- apoptosis

Learning Outcomes

  • Define apoptosis and distinguish it from necrosis.

  • Understand the role of the Bcl-2 protein family and the caspase cascade.

  • Analyze the intrinsic (mitochondrial) and extrinsic (death receptor) pathways.

Definition and Significance of Apoptosis

  • Apoptosis: A genetically programmed process of cellular self-destruction. Unlike necrosis, it is energy-dependent (ATP-dependent).

  • Physiological Importance:

    • Development: Essential for morphogenesis (e.g., separation of fingers and toes, tadpole tail resorption).

    • Homeostasis: Maintains cell numbers in adult tissues. Approximately 50 to 70 billion cells die due to apoptosis each day in humans.

    • Immune System: Deletion of self-reactive T-cells in the thymus (negative selection).

    • Disease Prevention: Eliminates cells with damaged DNA or viral infections.

  • Morphological Characteristics:

    • Cell Shrinkage

    • Nuclear Fragmentation

    • Chromatin Condensation

    • Formation of Apoptotic Bodies

    • Phagocytic Signaling: Phosphatidylserine (PS) flips to the outer membrane, acting as an "eat-me" signal.

Comparison: Apoptosis vs. Necrosis

Feature

Apoptosis

Necrosis

Mechanism

Programmed, active process

Passive, accidental

Inflammation

No

Yes

DNA Breakdown

Internucleosomal cleavage (Laddering)

Random degradation (Smearing)

Molecular Mechanisms: The Caspase Cascade

  • Caspases: Cysteine-dependent aspartate-directed proteases. Exist as inactive zymogens (pro-caspases) and are activated by proteolytic cleavage.

  • Classification:

    1. Initiator Caspases: Caspase-8, 9 - initiate the cascade.

    2. Executioner Caspases: Caspase-3 - carry out mass proteolysis of cellular proteins.

The Intrinsic (Mitochondrial) Pathway

  • Triggered by internal signals: DNA damage, oxidative stress, lack of growth factors.

  • Bcl-2 Family Proteins:

    • Pro-apoptotic: Bax and Bak - form pores in mitochondrial membrane.

    • Anti-apoptotic: Bcl-2, Bcl-xL - prevent pore formation.

  • Pathway Sequence:

    1. Bax/Bak form pores in mitochondrial membrane.

    2. Cytochrome c leaks into the cytosol.

    3. Cytochrome c binds to Apaf-1 and dATP.

    4. Forms the Apoptosome.

    5. Apoptosome activates Caspase-9.

    6. Caspase-9 activates Caspase-3.

The Extrinsic (Death Receptor) Pathway

  • Triggered by extracellular ligands binding to death receptors (e.g., Fas receptor).

  • Mechanism:

    1. Ligand binding causes receptor trimerization.

    2. Recruitment of adapter protein FADD.

    3. Recruitment of Pro-caspase-8.

    4. Formation of the DISC (Death-Inducing Signaling Complex).

    5. Activation of Caspase-8.

    6. Caspase-8 activates Caspase-3.

Summary

Apoptosis is regulated by the balance of Bcl-2 family proteins and executed by caspases. The intrinsic pathway involves cytochrome c release from mitochondria, while the extrinsic pathway relies on death receptor signaling.