Mechanisms of apoptosis and its pathological characteristics

1. Definition

• Apoptosis (アポトーシス) = programmed cell death (“cell suicide”); energy (ATP)-dependent.
• Activated enzymes degrade DNA, nuclear and cytoplasmic proteins.
• Cell membrane stays intact but is altered to flag the cell for phagocytosis → no inflammation.

2. Apoptosis vs Necrosis

	Apoptosis	Necrosis
Energy required	Yes	No
Inflammation	No	Yes
Membrane	Intact	Broken
Cells affected	Single cells	Groups of cells
Cell size	Shrinkage	Swelling
Mechanism	Caspase activation	ATP depletion, membrane/free-radical injury
Nature	Physiological + pathological	Only pathological

3. Causes

Physiological (maintains steady cell number)

• Embryogenesis (e.g. interdigital webbing / finger separation)
• Hormone-dependent involution (e.g. endometrial shedding in menstruation)
• Death of inflammatory cells at the end of an immune response
• Negative feedback removal of proliferating cells

Pathological (removes altered/irreparable cells without host reaction)

• DNA damage (radiation, chemotherapy, heat, hypoxia) → prevents malignant transformation
• Misfolded protein accumulation → ER stress → apoptosis
• Viral infection (integration → cell-cycle arrest)
• Pathological atrophy (O₂/nutrient shortage)

4. Morphology

• Nuclear condensation → aggregation → karyorrhexis
• Eosinophilic cytoplasm, cell shrinkage
• Apoptotic bodies = membrane-bound vesicles, phagocytosed with no enzyme leakage

5. Molecular Mechanisms

Both pathways converge on caspases (proteases) → degradation of DNA, nucleoproteins, cytoskeleton.

Intrinsic (mitochondrial) pathway

• Trigger: DNA damage, growth-factor withdrawal, misfolded proteins
• Bcl-2 sensors activate Bax/Bak → mitochondrial channels → cytochrome c release
• → pro-caspase 9 → effector caspases 3, 6, 7 → apoptosis

Extrinsic (death-receptor) pathway

• Fas (CD95)/FasL or TNF/TNF-R → adaptor FADD → pro-caspase 8 → effector caspases → apoptosis
• Key in immune regulation

Regulation

• Anti-apoptotic: Bcl-2, Bcl-xʟ; pro-apoptotic: Bax, Bak; p53 promotes apoptosis.

6. Autophagy (related)

• Self-digestion of cell components = survival mechanism of starving cells (autophagolysosome = ER + lysosome); removes misfolded proteins; may progress to apoptosis.

💡 High-yield: Overexpression of anti-apoptotic Bcl-2 (t14;18) → follicular lymphoma; loss of p53 removes a key pro-apoptotic checkpoint in many cancers.