Apaf1dependent

Apaf1-dependent, or Apaf-1–dependent apoptosis, denotes the mitochondrial or intrinsic pathway of programmed cell death in which Apaf-1 acts as a central adaptor to activate procaspase-9 and initiate the caspase cascade.

Activation begins when mitochondrial outer membrane permeabilization leads to cytochrome c release into the cytosol. Cytochrome c binds to the WD40 repeats of Apaf-1 in the presence of dATP/ATP, promoting conformational change and oligomerization into the heptameric apoptosome. The apoptosome recruits procaspase-9 through CARD–CARD interactions, facilitating procaspase-9 dimerization and autocatalytic activation. Active caspase-9 then cleaves and activates effector caspases such as caspase-3 and caspase-7, executing apoptosis.

Apaf-1 comprises a N-terminal caspase recruitment domain (CARD), a central nucleotide-binding and oligomerization domain (NB-ARC), a helix-rich linker region, and C-terminal WD40 repeats necessary for cytochrome c binding. In mammals, the APAF1 gene encodes Apaf-1. Apaf-1–dependent apoptosis is tightly regulated by Bcl-2 family proteins, which govern cytochrome c release, and by cellular inhibitors of apoptosis (IAPs) and other proteolytic regulators.

Loss or reduced expression of Apaf-1 has been observed in some cancers and is associated with resistance to cytotoxic stimuli. Conversely, excessive activation of Apaf-1–dependent pathways can contribute to neurodegeneration or ischemia-reperfusion injury. Apaf-1 is evolutionarily related to CED-4, the apoptotic adaptor in C. elegans, illustrating conservation of the intrinsic death program.