Apoptosis, or programmed cell death, can be initiated through two primary pathways: the intrinsic (mitochondrial) pathway and the extrinsic (death receptor) pathway.
Intrinsic Pathway (Mitochondrial Pathway)
The intrinsic pathway is triggered by internal cellular stress signals, indicating damage or abnormalities within the cell. This pathway relies on the mitochondria as a central regulator.
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Cellular Stress: Events like DNA damage, growth factor deprivation, hypoxia, or the presence of toxins can activate the intrinsic pathway.
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Mitochondrial Involvement: These stressors cause the mitochondria to release pro-apoptotic proteins, such as cytochrome c, into the cytoplasm.
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Apoptosome Formation: Cytochrome c binds to Apaf-1 (apoptotic protease activating factor 1), which then recruits and activates caspase-9, forming a complex called the apoptosome.
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Caspase Activation Cascade: The apoptosome activates downstream effector caspases (like caspase-3), initiating a cascade of events that ultimately lead to cell dismantling.
Extrinsic Pathway (Death Receptor Pathway)
The extrinsic pathway is activated by external signals from other cells. This pathway involves death receptors on the cell surface.
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Death Receptors: These are transmembrane receptors belonging to the tumor necrosis factor (TNF) receptor superfamily, such as Fas (CD95) and TNF-R1.
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Ligand Binding: Death receptors are activated when they bind to their corresponding ligands, such as Fas ligand (FasL) or TNF-α.
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DISC Formation: Upon ligand binding, the death receptors recruit adaptor proteins, such as FADD (Fas-associated death domain), forming a death-inducing signaling complex (DISC).
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Caspase-8 Activation: Within the DISC, caspase-8 is activated.
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Caspase Activation Cascade: Activated caspase-8 can directly activate effector caspases (like caspase-3), leading to apoptosis, or it can activate the intrinsic pathway by cleaving Bid, a pro-apoptotic protein.
Cross-Talk Between Pathways
While these pathways are distinct, there is significant cross-talk between them. Activation of one pathway can influence the other. For example, caspase-8 from the extrinsic pathway can activate Bid, which then triggers the release of cytochrome c from the mitochondria, activating the intrinsic pathway. Similarly, weak external signals can activate the intrinsic pathway.
Summary
In essence, to start apoptosis, you either need to induce significant cellular stress that damages the cell from within (intrinsic pathway) or provide an external signal that tells the cell to self-destruct (extrinsic pathway).
