Apoptosis is a highly regulated and controlled process that confers advantages during an organism's lifecycle. For example, the separation of fingers and toes in a developing human embryo occurs because cells between the digits undergo apoptosis.

Apoptosis produces cell fragments called apoptotic bodies that phagocytic cells are able to engulf and quickly remove before the contents of the cell can spill out onto surrounding cells and cause damage.

Because apoptosis cannot stop once it has begun, it is a highly regulated process. Apoptosis can be initiated through one of two pathways. In the intrinsic pathway the cell kills itself because it senses cell stress, while in the extrinsic pathway the cell kills itself because of signals from other cells. Both pathways induce cell death by activating caspases, which are proteases, or enzymes that degrade proteins. The two pathways both activate initiator caspases, which then activate executioner caspases, which then kill the cell by degrading proteins indiscriminately.

In addition to its importance as a biological phenomenon, defective apoptotic processes have been implicated in a wide variety of diseases. Excessive apoptosis causes atrophy, whereas an insufficient amount results in uncontrolled cell proliferation, such as cancer. Some factors like Fas receptors and caspases promote apoptosis, while some members of the Bcl-2 family of proteins inhibit apoptosis.

Apoptosis does not lead to induction of inordinate inflammation. It is contrasted with cell necrosis which does lead to induction of inflammatory responses.

During apoptosis, the cell shrinks in size. Its plasma membrane undergoes irregular blebbing and becomes leaky; this exposes phosphatidylserine, normally buried in the membrane's inner leaflet, to the surface. Internally the cell's organelles, especially the mitochondria, swell and break apart releasing proteins that are normally sequestered. Nuclear chromatin condenses, fragments, and is degraded. Ultimately the entire cell breaks into irregular, membrane-limited apoptotic bodies, displaying phosphatidyl serine on their surface, which attracts and activates phagocytic cells to remove them.

1.  

   Biochemical events lead to characteristic cell changes and death.

   These changes include

   nuclear fragmentation

   chromatin condensation

   chromosomal DNA fragmentation

   global mRNA decay.

   Signaling through various "death receptors" on the surface of cells (e.g., tumor necrosis factor (TNF) receptors, CD95) leads to a cascade that involves activation of the caspase family of molecules and leads to DNA cleavage and cell death.

 

 

In adults, apoptosis is primarily a response to cell or tissue damage beyond the cell's ability to restore its normal structure and function (e.g., sublethal mechanical or chemical trauma, viral infection, cancer). During development, it is a specialized form of differentiation in response to signals dictating the normal removal of otherwise healthy cells (e.g., removal of interdigital tissue leading to digit separation during embryonic development).

 

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1. Intrinsic (Mitochondrial) Pathway. Mitochondria express a protein, Bcl-2, on their surface that is associated with protection against apoptosis by preventing the release of mitochondrial cytochrome C. Mitochondrial damage, as occurs for example in the presence of reactive oxygen species and resulting lipid peroxidation, allows other mitochondrial proteins, (e.g., Bax, Bad, or Bak) to reach the mitochondrial surface and inactivate Bcl-2's anti-apoptotic effect. These Bcl-2 inactivators thus initiate perforation of the mitochondrial membrane, releasing cytochrome C into the cytoplasm, where it forms a complex with apoptotic protease-activating factor-1 (APAF-1) and ATP. These complexes aggregate to form apoptosomes, which bind and activate the protease caspase-9 (an initiator caspase). By then activating effector caspases (e.g., caspase 3 and caspase 7), caspase 9 initiates a cascade of protease activity that leads to destruction of cytoplasmic proteins, degradation of nuclear DNA, cell fragmentation, and phagocytosis of apoptotic bodies. Another intrinsic pathway involves the tumor suppressor protein p53, which halts the cell cycle when sufficient DNA breaks or mutations occur (e.g., after exposure to excess radiation; 3.VI.B.5.a). Sufficient p53 enhances apoptosis through interactions with multiple pro-apoptotic mitochondrial factors (e.g., Bax and Bid).

2. Extrinsic Pathway. Several external signals affect apoptosis. Growth factors (e.g., FGF) and cytokines (e.g., IL-2) can promote cell survival and thus protect against apoptosis. Other signals (e.g., FAS ligand and tumor necrosis factor (TNF) bind to cell surface receptors that then trigger apoptosis by activating the initiator caspase, caspase-8, which, like caspase-9, activates a protease cascade leading to protein and DNA degradation, cell fragmentation, and death.

During growth and development, some cells serve a function in the growth phase but need to be removed after their purpose is fulfilled. In neonates, a rapid cell growth rate is necessary; in adults, however, unrestrained cell growth can lead to cancer.

When DNA sustains irreparable damage (e.g., after low-dose radiation exposure), the cell must be destroyed so mutations that have developed will not be propagated. In this manner, apoptosis serves as a safety step by removing damaged cells from the body.