Apoptosis: Role in Removing Damaged Cells

Role of Apoptosis in Removing Damaged Cells

• Apoptosis removes damaged cells to prevent cancer development
• Exposure to UVB (290-320nm) leads to thymine dimers, disrupting DNA structure and causing mutations
• Thymine dimers are usually repaired by the Nucleotide Excision Repair (NER) pathway
• If DNA damage is excessive, apoptosis removes the cell to prevent cancer development

Morphological Changes During Apoptosis

• Cells become smaller
• Cytoskeleton collapses
• Nuclear envelope disassembles
• Chromatin condenses and is fragmented
• Cell surface bulges (blebs)
• Cells break up into membrane-bound "apoptotic bodies"
• Apoptotic bodies are engulfed and destroyed by phagocytosis by macrophages
• Apoptosis is a rapid process, with few dead cells observed in tissue

Caspases – Intracellular Mediators of Apoptosis

• Caspases are a family of proteases that trigger a sequence of intracellular events during apoptosis
• Caspases are synthesized as inactive precursors that are activated by cleavage during apoptosis
• Initiator caspases are activated by dimerization and cleavage, then activate executor caspases
• Executor caspases activate all the changes in cell biology observed in apoptosis

DNA Fragmentation

• Executioner caspases activate a specific endonuclease, CAD, which fragments DNA into discrete chunks
• DNA fragmentation occurs between nucleosomes, resulting in a ladder of fragments

Extrinsic Pathway to Trigger Apoptosis

• Apoptosis can be triggered from outside the cell through activation of death receptors on the cell surface
• Binding of Fas ligand to the Fas receptor activates the caspase cascade
• Death receptors are part of the tumour necrosis factor (TNF) family of receptors

Intrinsic Pathway (Mitochondrial) to Trigger Apoptosis

• The intrinsic pathway is activated in response to DNA damage, detected via the p53 pathway
• p53 stimulates the aggregation of Bax and Bak in the mitochondrial membrane, leading to mitochondrial outer membrane permeabilization (MOMP) and cytochrome c release
• Cytochrome c binds to Apaf1 to form the apoptosome complex, which recruits initiator caspases and triggers the caspase cascade

Removal of Apoptotic Cell by Macrophage

• Cells undergoing apoptosis are detected and removed by phagocytosis
• Phosphatidylserine (PS) is flipped to the outer leaf of the membrane, which is detected and triggers phagocytosis

Survival Factors Block Apoptosis

• Some proteins, such as Bcl2, interfere with Bax/Bak aggregation and block apoptosis
• Most cells require continuous signaling by survival factors produced by neighboring cells that block apoptosis
• Survival factors bind to cell surface receptors, leading to the synthesis of Bcl2

Necrosis – Cell Death with Collateral Damage

• Necrosis occurs in response to a dramatic event, such as hypoxia, ischemia, high temperature, or chemical exposure
• Cells swell (oncosis) and the membrane becomes leaky and breaks, releasing contents and triggering an inflammatory response

Other Mechanisms of Cell Death: Necroptosis

• Necroptosis is a programmed form of necrosis that occurs through the binding of death ligand to death receptor
• The necroptosis pathway involves receptor interacting protein kinase 1 (RIPK1) and RIPK3, leading to the formation of an ion channel in the plasma membrane
• The cell then swells and breaks, resulting in cell death