A hepatocyte undergoing apoptosis is found to have cytochrome c released from mitochondria into the cytosol. Which downstream event is DIRECTLY triggered by cytosolic cytochrome c?
- A Formation of the apoptosome with Apaf-1 and pro-caspase-9, activating caspase-9 ✓
- B Activation of caspase-8 via DISC (death-inducing signaling complex) formation
- C Activation of RIPK3 leading to mixed lineage kinase domain-like (MLKL) phosphorylation
- D Direct activation of caspase-3 without intermediate adapter molecules
Correct answer: A. Formation of the apoptosome with Apaf-1 and pro-caspase-9, activating caspase-9
Explanation
Cytochrome c released from mitochondria (intrinsic pathway) binds Apaf-1 (apoptotic protease-activating factor-1) in the cytosol. This complex, together with dATP, recruits and activates pro-caspase-9 to form the apoptosome (a heptameric wheel structure). Activated caspase-9 then cleaves and activates downstream effector caspases-3 and -7. Caspase-8 is activated by the extrinsic pathway through DISC. RIPK3/MLKL is the necroptosis pathway.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
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