1.7 about 20 minDeep Learning viewL1 p.42–45

Apoptosis

Apoptosis is programmed, energy-dependent, caspase-driven cell death. Single cells shrink and are quietly eaten, without inflammation. Three routes lead to the same executioner caspases.

When cells are meant to die

L1 p.42

Apoptosis needs ATP and enzymes. It removes cells that are no longer needed or are dangerous, one at a time, without spilling their contents. It occurs in health and in disease.

Physiologic

  • Embryogenesis: sculpting tissues, removing interdigital webs
  • Hormone withdrawal: endometrium at menses
  • Thymic involution with age and deletion of self-reactive lymphocytes
  • Removal of neutrophils after acute inflammation
  • Corticosteroid-induced death of lymphocytes

Pathologic

  • DNA damage from radiation, chemotherapy, free radicals and toxins
  • Accumulated misfolded proteins (e.g. β-amyloid in Alzheimer disease)
  • Virus-infected cells and tumour cells killed by cytotoxic T cells
  • Atrophy after duct obstruction or denervation
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Intrinsic (mitochondrial) pathway

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Pathway schematic

Intrinsic (mitochondrial)

  1. DNA damage (p53), lost survival signals, misfolded proteins
  2. BH3-only sensors activate BAX/BAK; BCL-2 opposes them
  3. Outer mitochondrial membrane leaks cytochrome c
  4. Cytochrome c + APAF-1 = apoptosome → caspase-9

Extrinsic (death receptor)

  1. FasL binds Fas (CD95), or TNF binds TNFR1
  2. Adaptor (FADD) clusters at the receptor
  3. Initiator caspase-8 / -10 activated

Cytotoxic T cell

  1. CD8⁺ T cell recognizes antigen on MHC I
  2. Perforin makes pores
  3. Granzyme B enters and activates caspases
Executioner caspases (3, 6, 7) cleave cytoskeletal and nuclear proteins and activate DNase → shrinkage, nuclear condensation and fragmentation, blebs, apoptotic bodies → phagocytosis without inflammation
Three routes to the executioner caspases.L1 p.43–44

The lecture calls the intrinsic pathway the most important. Sensors of the BCL-2 family (BH3-only proteins) detect trouble: DNA damage (through p53), loss of growth-factor or survival signals, misfolded proteins. They neutralize the anti-apoptotic proteins BCL-2 and BCL-XL and activate BAX and BAK, which form channels in the outer mitochondrial membrane. Cytochrome c leaks into the cytosol, binds APAF-1 to form the apoptosome, and activates the initiator caspase-9, which activates the executioner caspases.

Core activity · The Missing Arrow

The Missing Arrow

Complete the causal chain. Place the missing step by dragging a card onto a gap, or tap a card and then tap the gap. Some gaps need an event; others need the mechanism that links one event to the next.

A muscle fibre after its nerve is cut loses survival signals. Complete the mitochondrial pathway of apoptosis.

One gap needs the event (what leaves the mitochondrion); the next needs the mechanism that turns it into caspase activity.

  1. Loss of survival signals or DNA damage
  2. BH3-only sensors (and p53 after DNA damage) are activated
  4. the outer mitochondrial membrane becomes permeable
  7. Executioner caspases (3, 7) cleave proteins and activate DNase
  8. the cell is dismantled from inside, membrane intact

Cards

Tap or drag a card. Placing a used card moves it.

Extrinsic (death receptor) pathway

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Death receptors of the TNF receptor family carry an intracellular death domain. When Fas ligand on activated T cells binds Fas (CD95), or TNF binds TNFR1, the receptors cluster and recruit an adaptor (FADD), which activates the initiator caspase-8 (and caspase-10). These activate the executioner caspases. The pathway eliminates self-reactive lymphocytes and lets some cytotoxic T cells kill through Fas ligand.

Cytotoxic T cells

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A CD8⁺ cytotoxic T cell that recognizes a viral or tumour peptide on MHC class I releases its granules onto the target. Perforin inserts into the target membrane and forms pores; granzyme B, a serine protease, enters through them and activates caspases directly (and by cleaving BID, links to the mitochondrial pathway). The infected cell dies by apoptosis, without releasing virus into the tissue. Natural killer cells use the same machinery.

What apoptosis looks like

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  • The cell detaches from its neighbours and shrinks; its cytoplasm becomes dense and deeply eosinophilic on H&E.
  • Chromatin condenses against the nuclear membrane (pyknosis), then the nucleus fragments (karyorrhexis).
  • The membrane blebs and buds off membrane-bound apoptotic bodies containing cytoplasm and nuclear fragments.
  • Changes in the membrane (exposed phosphatidylserine) signal macrophages to engulf the bodies quickly.
  • No inflammatory infiltrate. Affected cells are scattered singly or in small clusters.
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Apoptosis or necrosis?

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  • Cell size

    Apoptosis
    Shrunken
    Necrosis
    Swollen

  • Nucleus

    Apoptosis
    Pyknosis, then fragmentation
    Necrosis
    Pyknosis, karyorrhexis, karyolysis

  • Plasma membrane

    Apoptosis
    Intact, with altered surface
    Necrosis
    Disrupted

  • Contents

    Apoptosis
    Packaged in apoptotic bodies
    Necrosis
    Leak out; enzymatic digestion

  • Distribution

    Apoptosis
    Single cells
    Necrosis
    Groups of cells, zones of tissue

  • Inflammation

    Apoptosis
    None
    Necrosis
    Usually present

  • Energy

    Apoptosis
    Requires ATP
    Necrosis
    Follows ATP loss

  • Physiologic?

    Apoptosis
    Often
    Necrosis
    Never

Core activity · Almost Twins

Almost Twins

Two look-alikes side by side. Decide what they share, then pick the clue that separates them and say why it works.

Look-alike A

Apoptotic cell

Single cell in a tissue (schematic).
  • Condensed (pyknotic), fragmenting nucleus
  • Dense, deeply eosinophilic cytoplasm
  • Shrunken, membrane intact, apoptotic bodies, single cell, no inflammation
  • Membrane blebs

Step 1 · What they share

Which features can both show?

Select every feature that both show.

Knowledge check · 1.7

Answer, read why, and try again whenever you like. Answers are kept in both study modes.

0 of 5 correct
  1. Q1Caspases in physiologic apoptosisL1 p.42, 50

    The human thymus begins to shrink after puberty, without inflammation. Which enzymes most directly carry out this process?

  2. Q2Intrinsic apoptosisL1 p.43, 51

    A biopsy of a denervated calf muscle from an 80-year-old woman shows shrunken fibres with dense eosinophilic cytoplasm, condensed nuclei and membrane blebs, without inflammation.

    Which event best explains these findings?

  3. Q3Cytotoxic T-cell killingL1 p.43, 53

    CD8⁺ T cells are added to a culture of virus-infected cells, which then undergo apoptosis.

    Which molecule released by the T cells enters the target cells and activates caspases?

  4. Q4BCL-2L1 p.43–44

    A lymphoma carries the translocation t(14;18) and overexpresses BCL-2. What is the effect on its cells?

  5. Q5Apoptosis versus necrosisL1 p.45

    A liver biopsy in acute viral hepatitis shows scattered single hepatocytes that are shrunken and intensely eosinophilic with fragmented nuclei, with no inflammation immediately around them.

    What process do these cells show?

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