Mechanisms of cell death

1. Necrosis. 

Necrosis is usually characterised by:

1)    1) The loss of cellular compartments by lysis resulting in the destruction of cellular membranes and release of its components including digestive enzymes, such as lysosomal enzymes.

2)     2) Inflammation as the tissue recruits immune cells to the site of injury trying to neutralize its effect, limit it and hopefully eliminate it.

3)     3) Debris (pus) which results from the digestion of cellular components by the enzymes released from these inflammatory cells.

4)     4) Calcification which can occur intracellularly due to the combination of calcium, which enters the cell as it undergoes necrosis, to phosphates within the mitochondria. This combination results in the production of hydroxyapatite crystals, which are the main components of our bones. Crystal formation then propagate depending on the local concentration of phosphate and calcium, as well as the amount of collagen present (as it leads to the enhancement of the process).  

 In fact, the destruction and death of the surrounding tissue is as a result of the exposure of the cells to the digestive enzymes, such as proteases, that has been released by the necrotic cell. This exposure usually results in the degradation of the intracellular and extracellular components which sometimes result in the destruction and the death of that part of the tissue and often scarring.

2. Apoptosis.

Apoptosis was firstly and hence very well understood in the nematode worm Caenorhabditis elegans (or C. elegans). This is because it has been used as a model for the study of cell death (especially apoptosis) for several years, although various mammalian mechanisms have been discovered. The C. elegans has approximately 1100 cells from which it normally loses 131 cells during development.  

 

CED genes (or C. elegans death genes): 

 

This is a group of genes that has been found to be critical for worm cells to undergo apoptosis. It is consisted of more than 10 genes, with four key genes. In fact, it was discovered that cell death is affected by the up- or down-regulation of those 4 genes in particular. The four genes are EGL-1, Ced 3, Ced 4 and Ced 9. Those genes are either pro-apoptosis (promotes it) or Anti-apoptosis (inhibits it)

EGL-1= this encodes for a protein that contain apoptotic activator domain, functions by blocking Ced 9.

Ced 3= triggers apoptosis, it encodes a protease that is reqired for apoptosis (pro-apoptotic gene).

Ced 4=  encodes for a protein that is required to activate Ced-3 (pro-apoptotic gene).

Ced 9= the only apoptosis inhibitor of C. elegans, does so by preventing mitochondrial porin channels opening, acts to inhibit Ced 4 (anti-apoptotic gene).

This diagram illustrates Ced genes and their roles in apoptosis induction. This is adapted from http://www.ecdo.eu/PDF_word%20documents/Franc.pdf.

 

 Mammalian Homologues of Ceds:

 BH3-only proteins= EGL-1 homologue, those are either synthesised or activated upon apoptotic stimulation (pro-apoptotic). 

The caspases= Ced 3 homologues, those are called " the executioners of cell death", there are at least 10 of those in mammals. They are synthesised as procaspeses, which are activated by proteolytic cleavage.

Apaf1= Ced 4 homologue, pro-apoptotic, this gene encodes a cytoplasmic protein, procaspase-activating adaptor protein, that forms the central hubs in the apoptosis regulation network.

Bcl-2= Ced 9 homologue, anti-apoptotic gene, mainly located on the cytosolic surface of mitochondrial outer surface and nuclear membrane to help conserving their integrity.

 

Mammals have two pathways of apoptosis:

1) Extrinsic pathway which is stimulated by the binding of extracellular signal protein to the so-called cell-surface death receptors. Those are single transmembrane proteins with an extracellular ligand-binding domain and an intracellular death domain, (an illustration of death receptors). Death receptors are homotrimers which belong to the tumor necrosis factor(TNF) receptor family. This family consists of a receptor for TNF and the Fas death receptor. When those receptors are activated, their death domain recruits intracellular adaptor proteins forming a death-inducing signaling complex (DISC). Those complexes recruit initiator procaspases (procaspase 8, 10 or both) and initiate them, which in turn activate executioner procaspases downstream leading to the induction of apoptosis. 

2) Intrinsic pathway which is usually activated as a response to an injury, DNA damage or any other stress inside the cell. It depends on the release of some proteins from mitochondria that are normally desidents of mitochondrial intermembrane space. Some of these released proteins triggers a caspase proteolytic cascade in the cytoplasm which ultimately results in apoptosis. For instance, Cytochrome C binds to Apaf 1 which oligmerizes to a heptamer structure called apoptosome. Then, Apaf 1 in the apoptosome recruits initiator procaspeases, similar to procaspases 8 and 10 by DISCs. This then activates caspase 9 which activates downstream proteases inducing apoptosis.

 

 

A diagram showing an overview of the extrinsic and the intrinsic pathways.