The intrinsic apoptosis signaling pathways that initiate apoptosis involve a diverse array of non-receptor-mediated stimuli that produce intracellular signals that act directly on targets within the cell and are mitochondrial-initiated events.
The stimuli that initiate the intrinsic apoptosis signaling pathway produce intracellular signals that may act in either a positive or negative fashion. Negative signals involve the absence of certain growth factors, hormones and cytokines that can lead to failure of suppression of death programs, thereby triggering apoptosis.
In other words, there is the withdrawal of factors, loss of apoptotic suppression, and subsequent activation of apoptosis. Other stimuli that act in a positive fashion include, but are not limited to, radiation, toxins, hypoxia, hyperthermia, viral infections, and free radicals.
All of these stimuli cause changes in the inner mitochondrial membrane that results in an opening of the mitochondrial permeability transition (MPT) pore, loss of the mitochondrial transmembrane potential and release of two main groups of normally sequestered pro-apoptotic proteins from the intermembrane space into the cytosol. The first group consists of cytochrome c, Smac/DIABLO, and the serine protease HtrA2/Omi. These proteins activate the caspase-dependent mitochondrial pathway. Cytochrome c binds and activates Apaf-1 as well as procaspase-9, forming an “apoptosome”.
The clustering of procaspase-9 in this manner leads to caspase-9 activation. Smac/DIABLO and HtrA2/Omi are reported to promote apoptosis by inhibiting IAP (inhibitors of apoptosis proteins) activity. Additional mitochondrial proteins have also been identified that interact with and suppress the action of IAP however gene knockout experiments suggest that binding to IAP alone may not be enough evidence to label a mitochondrial protein as “pro-apoptotic”.