19.5: When Cells Die

As noted, few cell types live forever; most are destined to turn over (another euphemism for dying), mediated by programmed cell death, or apoptosis. Apoptosis occurs in normal development when cells are only temporarily required for a maturation process (e.g., embryonic development and metamorphosis). When older cells are no longer necessary or when cells are genetically damaged, they too are detected and signaled to undergo apoptosis. Frog metamorphosis is a well-known example of apoptosis. Signaled by thyroid hormone, tadpoles digest their tail cells, reabsorbing and recycling the digestion products. These in turn serve as nutrients to grow adult frog structures. Normal and apoptotic cells are compared in micrographs and drawings in Figure 19.14.

Figure 19.14: Electron micrographs and corresponding drawings compare normal (A,A′) with apoptotic cells (B,B′ and C,C′). In (B,B′), a black arrowhead indicates pyknosos (nuclear condensation), gray arrowheads indicate membrane blebs, and a white arrowhead indicates apoptotic bodies. Later in apoptosis, nuclei break down (karyorrhexis, lower right in C; upper left in C'), leaving ghost cells (gc in C), and apoptotic bodies (arrowheads, C'). A phagocyte is engulfing an apoptotic body containing a mitochondrion in C′.

Apoptosis is first associated with nuclear fragmentations and cell shrinkage ([B, B′] and [C, C′] in Figure 19.14). Apoptotic bodies in the cell leave the cell in or as “blebs” (evaginations) where they may be engulfed by phagocytes. Look at Cancer Cell Apoptosis to see a time-lapse movie of live prostate cancer cells that were chemically induced to undergo apoptosis. Look for the formation of numerous apoptotic bodies; you might also see some nonapoptotic cells undergoing cytokinesis!

We now understand the basic metabolic pathway leading to apoptosis. During development, apoptotic cell death starts with an external signal programmed to appear at a specific time in development. Similar signals appear in response to cell obsolescence or genetic damage. The biochemical pathway to apoptosis is illustrated below in Figure 19.15.

Figure 19.15: Mitochondrial proteins play a role in the biochemistry of apoptosis (programmed cell death).

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.

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, which 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 autodigestion of the cell. 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.

In contrast to apoptosis, cells that die unexpectedly from external injury undergo necrosis, an accidental rather than a programmed death. Key differences between the two cell deaths are summarized below in the illustration in Figure 19.16.

Figure 19.16: Comparison of the cellular events of apoptosis and necrosis.

From the illustration,

• The nuclei of necrotic cells do not shrink or fragment while plasma membranes extend processes to form blebs and eventually burst, releasing the cell contents.
• The nuclei of apoptotic cells shrink and fragment while the plasma membrane blebs also form, enclosing organelles and eventually fusing. The organelles can remain functional for a time.