Apoptosis and autolysis

Overview

Apoptosis is a tightly regulated "cell suicide" programme. Unwanted or damaged cells switch on enzymes that dismantle them neatly, without spilling their contents or causing inflammation.

It is essential in development and normal life, and its failure or excess underlies many diseases.

Physiological apoptosis (normal)

• Embryogenesis: removal of cells between fingers and toes; shaping organs.
• Hormone withdrawal: shedding of the endometrium in menstruation; breast regression after weaning; prostate atrophy after castration.
• Cell turnover in proliferating tissues (gut lining, skin).
• Immune system: removal of self-reactive lymphocytes; death of immune cells after an infection ends.
• Killing of infected or tumour cells by cytotoxic T cells.

Pathological apoptosis

• DNA damage (radiation, anticancer drugs) that cannot be repaired.
• Misfolded proteins (endoplasmic reticulum stress): some neurodegenerative diseases.
• Viral infections: for example Councilman bodies (apoptotic hepatocytes) in viral hepatitis and yellow fever.
• Atrophy of organs after duct obstruction (pancreas, kidney).

Mechanisms

Intrinsic (mitochondrial) pathway

The main pathway in most situations.

1. Cell stress, DNA damage or loss of growth factors.
2. BCL-2 family balance shifts:
   • Anti-apoptotic: BCL-2, BCL-XL (keep mitochondria sealed).
   • Pro-apoptotic: BAX, BAK (open mitochondrial membrane channels); BH3-only sensors (such as BIM, PUMA) detect stress.
3. Cytochrome c leaks from mitochondria into the cytoplasm.
4. It forms an apoptosome with APAF-1, activating caspase-9, then the executioner caspases (3, 6, 7).

p53 ("guardian of the genome") stops the cell cycle after DNA damage to allow repair; if repair fails, it triggers apoptosis by increasing pro-apoptotic proteins.

Extrinsic (death receptor) pathway

1. A death receptor on the cell surface (Fas/CD95, TNF receptor) binds its ligand (Fas ligand, TNF).
2. Adaptor proteins activate caspase-8.
3. Caspase-8 activates the executioner caspases.

Used by cytotoxic T cells and to remove self-reactive lymphocytes.

Execution

Caspases (cysteine proteases that cut after aspartate) break down the cytoskeleton and nuclear proteins and activate DNA-cutting enzymes (DNA fragments in multiples of about 180 base pairs give a "DNA ladder" on gel electrophoresis).

The dying cell displays phosphatidylserine on its outer membrane, an "eat me" signal for macrophages.

Morphology of apoptosis

• Cell shrinkage with dense, deeply eosinophilic cytoplasm.
• Chromatin condensation (pyknosis) against the nuclear membrane, then nuclear fragmentation.
• Membrane blebs and formation of apoptotic bodies (membrane-bound fragments).
• Phagocytosis by macrophages.
• No inflammation.
• Usually affects single cells or small clusters.

Apoptosis vs necrosis

Apoptosis and disease

• Too little apoptosis:
  • Cancer: loss of p53 (common in many cancers) or over-expression of BCL-2 in follicular lymphoma due to translocation t(14;18) lets damaged cells survive.
  • Autoimmune diseases: failure to remove self-reactive lymphocytes (for example defects in Fas).
• Too much apoptosis:
  • Neurodegenerative diseases (Alzheimer's, Parkinson's).
  • Ischaemic injury (with necrosis).
  • Loss of CD4 cells in HIV.
  • Death of virus-infected cells.

Autolysis and heterolysis

• Autolysis: self-digestion of a cell by its own lysosomal enzymes after death. It happens in all tissues after somatic death (seen at autopsy), fastest in enzyme-rich tissues such as the pancreas, gastric mucosa and adrenal medulla. There is no inflammation because the body is dead.
• Heterolysis: digestion of dead cells by enzymes from other cells, mainly neutrophils in the inflammatory response (as in necrosis in living tissue).

Quick revision

• Apoptosis: programmed, ATP-dependent; shrinkage; no inflammation.
• Intrinsic: DNA damage → BAX/BAK → cytochrome c → caspase-9.
• Extrinsic: Fas, TNF → caspase-8.
• Executioners: caspases 3, 6, 7. BCL-2 anti-apoptotic; p53 pro-apoptotic.
• Follicular lymphoma: BCL-2 over-expression, t(14;18).
• Autolysis: own enzymes after death; heterolysis: enzymes from neutrophils.

Written by The House Job from standard pathology references (Robbins and Cotran Pathologic Basis of Disease is the book named in the UHS PGET syllabus).

FAQ