Apoptosis and Cell Death

Cell Death Types - Meet the Reapers

• Apoptosis: Programmed cell death ("cell suicide").
  • No inflammation. Caspase-dependent.
  • Features: Cell shrinkage, chromatin condensation, apoptotic bodies.
• Necrosis: Uncontrolled cell death ("cell homicide").
  • Inflammation present. Typically caspase-independent.
  • Features: Cell swelling (oncosis), membrane rupture, enzymatic digestion.
• Necroptosis: Programmed necrosis.
  • Inflammatory, caspase-independent. RIPK1/RIPK3 mediated.

⭐ Apoptosis is an active, ATP-dependent process, unlike typical necrosis which often involves ATP depletion and passive cell lysis.

Apoptosis Pathways - Orderly Dismantling

• Energy-dependent, programmed cell death; no inflammation. Key enzymes: Caspases.

• Two Main Routes:
  • Intrinsic (Mitochondrial):
    • Stimuli: DNA damage, ↓growth factors.
    • Bcl-2 family (Bax/Bak vs Bcl-2) controls mitochondrial permeability.
    • ↑Bax/Bak → Cytochrome c release.
    • Apoptosome (Apaf-1, Cytochrome c, Procaspase-9) → Caspase-9 (initiator). 📌 iNtrinsic: Caspase-NINE.
  • Extrinsic (Death Receptor):
    • Ligands (FasL, TNF-α) bind Death Receptors (Fas/CD95, TNFR1).
    • DISC (FADD, Procaspase-8/10) → Caspase-8/10 (initiators). 📌 Extrinsic: Caspase-EIGHT.
• Convergence: Initiators activate Executioner Caspases (Caspase-3, -6, -7) → protein cleavage.
• Regulators:
  • Anti-apoptotic: Bcl-2, Bcl-xL.
  • Pro-apoptotic: Bax, Bak; BH3-only (Bid, Bad).
  • IAPs (Inhibitors of Apoptosis Proteins): Block caspases.

⭐ Caspase-3: key executioner, activated by both pathways, dismantles cell.

Necrosis & Variants - When Cells Explode

• Uncontrolled cell death: acute injury → cell swelling, membrane rupture, inflammation.
• Nuclear changes: Pyknosis (shrinkage) → Karyorrhexis (fragmentation) → Karyolysis (dissolution). (📌 PKK sequence)
• Cytoplasm: ↑Eosinophilia, myelin figures.
• Types of Necrosis:
  • Coagulative: Most common (not brain). Ischemia (e.g., MI). Architecture preserved initially.
  • Liquefactive: Bacterial/fungal infections, CNS hypoxia. Enzymatic digestion → pus.
  • Caseous: "Cheese-like". TB, systemic fungi. Amorphous debris, granulomas.
  • Fat: Pancreatitis, trauma (breast). Saponification ($Ca^{2+} + \text{FAs} \rightarrow \text{chalky deposits}$).
  • Fibrinoid: Immune reactions in vessels (vasculitis). Eosinophilic, fibrin-like.
  • Gangrenous: Ischemic limb necrosis. Dry (desiccation) vs. Wet (superimposed infection, liquefaction).

⭐ Liquefactive necrosis is characteristic of brain infarcts and abscesses.

• Regulated Necrosis-like Pathways:
  • Necroptosis: Programmed. RIPK1/RIPK3/MLKL. Caspase-independent. Mimics necrosis morphology.
  • Pyroptosis: Inflammasome (Caspase-1/11). IL-1β release, fever. Microbial defense.

Cell Death in Disease - Clinical Crossroads

• Dysregulated Apoptosis:
  • ↓ Apoptosis (Deficient):
    • Cancer: Evasion via p53 mutations, ↑Bcl-2 overexpression.
    • Autoimmune diseases: Failure to eliminate self-reactive lymphocytes (e.g., SLE, rheumatoid arthritis).
  • ↑ Apoptosis (Excessive):
    • Neurodegenerative: Alzheimer's (amyloid-beta), Parkinson's (alpha-synuclein).
    • Ischemic injury: MI, stroke (reperfusion can exacerbate).
    • Viral infections: AIDS (HIV-induced CD4+ T-cell depletion).
• Necrosis & Necroptosis in Disease:
  • Necrosis: MI, stroke, trauma, acute pancreatitis.
  • Necroptosis: Implicated in sepsis, IBD, some viral infections.
• Therapeutic Strategies:
  • Inducing apoptosis: Cancer therapies (e.g., BH3 mimetics like Venetoclax).
  • Inhibiting apoptosis: Neuroprotection, limiting ischemic damage.
  • Targeting necroptosis: RIPK1 inhibitors for inflammatory diseases.

⭐ The p53 tumor suppressor gene is crucial for initiating apoptosis in damaged cells; its mutation, present in over 50% of human cancers, allows malignant cells to evade death.

High‑Yield Points - ⚡ Biggest Takeaways

• Apoptosis: Programmed cell death, an active, non-inflammatory process distinct from necrosis.
• Hallmarks: Cell shrinkage, chromatin condensation, membrane blebbing, formation of apoptotic bodies.
• Caspases are central executioners: initiators (e.g., -8, -9) activate executioners (e.g., -3, -6, -7).
• Intrinsic pathway (mitochondrial): Cytochrome c release, Apaf-1, caspase-9 activation. Regulated by Bcl-2 family.
• Extrinsic pathway (death receptor): FAS/TNF receptors bind specific ligands, activating caspase-8.
• Key markers: Phosphatidylserine externalization ("eat-me" signal) and DNA laddering on gel electrophoresis.