Mitochondrial Roads to Ruin
Two related ways in which mitochondria contribute to cell death are pictured. In the first, mitochondrial outer membrane permeabilization (MOMP) occurs when the proapoptotic Bcl-2 family proteins Bax and/or Bak are activated by BH3-only proteins in response to apoptosis-inducing signals. This results in the release of proteins of the mitochodrial intermembrane space, including cytochrome c, Smac/DIABLO, and Omi/HtrA2. Cytochrome c activates APAF-1, which oligomerizes to form an apoptosome, that in turn recruits and activates caspase-9. The activated caspase-9 cleaves and activates executioner caspases. Inhibitor of apoptosis proteins (IAPs) block caspase-9 function, and this is disinhibited by Smac and Omi. A second pathway to cell death is triggered by conditions that engage the mitochondrial permeability transition in the mitochondrial inner membrane, leading to matrix swelling and rupture of the outer membrane. This death pathway appears to engage a necrotic form of death. While evidence suggests that these two mitochondrial pathways are distinct, it is suspected that there is significant overlap between them.
