Cell Death in Medical Science

Teaching Objectives

• Understand the timing and significance of cell death.
• Differentiate between necrosis and apoptosis.
• Define apoptosis and necrosis intracellular pathways.
• Recognize the clinical implications of apoptosis.

Apoptosis vs Necrosis

• Apoptosis:

  • Regulated cell death, occurs in a controlled manner.
  • Cells quickly removed without releasing contents.
  • Triggers include extrinsic factors (e.g., Fas ligand) and intrinsic factors (e.g., DNA damage).
  • Does not invoke an inflammatory response.

• Necrosis:

  • Accidental cell death due to lack of ATP (e.g., hypoxia or ischemia).
  • Results from physical damage to cells.
  • Contents released, leading to inflammation.

Role of Apoptosis

• Essential in tissue remodeling and development.
• Critical during:
  • Metamorphosis in amphibians.
  • Limb development in embryos.
  • Establishment of the adaptive immune system.

Removal of Damaged Cells

• Apoptosis eliminates cells with excessive DNA damage such as thymine dimers (caused by UVB exposure).
• Thymine dimers can disrupt DNA replication, leading to potential mutations and cancer development.
• Keratinocytes in skin form "sunburn cells" and undergo apoptosis from excessive UV exposure.

Morphological Changes in Apoptosis

• Cells shrink and lose cytoskeletal structure.
• Disassembly of the nuclear envelope and fragmentation of chromatin.
• Formation of membrane-bound "apoptotic bodies."
• Rapid clearance of apoptotic bodies by macrophages with minimal observable dead cells.

Caspases and Their Role

• Caspases, a family of proteases, mediate the apoptosis process.
• Synthesized as inactive precursors; activated by cleavage.
• Initiator caspases: Triggered by external signals, dimerize, and get activated.
• Executor caspases: Activated by initiators to carry out cellular changes associated with apoptosis.

DNA Fragmentation Mechanism

• Executioner caspases cleave iCAD, allowing CAD (specific endonuclease) to fragment DNA.
• Results in ladder-like patterns of DNA fragments due to cleavage between nucleosomes.

Extrinsic Apoptosis Pathway

• Triggered by external signals via death receptors on cell membranes.
• Activation of Fas receptor by Fas ligand leads to the formation of the death-inducing signaling complex (DISC), initiating the caspase cascade.
• Part of the TNF receptor family.

Intrinsic Apoptosis Pathway

• Activated in response to intracellular DNA damage via the p53 pathway.
• p53 facilitates the aggregation of Bax and Bak proteins in the mitochondrial membrane.
• Mitochondrial outer membrane permeabilization leads to cytochrome c release, forming the apoptosome with Apaf1, recruiting initiator caspases and triggering apoptosis.

Apoptosis and Cancer

• Cancers result from uncontrolled cell proliferation owing to mutations.
• An increase in cell division or a decrease in apoptosis contributes to tumor development.
• Tumors often have necrotic cores due to insufficient blood supply.

Summary Points

• Recognize significant differences between necrosis and apoptosis.
• Understand the functional roles of apoptosis in biological processes.
• Comprehend both extrinsic and intrinsic pathways of apoptosis.
• Appreciate the crucial role of survival factors in cell fate.

This quiz focuses on the fundamental concepts of cell death, including the differences between necrosis and apoptosis. It will explore intracellular pathways involved in both processes and their clinical significance. Prepare to assess your understanding of cell biology related to medical science.