Apoptosoms

Apoptosomes are cytosolic multiprotein complexes that initiate the intrinsic pathway of programmed cell death. In humans, the canonical apoptosome forms after cytochrome c is released from mitochondria into the cytosol and binds to APAF1 in the presence of dATP or ATP. This binding triggers conformational changes and oligomerization of APAF1 into a wheel-like heptamer that serves as a platform for recruiting procaspase-9 via CARD-CARD interactions.

Activated procaspase-9 is then processed to its active form, initiating a caspase cascade that activates executioner caspases such as caspase-3, caspase-6, and caspase-7 and leads to apoptosis through proteolysis of cellular substrates.

Structural studies depict the apoptosome as a seven-armed wheel; the core is APAF1, with cytochrome c as a cofactor that promotes assembly. In other organisms, similar complexes exist. In Drosophila, the Apaf-1–like protein Dark interacts with Dronc (caspase-9 homolog). In C. elegans, ced-4 forms a complex with ced-3 to activate apoptosis. While the components differ, the basic mechanism converges on caspase activation.

Regulation occurs at multiple steps: release of cytochrome c is controlled by Bcl-2 family proteins; IAPs can inhibit active caspases; p53 and other stress signals can influence apoptosome formation. Dysregulation of apoptosome activity is linked to cancer, neurodegenerative diseases, and ischemic injury. Therapeutic strategies aim to promote apoptosome assembly in cancer or to inhibit it in neurodegenerative contexts.

Apoptosomes were identified in the late 1990s as essential mediators of the intrinsic apoptotic pathway, underscoring a central mechanism by which cells translate mitochondrial distress into a regulated death program.