Apoptosis

Apoptosis is a process by which cells in a multicellular organism undergo a controlled death. This programmed cell death (PCD) involves a highly regulated series of cellular reactions that result in characteristic changes in cell morphology and the degredation of cellular components while maintaining cell membrane integrity. In contrast to necrosis, apoptotic cells remain in control of their physiology and maintain their energy balance and osmotic potential. This is important because by avoiding osmotic lysis, apoptotic cells do not release their contents into the extracellular space; some of such released components can signal the initiation of an inflammatory responses that can cause further cell injury or death in surrounding tissue.

Apoptosis is a normal, physiological process important for the growth, development and maintenance of multicellular organisms. The first function of apoptosis occurs during embryological development, wher it aids in in defining organ shape. For example, differentiation of fingers and toes of some organisms occurs by the apoptosis of cells between these digits.

It can be activated by cells that have been injured or stressed before they become unable to control their metabolism, avoiding necrosis. Cells may also apoptose if they undergo changes (e.g. genetic mutations) that lead to uncontrolled or inappropriate cell division; this process benefits the organism by removing cells that are functioning abnormally and which could potentially become cancerous. Apoptosis is also important in allowing cells no longer needed by the body to be removed efficiently and safely.

Defects in apoptosis are implicated in a large variety of diseases. For example, impaired activity or loss of apoptotic pathways act as contributing factors to the formation of cancer. Anti-cancer treatments can include drugs that encourage apoptosis of these deficient cells to prevent their proliferation. An increase in apoptosis has also implicated as having a significant role in autoimmune disease as well as the neurodegenerative Alzheimer’s and Parkinson’s diseases.

The process of apoptosis

Apoptosis is controlled by a number of tightly regulated signalling pathways that control a cell's survival based on its local environment and internal condition. All of these terminate on a final effector pathway involving a group of proteases called caspases, many of which are the final effectors of apoptosis. Caspases recognise specific sequences containing aspartate residues in certain proteins and can cleave them when active. They perform apoptosis both by breaking down cellular proteins directly and also by activation of other hydrolytic enzymes such as caspase activated DNAse (CAD); together the enzymes break down the cell's contents in a controlled fashion.

The extrinsic pathway

This pathway involves the direct activation of the apoptotic cascade by an external signalling molecule, called a death ligand, which allow cells to order other cells to undergo apoptosis. Two important examples of this apoptotic mechanism in mammals are the tumour necrosis factor (TNF) induced model and the Fas-Fas ligand-mediated model. TNF is a cytokine produced by activated macrophages, and plays important roles in both apoptotic and cell survival processes. It has two receptors, called TNF-R1 and TNF-R2, both of which are found on most cells in the human body. In the apoptotic pathway, TNF binding to TNF-R1 allows the receptor to bind the membrane proteins TNF receptor 1-associated death domain (TRADD) and Fas-associated death domain (FADD) via a special sequence on the intracellular portion of the receptor called a death domain. Both FADD and TRADD can then recruit inactive caspase-8 via another domain called a death effector domain to the receptor complex. Once recruited, caspase-8 can undergo autoproteolysis, activating itself; it can then activate caspase-3 by proteolysis, which starts the signalling cascade that leads to apoptosis.