Mitochondrial Proteins

An alteration in the permeability of the mitochondrial membrane is a hallmark of the intrinsic pathway of caspase activation. This change in permeability leads to the cytosolic release of multiple proteins, including cytochrome c, Smac/Diablo, HTRA2/Omi, Apoptosis Inducing Factor (AIF), and Endonuclease G from the intermembrane space of the mitochondria. The release of these proteins, which are normally sequestered, has severe consequences for the cell. For example, cytoplasmic cytochrome c and dATP initiate the assembly of the apoptosome with APAF-1 and pro-caspase-9. The assembly of this complex promotes the activation of caspase-9 which subsequently leads to the activation of caspase-3, -6, and -7 to induce apoptosis. In addition, Smac/Diablo and HTRA2/Omi interact with the IAP proteins disrupting their abilities to inhibit caspase activity, while AIF and Endonuclease G translocate to the nucleus upon mitochondrial release and promote chromatin condensation and DNA fragmentation.