Programmed cell death. Intrinsic (mitochondrial) pathway: pro-apoptotic BH3-only proteins (BIM, BID, PUMA, NOXA) activate effector BAX/BAK → MOMP (mitochondrial outer membrane permeabilization) → cytochrome c release → apoptosome (Apaf-1 + caspase-9) → executioner caspase-3/7. Antagonized by anti-apoptotic Bcl-2 family (BCL-2, BCL-xL, MCL-1, BCL-w). Extrinsic (death receptor): Fas/TNF/TRAIL → DISC → caspase-8 → caspase-3/7 + BID truncation (crosstalk to mitochondria). VENETOCLAX is a BH3-mimetic that selectively occupies Bcl-2's BH3 groove → frees pro-apoptotic effectors → triggers apoptosis in Bcl-2-dependent cancer cells (CLL, AML). Navitoclax adds BCL-xL inhibition (causes thrombocytopenia — platelets depend on BCL-xL).
Organ Systems
immune-hematologic
reproductive
Pathway Steps
death-signal-intrinsic → bax-bak-activation — via BH3-only proteins released by p53 / DNA damage / growth factor withdrawal. The intrinsic pathway is set by the BCL-2 family balance: BH3-only proteins (BIM, BID, PUMA, NOXA — induced by p53, DNA damage, or growth-factor withdrawal) either directly activate the effectors BAX/BAK or neutralize the anti-apoptotic guardians (BCL-2, BCL-XL, MCL-1). The pro- to anti-apoptotic ratio sets the death threshold (“priming”).
bax-bak-activation → cytochrome-c-release — via mitochondrial outer membrane permeabilization (MOMP). Activated BAX/BAK oligomerize to permeabilize the mitochondrial outer membrane (MOMP) — the commitment point of intrinsic apoptosis. Anti-apoptotic BCL-2/BCL-XL/MCL-1 block it by sequestering BAX/BAK and activator BH3-only proteins; BH3-mimetics (venetoclax/ABT-199 for BCL-2) free them, the basis of CLL/AML therapy.
cytochrome-c-release → apoptosome — via Apaf-1 + procaspase-9 oligomerization. Released cytochrome c binds Apaf-1, driving oligomerization with procaspase-9 into the wheel-shaped apoptosome — coupling mitochondrial damage to caspase activation. IAPs (e.g. XIAP) restrain it, while mitochondrial SMAC/DIABLO neutralizes IAPs — the target of SMAC-mimetic drugs.
apoptosome → executioner-caspase-activation — via caspase-9 → caspase-3/7 → DNA fragmentation + cytoskeletal cleavage. The apoptosome activates initiator caspase-9, which cleaves executioner caspases-3/7 to dismantle the cell (DNA fragmentation, PARP/cytoskeletal cleavage, phosphatidylserine exposure for phagocytic clearance). The extrinsic (death-receptor/caspase-8) pathway converges here and can amplify via BID→mitochondria.