Intrinsic vs Extrinsic Apoptosis: Two Routes to Cell Death

The Intrinsic (Mitochondrial) Pathway

The intrinsic pathway responds to internal stress: DNA damage, oncogene activation, growth-factor withdrawal, hypoxia and loss of attachment. These signals shift the balance of the BCL-2 protein family toward death.

When the effector proteins BAX and BAK are activated, they permeabilise the outer mitochondrial membrane. Cytochrome c is released, forms the apoptosome with APAF1, and activates initiator caspase-9, which then activates the executioner caspases.

The Extrinsic (Death-Receptor) Pathway

The extrinsic pathway is triggered by ligands binding cell-surface death receptors such as FAS, the TRAIL receptors and TNF receptor 1. Receptor clustering assembles the death-inducing signalling complex (DISC).

The DISC recruits and activates initiator caspase-8. In some cell types caspase-8 directly activates executioner caspases; in others it needs to amplify the signal through the mitochondria.

Where the Two Pathways Meet

Caspase-8 cleaves the BH3-only protein BID to form truncated BID (tBID), which activates BAX and BAK. This connects the extrinsic pathway to mitochondrial permeabilisation and lets a weak death-receptor signal be amplified.

Both pathways ultimately converge on executioner caspases-3 and -7, which dismantle the cell in an orderly way that avoids spilling contents and provoking inflammation.

How Cancers Evade Apoptosis

Common mechanisms include overexpression of anti-apoptotic BCL-2 family members (BCL2, BCL-XL, MCL1), loss or mutation of BAX/BAK, inactivation of p53 so that pro-apoptotic transcription is lost, and silencing of caspase-8 in some paediatric tumours.

Because evasion of cell death is a hallmark of cancer, restoring apoptotic sensitivity is a long-standing therapeutic goal.

A Note on Nomenclature

Cell-death terminology has been formalised by the Nomenclature Committee on Cell Death. Terms such as intrinsic apoptosis, extrinsic apoptosis, necroptosis and pyroptosis have specific molecular definitions and are not interchangeable.

Reports and papers that use these terms loosely can be misleading; the defining feature of apoptosis is caspase-driven, regulated dismantling of the cell.

Key Takeaways

• ·Intrinsic apoptosis starts at the mitochondria via BAX/BAK and caspase-9.
• ·Extrinsic apoptosis starts at death receptors via caspase-8.
• ·BID cleavage links the two, and both converge on caspases-3 and -7.
• ·Cancers evade apoptosis by raising anti-apoptotic proteins, losing BAX/BAK, or inactivating p53.