Apoptosis

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Apoptosis

 

Introduction

Cells in an organism can die through necrosis, because the cell has been damaged or has been exposed to chemical radiation. The cell in this case swells, bursts and releases its content in the surrounding tissue, and can lead to inflammation (1, 2).

Or cells can die through apoptosis that has been likened to cell suicide, where the cell dies and its contents are cleaned systematically to avoid spillage. This also helps in reuse and recycling of the organic compounds of the died cell (1, 2).

The word 'Apoptosis' was coined only in 1972 by Kerr, Wyllie, and Currie, even though some parts of the process were identified earlier (1).

Definition

Apoptosis is referred to as programmed cell death (1). It is a very complex process that has two possible pathways. If the process is triggered by the organism it is the extrinsic or death receptor pathway. If the process is initiated from within the cell itself it is through the intrinsic or mitochondrial pathway (1). So far apoptosis has been seen only in animals (3).

Uses of Apoptosis

Apoptosis is an important part of development, survival and of aging in animals (3). It is the process by which cells that are no longer needed, or those produced in excess or those that become dangerous to the rest of the animal are destroyed (3).

Development

During the embryonic and early stages apoptosis destroys cells that are no longer needed, or those produced in excess. For example tadpoles have a tail that they lose during metamorphosis into an adult frog. The cells in the tails are destroyed by apoptosis (3).

In embryonic stage in humans, the hand is a web, and the connecting tissue between the fingers is lost through apoptosis (4). Nerves cells are also produced in excess, as linking nerves is an intricate job. Those cells that that do not succeed in forming proper connection, are not functional and have to be discard through apoptosis (3)

Survival

Due to mutations in the DNA some cells may become defective. These kinds of defective cells that are potentially dangerous to the entire body have to be destroyed. Cells which become infected by virus recognise that they are infected, and destroy themselves to prevent the infection from spreading further (3). Cancer is an example where the cell division of dangerous cells is not stopped by apoptosis (5).

Aging

Cell multiplication and apoptosis occur all the time in an organism. As the organism grows older, there is more cell death than cell multiplication leading to aging and then death (6).

Mechanism of Apoptosis

During apoptosis, the cytoskeleton, which are protein filaments maintaining the cell shape are broken down (4). So is the nuclear membrane and the nuclear DNA is fragmented. The cell surface is changed by blebbing, attracting specialized macrophages or any other surrounding cells to engulf the dying cell (4, 6).

Apoptosis occurs on a cell basis (7). There are two main parts, initiation and execution (7). The set of enyzmes necessary for apoptosis called procaspases exist in an inactive form in every cell, waiting to be activated. When these are activated they trigger a cascade of action that executes apoptosis (4). The initiation phases are different in intrinsic and extrinsic apoptosis. The execution phase is the same.

Initiation

In both cases, there is a sequence of actions involving different proteins, much like a domino effect. Initiation deals with how the domino effect starts.

Intrinsic or mitochondrial pathway

In a healthy cell, mitochondria have a protein Bcl-2 which inhibits apoptosis. When the cell is damaged, a protein called Bax is activated. Bax moves to the mitochondria and inhibits Bcl-2, then it breaks down the mitochondrial membrane by making holes in it. Cytochrome-c from the mitochondria is released into the cytoplasm. It binds to the protein Apaf-1 to form a complex called apotosomes (2).

Apotosomes bind to Caspase-9, activating it. Caspase-9 in turn activates Caspace-3 starting the caspace cascade (1, 2).

Extrinsic pathway or death receptors

The trigger for apoptosis comes from outside the cell. For example, when the organism detects a damaged or infected cell, it sends lymphocytes. These carry two proteins FAS ligand (FASL) and TNF, the death activators (2).

Each cell has corresponding death receptors for these two proteins. When FASL and TNF bind with their receptors, they attract adaptors inside the cell which activate Caspase-8 found in the cytoplasm of the cell (1, 2)

Caspase-8 in turn activates Caspace-3 starting the caspace cascade (1).

Execution phase

During the caspace cascade, many Caspace-3 molecules are activated, which work by cleaving proteins, including those that form the cytoskeleton, nuclear membrane, and DNA (1, 2).

Caspace-3 also activates endonucleases that breakdown DNA, and proteases that breakdown cytoplasm (a). This results in chromatin (nuclear material) and cytoplasm condensation. So the cell shrinks in size, and next breaks down to give cytoplasmic blebs and apopotic bodies (1, 4).

The last part is phagocyctsis, where the apopotic bodies, the remains of the dead cell, are absorbed by neigbouring cells or by special macrophages. This way the organic compounds in the dead cell are recycled (1).

Following is a video, made by the the Walter and Eliza Hall Institute of Medical Research Melbourne, Australia which explains both the initiation processes and the execution phases (8).

https://www.youtube.com/watch?v=9KTDz-ZisZ0

Medical Applications

Anti-cancer drugs and radiation are trying to find cures for cancer by triggering apoptosis of cancer cells. In other diseases like AIDS, Alzheimer's and Parkinson's diseases apoptosis activity is very high, and research is on to find ways of regulating it to cure these problems (9).

Summary

Apoptosis is programmed cell death that occur at the level of a cell, in animals. It is a necessary mechanism for the development and survival of an organism and also causes aging.

The process can be triggered internally by the mitochondrial pathway, or through external activation of death receptors in the cell wall. It is a very complex mechanism involving many proteins.

Sources

  1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2117903/
  2. http://www.biology-pages.info/A/Apoptosis.html
  3. https://www.scientificamerican.com/article/why-does-programmed-cell/
  4. https://www.ncbi.nlm.nih.gov/books/NBK26873/
  5. http://protein.bio.msu.ru/biokhimiya/contents/v75/full/75130155.html
  6. https://www.promega.de/resources/product-guides-and-selectors/protocols-and-applications-guide/apoptosis/
  7. https://www.britannica.com/science/apoptosis
  8. https://www.youtube.com/watch?v=9KTDz-ZisZ0
  9. http://science.howstuffworks.com/life/cellular-microscopic/apoptosis.htm

 

 

 

 

 

 

 

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