Figure 268

Schematic diagram showing the relationship between cell death and cell division. Under normal physiologic conditions (homeostasis), the rate of cell division and the rate of cell death are similar. If the rate of cell death is higher than that of cell divisions, a net loss of cell num ber will occur. Such conditions are categorized as cell loss disorders. When the situation is reversed and the rate of cell division is higher than the rate of cell death, the net gain in cell number will be prominent, leading to a variety of disorders of cell accumulation.

Necrosis begins with impairment of the cell's ability to maintain homeostasis

As a result of cell injury, damage to the cell membrane leads to an influx of water and extracellular ions. Intracellular organelles, such as the mitochondria, rER, and nucleus, undergo irreversible changes that are caused by cell swelling and cell membrane rupture (cell lysis). As a result of the ultimate breakdown of the plasma membrane, the cytoplasmic contents, including lysosomal enzymes, are released into the extracellular space. Therefore, necrotic cell death is often associated with extensive surrounding tissue damage and an intense inflammatory response (Fig. 2.69).

Apoptosis is a mode of cell death that occurs under normal physiologic conditions

In apoptosis, the cell is an active participant in its own demise ("cellular suicide"). This process is activated by a variety of extrinsic and intrinsic signals. Cells undergoing apoptosis show characteristic morphologic and biochemical features (see Fig. 2.69):

• DNA fragmentation occurs in the nucleus and is an irreversible event that commits the cell to die. DNA fragmentation is a result of Ca2+-dependent and Mg2+-dependent activation of nuclear endonucleases. These enzymes selectively cleave DNA, generating small oligonucleosomal fragments. Nuclear chromatin then aggregates, and the nucleus may divide into several discrete fragments bounded by the nuclear envelope.

• Decrease in cell volume is achieved by shrinking of the cytoplasm. The cytoskeletal elements become reorganized in bundles parallel to the cell surface. Ribosomes become clumped within the cytoplasm, the rER forms a series of concentric whorls, and most of the endocytotic vesicles fuse with the plasma membrane.

• Loss of mitochondrial function is caused by changes in the permeability of the mitochondrial membrane channels. The integrity of the mitochondrion is breached, the mitochondrial transmembrane potential drops, and the electron transport chain is disrupted. Proteins from the mitochondrial intermembrane space, such as cytochrome c, are released into the cytoplasm to activate a cascade of proteolytic enzymes called caspases that are responsible for dismantling the cell. The regulated release of cytochrome c suggests that mitochondria, under the influence of Bcl-2 proteins (see page 74), are the decision makers for initiating apoptosis. Thus many researchers view mitochondria either as the "headquarters for the leader of a crack suicide squad" or as a "high security prison for the leaders of a military coup."

• Membrane blebbing results from cell membrane alterations. One alteration is related to translocation of certain molecules (e.g., phosphatidylserine) from the cytoplasmic surface to the outer surface of the plasma membrane. These changes cause the plasma membrane

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