Cell Death | Zoology Optional Notes for UPSC PDF Download

Why do cells undergo apoptosis?

Cells undergo apoptosis for various reasons, and it is an intrinsic part of the cell cycle. This process is crucial for eliminating unnecessary or infected cells and is involved in normal cell cycle progression, immune system function, embryonic development, and the removal of old cells to maintain homeostasis.

Reasons for Apoptosis

1. Infection and DNA Defects: Apoptosis is triggered in cells with viral infections or irreparable DNA defects. The cell recognizes DNA abnormalities and initiates apoptosis when repair is not possible.

2. Immune System Regulation: Apoptosis is essential for the immune system to eliminate pathogen-specific immune cells once the foreign threat is removed. This prevents the persistence of immune cells that could cause autoimmune diseases.

3. Homeostasis: To maintain balance in the body, old cells undergo apoptosis to create space for new cells. This process ensures the continuous renewal of tissues and organs.

Apoptosis Mechanisms

The process of apoptosis involves three main pathways:

1. Extrinsic (Death Receptor) Pathway:

   • Initiated by ligand-receptor interactions in the tumor necrosis factor (TNF) family.
   • Involves death receptors with a death domain transmitting signals to intracellular pathways.
   • Leads to the activation of caspase-8 and the formation of the death-inducing signaling complex (DISC), ultimately triggering apoptosis.

2. Intrinsic (Mitochondrial) Pathway:

   • Initiated by non-receptor-mediated processes that produce intracellular signals affecting mitochondria.
   • Involves factors promoting or inhibiting apoptosis, leading to mitochondrial membrane permeability changes.
   • Release of pro-apoptotic proteins (e.g., cytochrome c) activates caspase cascades, resulting in apoptosis.

3. Perforin/Granzyme Pathway:

   • Employed by cytotoxic T lymphocytes to induce apoptosis in tumor or virus-infected cells.
   • Involves secretion of perforin, creating pores for granzyme A and B to activate caspases or induce caspase-independent pathways.

4. Execution Pathway:

   • Culmination of both extrinsic and intrinsic pathways.
   • Activation of caspase-3 leads to the degradation of cellular components, nuclear material, and cytoskeletal proteins, resulting in apoptosis.

Inhibition of Apoptosis

• Negative regulators, such as Inhibitors of Apoptosis Proteins (IAPs) and Bcl-2, prevent cell death signaling.
• IAPs bind caspases to inhibit their activation, while Bcl-2 regulates mitochondrial membrane permeability.
• Cancer cells often escape apoptosis, contributing to tumor growth.

Regulation of Apoptosis

• Proteins like c-FLIP and Toso regulate the extrinsic pathway by inhibiting caspase activation.
• Bcl-2 family proteins control mitochondrial permeability in the intrinsic pathway.
• Various proteins and genes tightly regulate apoptosis at different stages.

Apoptosis Assays

1. Cytomorphological Alteration:

   • Light microscopy and transmission electron microscopy visualize apoptotic cells and structural changes.

2. DNA Fragmentation:

   • DNA laddering and TUNEL assay detect DNA cleavage during apoptosis, confirming later stages.

3. Caspase Detection:

   • Various assays detect caspase activity, cleaved substrates, and regulators using techniques like western blot and immunohistochemistry.

4. Membrane Alterations:

   • Annexin V staining detects phosphatidylserine residues on apoptotic cell membranes.

5. Whole Mount Detection:

   • Dyes like acridine orange visualize apoptosis in tissues or embryos, but differentiation from necrotic debris is necessary.

6. Mitochondrial Assays:

   • Monitor mitochondrial events using laser scanning confocal microscopy, measuring permeability, depolarization, and other parameters.

Apoptosis Significance

• Essential in development, organ formation, and removal of unnecessary cells.
• Crucial for maintaining homeostasis and preventing autoimmune diseases.
• Impacts immune system function, neuronal development, and tissue remodeling.

Examples of Apoptosis

• Metamorphosis in frogs, nervous system development in humans, endometrium sloughing, and organ formation during embryonic development.

Apoptosis and Cancer

• Cancer cells often evade apoptosis, contributing to tumorigenesis.
• Genetic changes, imbalances in pro-apoptotic and anti-apoptotic proteins, and reduced caspase function play roles in cancer development.
• Targeting anti-apoptotic proteins is a strategy in cancer treatment.

Apoptosis in Plants

• Programmed cell death in plants shares similarities with animals but involves protease proteins instead of caspases.
• Controlled by oxidative status, phytohormones, and DNA methylation.
• Morphological changes lead to cell breakdown, with vacuolar incorporation