Figure 1.

Checkpoints for apoptosis in the mitochondrial pathway. Most mammalian cell death proceeds via the mitochondrial pathway, as illustrated. Stimuli for the induction of apoptosis predominantly act by engaging proapoptotic members of the Bcl-2 family, which work to cause MOMP, and this is countered by the antiapoptotic Bcl-2 family members. Other cell death stimuli can cause MOMP by the induction of a mitochondrial permeability transition. In either case, release of proteins from the intermembrane space triggers the activation of caspases via the formation of an Apaf-1 apoptosome, which recruits and activates caspase-9. This, in turn, cleaves and activates the executioner caspases. The activation of caspase-3, -7, and -9 is antagonized by XIAP, which in turn can be inhibited by Smac, Omi, and other proteins released upon MOMP. Not shown here are other pathways of caspase activation and apoptosis, including the death receptor pathway, and those resulting in activation of caspase-1 and -2 (see text). ANT, adenosine nuclear transporter; VDAC, voltage-dependent anion channel; IMS, intermembrane space; ΔΨ_m, mitochondrial transmembrane potential.