The pathway of apoptosis, or programmed cell death, primarily involves two main routes: the extrinsic (death receptor) pathway and the intrinsic (mitochondrial) pathway. Both pathways converge on a shared execution phase, ultimately leading to cell dismantling.
1. Extrinsic Pathway (Death Receptor Pathway)
-
Initiation: This pathway is triggered by extracellular signals, specifically ligands (e.g., TNF-α, Fas ligand) binding to death receptors (e.g., TNFR1, Fas) on the cell surface. These receptors are transmembrane proteins belonging to the tumor necrosis factor (TNF) receptor superfamily.
-
Formation of DISC: Ligand binding induces receptor trimerization and recruitment of adaptor proteins like FADD (Fas-associated death domain protein). FADD then recruits pro-caspase-8 (or -10), forming the Death-Inducing Signaling Complex (DISC).
-
Caspase Activation: Within the DISC, pro-caspase-8 molecules are cleaved and activated to caspase-8 (or -10). Caspases are a family of cysteine proteases that act as the executioners of apoptosis.
-
Execution Phase Activation: Activated caspase-8 can directly activate downstream effector caspases, such as caspase-3, leading to the execution phase. Alternatively, in some cell types, caspase-8 can activate the intrinsic pathway by cleaving Bid (BH3 interacting-domain death agonist) into tBid.
2. Intrinsic Pathway (Mitochondrial Pathway)
-
Initiation: This pathway is activated by intracellular stress signals, such as DNA damage, hypoxia, growth factor withdrawal, and accumulation of misfolded proteins. These stressors can cause changes in mitochondrial membrane permeability.
-
Mitochondrial Outer Membrane Permeabilization (MOMP): Stress signals lead to the activation of pro-apoptotic members of the Bcl-2 protein family (e.g., Bax, Bak). These proteins oligomerize and insert into the outer mitochondrial membrane, forming pores. At the same time, anti-apoptotic Bcl-2 family members (e.g., Bcl-2, Bcl-xL) are inhibited, thus allowing MOMP to proceed.
-
Release of Cytochrome c: MOMP results in the release of cytochrome c from the intermembrane space of the mitochondria into the cytosol.
-
Formation of the Apoptosome: In the cytosol, cytochrome c binds to Apaf-1 (apoptotic protease activating factor 1), which then oligomerizes to form the apoptosome.
-
Caspase Activation: The apoptosome recruits and activates pro-caspase-9.
-
Execution Phase Activation: Activated caspase-9 then activates downstream effector caspases, such as caspase-3, initiating the execution phase of apoptosis.
3. Execution Phase (Common to Both Pathways)
-
Activation of Effector Caspases: Both the extrinsic and intrinsic pathways converge on the activation of effector caspases (e.g., caspase-3, caspase-6, caspase-7).
-
Cell Dismantling: Effector caspases cleave a variety of cellular substrates, including structural proteins, DNA repair enzymes, and signaling molecules. This leads to:
- DNA fragmentation
- Cell shrinkage
- Plasma membrane blebbing
- Formation of apoptotic bodies
-
Phagocytosis: Apoptotic bodies are then recognized and engulfed by phagocytic cells (e.g., macrophages), preventing inflammation. This clearance is facilitated by "eat me" signals displayed on the apoptotic cell surface, such as phosphatidylserine.
In summary, apoptosis proceeds through distinct initiating pathways (extrinsic and intrinsic) that ultimately converge on a common execution phase mediated by caspases, leading to controlled cell death and clearance.
