually leads to the execution of cell death. In contrast, different proapoptotic stimuli initiate the intrinsic pathway by triggering mitochondrial membrane permeabilization (MMP). Following MMP, intermembrane space proteins are released into the cytosol, the mitochondrial transmembrane potential (Δψ_m) is dissipated, and the bioenergetic and redox-detoxifying functions of mitochondria are compromised. The resulting bioenergetic and redox crises, associated with the activation of both caspase-dependent and -independent executioner mechanisms, commit the cell to death. The two pathways are interconnected by the BH3-only protein Bid, whose truncated form (tBid) is generated by caspase-8 and can target mitochondria to trigger MMP. For a more detailed description of the intrinsic and extrinsic pathways of apoptosis please refer to the Introduction and to [1]. DISC, death-inducing signaling complex; ER, endoplasmic reticulum.