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General pathology · Cell injury, adaptation and death

Apoptosis: the intrinsic and extrinsic pathways !

  • Mechanism

Apoptosis is a tidy, programmed suicide: the cell shrinks, cuts itself into packets and is eaten without causing inflammation.

Updated 2026-11-01

What it is

Apoptosis is a regulated program of cell death that needs energy and is carried out by enzymes called caspases. It removes cells during development, ends immune responses, deletes self-reactive lymphocytes and eliminates cells with damaged DNA or misfolded proteins. Too little apoptosis favours cancer and autoimmunity; too much contributes to neurodegeneration and tissue loss.

Key facts

  • Physiologic examples: loss of the webs between fingers, shedding of the endometrium, thymic negative selection, death of neutrophils after inflammation.
  • Cytotoxic T cells and NK cells kill by Fas ligand and by perforin plus granzyme B, which activates caspases directly.
  • Viral hepatitis shows single dead hepatocytes as eosinophilic apoptotic (Councilman) bodies.
  • Failure to clear apoptotic debris is thought to feed autoantibody formation in lupus.

Structure

  • Single, scattered cells, not sheets.
  • Small cell with dense, deeply eosinophilic cytoplasm.
  • Pyknotic or fragmented nucleus; sometimes a clear halo around the cell.
  • No surrounding inflammatory infiltrate.

Step by step

  1. A trigger appears: DNA damage, growth factor withdrawal, misfolded proteins, or a death ligand on another cell.
  2. Intrinsic: p53 and other sensors activate BH3-only proteins, which overcome BCL-2 and free BAX and BAK.
  3. BAX and BAK make the mitochondrial outer membrane leaky; cytochrome c enters the cytosol.
  4. Cytochrome c binds APAF-1 to form the apoptosome, which activates caspase 9.
  5. Extrinsic: Fas ligand or TNF engage receptors; the adaptor FADD activates caspase 8 (which can also cleave BID to recruit the mitochondria).
  6. Both routes activate executioner caspases 3, 6 and 7.
  7. The cell shrinks, the chromatin condenses and breaks, and the cell buds into apoptotic bodies.
  8. Phosphatidylserine flips to the outer membrane and phagocytes engulf the bodies without inflammation.

Clinical notes

  • BCL-2 inhibitors are used in some lymphoid leukemias to restore apoptosis.
  • Many chemotherapy drugs and radiation work by damaging DNA and triggering p53-dependent apoptosis.

Test yourself

Think of the answer, then tap the question to see it.

What does cytochrome c do once it is released from mitochondria?

It binds APAF-1 to form the apoptosome, which activates caspase 9 and then the executioner caspases.

Which caspase starts the extrinsic pathway?

Caspase 8, activated through the adaptor FADD after Fas or TNF receptor engagement.

Which translocation causes BCL-2 overexpression and in which tumour?

t(14;18), which places BCL-2 next to the immunoglobulin heavy chain locus, in follicular lymphoma.

Why does apoptosis not cause inflammation?

The membrane stays intact and the apoptotic bodies display phosphatidylserine, so phagocytes remove them before contents leak.

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Educational content on the mechanisms of disease; not a diagnostic or treatment guide and no substitute for a health professional's advice. No doses are given.

Sources: Autoimmune lymphoproliferative syndrome: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2024); 4.6 Tissue Injury and Aging (OpenStax (Rice University), 2022).

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Representative model, for educational purposes only.