19.4: When Cells Die
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As noted, few cell types live forever; most live for a finite time. Most are destined to turn over (another euphemism for dying), mediated by programmed cell death, or apoptosis. This occurs in normal development when cells are only temporarily required for a maturation process (e.g., embryonic development, metamorphosis). When no longer necessary or when genetically or otherwise damaged, such cells are detected and signaled to undergo apoptosis. Programmed cell death starts with an external signal programmed to appear at a specific time in development. The signal molecule acts on target cells to induce transcription of Bcl2 genes. Bcl2 proteins Bak and Bax are outer mitochondrial membrane channel components that allow the release of cytochrome C into the cytoplasm. This sets off molecular events leading to apoptosis. The role of cytochrome C in apoptosis is illustrated below.
Mitochondrial exit of cytochrome C is possible because it is a peripheral membrane protein, only loosely bound to the cristal membrane. It exists in equilibrium between membrane-bound and unbound states. As some cytochrome C molecules exit the intermembrane space, others detach from the cristal membrane and follow. In the cytosol, cytochrome C binds to adaptor proteins that then aggregate. The cytochrome c-adaptor complex has a high affinity for a biologically inactive procaspase. Binding of procaspase to the cytochrome C-adaptor complex causes an allosteric change in the procaspase, releasing an active caspase. Caspases are proteolytic enzymes that start the auto-digestion of the cell.
One example of apoptosis is amphibian metamorphosis. Thyroid hormone signals tadpole metamorphosis. The hormone causes tadpoles to digest their own tail cells, allowing reabsorption and recycling of the digestion products. These in turn serve as nutrients to grow adult frog structures. For their work in identifying apoptosis genes, Sydney Brenner, H. Robert Horvitz and John E. Sulston shared the 2002 Nobel Prize in Physiology or Medicine.