Apoptosis, or programmed cell death, is a crucial process for maintaining tissue homeostasis and eliminating damaged or infected cells. It's activated through two primary pathways: the intrinsic (mitochondrial) and extrinsic (death receptor) pathways.
Intrinsic Pathway (Mitochondrial Pathway)
This pathway is triggered by internal cellular stress, such as DNA damage, oxidative stress, or growth factor deprivation. Stress signals lead to changes in the mitochondria, specifically increased mitochondrial permeability. This permeability shift allows the release of cytochrome c (CytoC) into the cytoplasm. CytoC then binds to Apaf-1, forming a complex called the apoptosome. The apoptosome activates caspase-9, an initiator caspase. Activated caspase-9 then triggers a cascade of caspase activation, ultimately leading to cell death. (Reference: Stress-induced apoptosis occurs by a mechanism that involves altering mitochondrial permeability and subsequent CytoC release and formation of the apoptosome, a catalytic multiprotein platform that activates Caspase-9. Activated Caspase-9 then cleaves Caspase-3, resulting in downstream events involved in cell death.)
- Key players: Cytochrome c, Apaf-1, apoptosome, caspase-9, caspase-3.
- Triggers: DNA damage, oxidative stress, lack of growth factors.
Extrinsic Pathway (Death Receptor Pathway)
The extrinsic pathway is initiated by external signals, primarily through the binding of ligands to death receptors on the cell surface. These death receptors, like Fas and TNF receptor 1 (TNFR1), belong to the tumor necrosis factor receptor (TNFR) superfamily. Ligand binding triggers receptor trimerization and the recruitment of adaptor proteins, like FADD (Fas-associated death domain protein). This complex then activates caspase-8, another initiator caspase. Caspase-8 subsequently activates downstream executioner caspases, ultimately causing cell death. (Reference: Each pathway activates its own initiator caspase (8, 9, 10) which in turn will activate the executioner caspase-3.)
- Key players: Death receptors (e.g., Fas, TNFR1), ligands (e.g., FasL, TNFα), FADD, caspase-8, caspase-3.
- Triggers: Extracellular signals, such as death ligands.
Convergence and Execution
Both intrinsic and extrinsic pathways converge on the activation of executioner caspases, such as caspase-3. These caspases execute the cellular dismantling processes that characterize apoptosis. (Reference: Both pathways induce cell death by activating caspases, which are proteases, or enzymes that break down proteins.) Reactive oxygen species (ROS) can also play a significant role in activating both pathways. (Reference: ROS play a central role in cell signalling as well as in regulation of the main pathways of apoptosis mediated by mitochondria, death receptors and the ...)
