Apoptosis and Cell Death Processes

Apoptosis

  • Definition: Programmed cell death (PCD) is a cellular process where specific signals activate an intracellular program leading to cell death.
    • Types of Cell Death:
      • Necrosis: Unintended cell death due to trauma, lack of oxygen or nutrients.
        • Characteristics:
          • Cell swelling and bursting.
          • Contents spilled into the extracellular environment.
          • Triggers inflammatory response.
      • Programmed Cell Death (PCD): Specific signals that may be extracellular or intracellular initiate multiple pathways leading up to cell death.
        • Apoptosis: A common and well-characterized type of PCD.

Morphological Changes in Apoptosis

  • Defined by Specific Changes:
    • Disassembly of cytoskeleton and nuclear envelope.
    • Chromatin condensation and fragmentation.
    • Water expulsion leading to cell shrinkage.
    • Possible fragmentation into smaller membrane-enclosed structures known as apoptotic bodies.
    • Membrane acquisition of phospholipid tags attracting phagocytes.
    • Phagocytes engulf dying cells and redistribute usable materials.
    • Key Feature: No inflammatory response occurs during apoptosis.

Types of Cell Death

  • Apoptotic Cell: Cells undergoing apoptosis are healthy prior to death.
  • Necrotic Cell: Cells undergoing necrosis are unhealthy at the time of death.

Functions of Apoptosis

  • Developmental Role:
    • Important in the sculpting of structures like hands and feet (e.g., digit separation).
    • Role in tadpole tail regression during metamorphosis.
  • Maintenance Role:
    • Facilitates turnover of adult organ structures (e.g., liver cells).
  • Quality Control: Eliminates abnormal or nonfunctional cells, such as lymphocytes post-infection.

Control of Apoptosis

  • Caspase Proteins:
    • These are proteases that function to cleave target proteins in apoptotic processes.
    • Synthesized as precursor forms called procaspases which are activated through cleavage.
    • The process includes the reassembly of components into an active complex.

Procaspase Cleavage Process

  • Mechanism:
    • Apoptotic signals are recognized by the cell.
    • Procaspases associate with adaptor proteins to form an activation complex.
    • In this complex, procaspases cleave and activate each other leading to further cascade activation.

Caspase Cascade

  • Cascade Dynamics:
    • Active initiator caspases activate more procaspases.
    • These activated executioner caspases cleave the final targets to complete the apoptotic process.

Apoptotic Signal Pathways

  • Two Main Pathways:
    • Extrinsic Pathway:
      • Activated by extracellular signals binding to death receptors.
    • Intrinsic Pathway:
      • Mitochondrial proteins released into the cytosol to induce formation of activation complexes.
      • These pathways often collaborate in executing apoptosis.

Extrinsic Pathway Details

  • Death Receptors:
    • Defined as single-pass transmembrane proteins with an extracellular ligand-binding site and an intracellular "death" domain.
    • Notable example: Fas death receptors.
  • Fas Extrinsic Pathway:
    • Interaction occurs between killer lymphocytes and target cells through Fas ligand and death receptors leading to formation of the death-inducing signaling complex (DISC).
    • Activates caspase-8 or caspase-10, which initiates the apoptosis process.

Inhibition of Extrinsic Pathway

  • Mechanisms of Control:
    • Some proteins act as restraint on the extrinsic pathway.
    • Cell-Surface Decoys:
      • Proteins that possess ligand-binding domains but lack an intracellular death domain to sequester death ligands.
    • Blocking Proteins:
      • Mimic initiator procaspases, competing for binding to adaptors to prevent inappropriate activation.

Intrinsic Pathway Details

  • Activation:
    • Triggered from within the cell due to DNA damage, lack of oxygen or nutrients, or absence of survival signals.
    • Proteins released from mitochondrial intermembrane space signal initiation of caspase cascade.
    • Cytochrome c:
      • Normally part of the electron transport chain, it plays a role in cytosol by forming the initiator complex in apoptosis.

Formation of Apoptosome in Intrinsic Pathway

  • Process Flow:
    1. Release of cytochrome c from mitochondria.
    2. Activation and recruitment of Apaf1 (apoptotic protease activating factor 1) triggered by cytochrome c.
    3. Hydrolysis of bound dATP into dADP facilitates assembly of the apoptosome which recruits and activates procaspase-9.
    4. Activation of procaspase-9 complete the caspase cascade leading to apoptosis.

Link Between Extrinsic and Intrinsic Pathways

  • The extrinsic pathway often activates the intrinsic pathway, amplifying apoptotic signals.
  • Recruitment involves the activation of Bcl2 proteins:
    • This large protein family includes pro-apoptotic and anti-apoptotic members, balancing cell survival and death.

Apoptosis and Disease Implications

  • Flawed Apoptotic Processes:
    • Too Much Apoptosis:
      • Can lead to conditions like heart attacks where cells die due to necrosis and reduced survival factors.
    • Too Little Apoptosis:
      • Mutations that inactivate death receptors can lead to cancers.
      • Example: Excessive production of Bcl2 protein linked to B cell lymphoma, allowing cells with mutations to survive longer than they should.
      • Defects in cell cycle control genes, such as mutations in the p53 gene (found in 50% of human cancers), result in the inability of cells to undergo apoptosis despite DNA damage, leading to uncontrolled cell proliferation and further mutations.