Released cytochrome c then triggers the assembly of the cytoplasmic apoptosome. The apoptosime is a protein complex of apoptotic protease activating factor 1 (Apaf1), cytochrome c, and procaspase-9; this is the engine that drives caspase-3 activation in mammalian cells (Figure 1) [125]. Bcl-2 and Bcl-xL block the release of cytochrome c [137,138] from mitochondria and thus the activation of caspase-3 (Figure 1) [125,126]. This Bcl-2 and Bcl-xL mediated retention of mitochondrial cytochrome c [126,139] is caused by inhibition of Bax channel-forming activity in the outer mitochondrial membrane [135] or by modulation mitochondrial membrane potential and volume homeostasis [139]. BH3-only proteins such as Bim, Bid, Puma, and Noxa appear to induce a conformational change in Bax or they serve as decoys for Bcl-xL that allow Bax to form pores in the outer mitochondrial membrane [140]. Cells without bax and bak genes are resistant to mitochondrial cytochrome c release during apoptosis [141].