Apoptosis, or programmed cell death, is primarily initiated through two main pathways: the extrinsic pathway and the intrinsic pathway.
Extrinsic Pathway: The Death Receptor Route
This pathway, also known as the DR-mediated pathway, begins with signals outside the cell.
- Signal Reception: Certain molecules, called death ligands, bind to specific receptors on the cell surface. These receptors, known as death receptors (DRs), are transmembrane proteins.
- Receptor Activation: Once the death ligand binds, the death receptor is activated.
- Formation of DISC: Upon activation, the death receptor recruits adapter proteins, which then recruit and activate initiator caspases. This assembly of proteins forms the Death-Inducing Signaling Complex (DISC).
- Caspase Cascade Initiation: The DISC activates initiator caspases, like caspase-8, which, in turn, activate executioner caspases that lead to the dismantling of the cell.
Intrinsic Pathway: The Mitochondrial Route
The intrinsic pathway, also known as the mitochondrial-mediated pathway, begins with signals arising within the cell.
- Internal Signals: These signals can include DNA damage, cellular stress, or the lack of growth factors.
- Mitochondrial Permeabilization: These internal signals trigger the mitochondria to release proteins from their intermembrane space into the cytoplasm.
- Cytochrome c Release: A key protein released is cytochrome c, which plays a crucial role in oxidative phosphorylation.
- Apoptosome Formation: Once in the cytoplasm, cytochrome c binds to another protein, Apaf-1, along with ATP, forming a complex known as the apoptosome.
- Caspase Activation: The apoptosome recruits and activates initiator caspases, primarily caspase-9, which then activate downstream executioner caspases to execute apoptosis.
Comparison of the Two Pathways
| Feature | Extrinsic Pathway | Intrinsic Pathway |
|---|---|---|
| Initiating Signal | Extracellular signals (death ligands) | Intracellular signals (stress, damage) |
| Key Players | Death receptors, DISC | Mitochondria, cytochrome c, apoptosome |
| Initiator Caspase | Caspase-8 | Caspase-9 |
In summary, apoptosis is initiated via two major routes. The extrinsic pathway is triggered by external signals activating death receptors, while the intrinsic pathway is triggered by internal cellular stresses leading to mitochondrial changes. Both pathways converge on the activation of executioner caspases, which carry out the dismantling of the cell.
