 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 95), 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 to change its physical and chemical properties and lead to blebbing without loss of membrane integrity (see Fig. 3.18).
 Formation of apoptotic bodies, the final step of apoptosis, results in cell breakage (Fig. 3.19a, b, and c). These membrane-bounded vesicles originate from the cytoplasmic bleb containing organelles and nuclear material. They are rapidly removed without a trace by phagocytotic cells. The removal of apoptotic bodies is so efficient that no inflammatory response is elicited. Apoptosis occurs more than 20 times faster than mitosis; therefore, it is challenging to find apoptotic cells in a routine H&E preparation (Fig. 3.19d).
Apoptosis is regulated by external and internal stimuli.
Apoptotic processes can be activated by a variety of external and internal stimuli. Some factors, such as tumor necrosis factor (TNF), acting on cell membrane receptors, trigger apoptosis by recruiting and activating the caspase cascade. Consequently, the TNF receptor is known as the “death receptor.” Other external activators of apoptosis include transforming growth factor  (TGF-), certain neurotransmitters, free radicals, oxidants, and UV and ionizing radiation. Internal activators of apoptosis include oncogenes (e.g., myc and rel ), tumor suppressors such as p53, and nutrient-deprivation antimetabolites (Fig. 3.20). Apoptotic pathways are also activated by the events leading to mitotic catastrophe—namely, malfunction of specific DNA-damage checkpoints in the cell cycle (see page 87). Mitotic catastrophe is accompanied by chromatin condensation, mitochondrial release of cytochrome c, activation of the caspase cascade, and DNA fragmentation.