Cell Death: Apoptosis and Necrosis

Cell Death

• There are three types of cell death: apoptosis, necrosis, and autophagy
• Apoptosis is a characteristic form of programmed cell death, essential for development, maintenance of tissue homeostasis, and elimination of damaged cells
• 50 billion or more cells die each day in the human adult, and each person replaces around 70 kg of cells every year

Apoptosis

• Apoptosis is a fundamental process that can lead to diseases such as neurodegenerative disorders or cancer if it occurs too much or too little
• Cancer cells must avoid apoptosis for tumors to arise
• Apoptosis is an active, energy-requiring process leading to a characteristic series of morphological changes that accompany the degradation of the cell

Signal Transduction Pathways that Mediate Apoptosis

• There are two pathways that trigger apoptosis: the extrinsic (death receptor pathway) and intrinsic (mitochondrial) apoptotic pathways
• The extrinsic pathway is activated by the engagement of death receptors on the cell surface
• The intrinsic pathway involves the release of cytochrome c and other proteins from the mitochondria

Apoptosome

• The apoptosome is a complex that activates procaspase-9 and is composed of cytochrome c, APAF-1, and procaspase-9
• APAF-1 contains a nucleotide binding domain (NBD), a caspase recruitment domain (CARD), and a long C-terminal extension containing 13 repeats of the WD40 motif
• Formation of the apoptosome leads to the activation of procaspase-9, which can go on to activate downstream executioner caspases

Caspases

• Caspases are highly selective cysteine proteases that have a preference for cleaving proteins after aspartate residues
• Caspases can be grouped into two categories: initiator caspases and effector (or executioner) caspases
• Initiator caspases (e.g. caspase-9) activate effector caspases (e.g. caspase-3 and caspase-7), which eventually lead to cell death