Death is inevitable. But if we look at the cellular level, every day a huge number of cells die in our body. It regulates our body functions and is also responsible for formation and shaping of body organs. Programmed cell death or apoptosis, in a way is an important part of our body functions. It helps in regulating our body .
Have you thought what will happens if the cells stop dying. They will go into an uncontrollable growth mode, which may lead to cancer. Excessive apoptosis is also harmful as it can cause excessive cell wasting and may cause Alzheimer’s and Parkinson’s disease.
Multicellular organisms have a highly regulated number of cells. Regulation not only occurs in cell division but also in the number of cells in a particular cell type. If the number exceeds some cells trigger their internal cell death programme and commit suicide.
In a healthy adult human billions of cells die in bone marrow and intestine every hour.
|1842||Carl Vogt||First describe the principle of apoptosis|
|1885||Walter Flemming||Give more precise description of PCD|
|1965||John Foxton Ross Kerr||Distinguish the apoptosis used by electronic microscopy|
|1972||John Foxton Ross Kerr||Initially used the apoptosis term|
|2002||Sydney Brenner, Horvitz and John E suston||Awarded to Nobel prize in medicine according they contribute in apoptosis research area.|
PURPOSE OF PROGRAMMED CELL DEATH
- During development some cells need to be deleted. For example, carving out digits out of a mass of cells in an embryo.Apoptosis during the metamorphosis of a tadpole into a frog. As a tadpole changes into a frog, the cells in the tadpole tail are induced to undergo apoptosis; as a consequence, the tail is lost.
- Abnormal or infected cells need to undergo cell daeth or they may harm other cells.
- apoptosis can be used by body as regulatory mechanism to control the number of cells in our body.
DIFFERENCE BETWEEN NECROSIS AND APOPTOSIS
Here the cells die due to infection, physical damage, or chemical injury. And in this process of necrosis the cell will swell and its contents leak out of the plasme membrane . Necrosis is also associated with inflammation, redness and pain in the affected area,.
In apoptosis the cells undergo a trigged and programmed cell death.The cells shrink and develop bubble-like protrusions (technical name: “blebs”) on their surface. The DNA in the nucleus gets chopped up into small pieces, and some organelles of the cell, such as the endoplasmic reticulum, break down into fragments. In the end, the entire cell splits up into small chunks, each neatly enclosed in a package of membrane.
Apoptosis can work mainly by two pathways Intrinsic pathway and extrinsic pathway
Intrinsic pathway of cell death is triggered when the cell experiences cell stress. Extrinsic pathway is triggered when the cell receives stimulus from other cells
The intrinsic pathway mainly triggers apoptosis in response to an internal stimuli such as
- Biochemical stress
- DNA damage (this activates the p53 gene – which halts the cell cycle and initiates DNA repair. If this repair attempt is unsuccessful, apoptosis can be induced)
- Lack of growth factors.
- Very high concentration of Ca2+ ions.
- Lack of oxygen.
- Severe genetic damage.
Mitochondria is a essential organ that helps in the survival of a cell, without mitochondria a cell may die very quickly. It also plays an important role in the release of apoptotic factors. During apoptosis, the mitochondria releases cytochrome c through the action of proteins Bax and Bak, which appears to stem from a multitude of Bax/Bak homo- and hetero-dimers of Bax/Bak inserted into the outer membrane.
Once cytochrome c is released it binds with Apoptotic protease activating factor – 1 (Apaf-1) and ATP, which then bind to pro-caspase-9 to create a protein complex known as an apoptosome. The apoptosome cleaves the pro-caspase to its active form of caspase-9, which in turn activates the effector caspase-3 and caspase-7 also known as executioner caspases that leads to cell death.
Mitochondria also releases proteins known as SMACs (second mitochondria-derived activator of caspases) into the cell’s cytosol following the increase in permeability of the mitochondria membranes. SMAC bind to the protein that inhibit apoptosis therefore allowing apoptosis to proceed.
In extrinsic pathway the stimulus that triggers cell death is external. The plasma membrane posses such receptors to external death stimuli. The exernal stimuli in most cases is a cytokine and the most studied cytokine involved in cell death is tumor necrosis factor(TNF). TNF is produced by immune cells in response to adverse conditions such as
- Exposure to viral toxins
- Exposure to radiation
- Exposure to other toxic substances.
In case any of the above adverse conditions arise the cell is triggered to be apoptotic by release of TNF from the immune cells. This TNF first binds to its receptor TNF 1 present on the plasma membrane.TNF1 is a transmembrane with an external ligand binding domain and a cytosolic domain.The cytosolic domain of TNF1 contains 70 amino acids that are known as death domain. The binding of TNF to TNF1 causes a conformational change in the death domain of TNF1. This conformational change causes recruitment of adaptor protein factors such as TRADD and FADD. Along with these proteins procaspase-8 also joins to form an multiprotein complex. the adaptor protein and death domain interact through their homologous regions. Procaspase-8 and FADD posses a homologous region known as ‘death effector domain’.
Due to these interactions the two procaspase-8 cleave each other and generate an active procaspase -8 that contains four polypeptide derived from two procaspase-8. The activated caspase-8 activates executioner procaspase-3 which carries out self destruction process of the cell.
AN EXAMPLE OF APOPTOTIC FAILURE
Syndactyly is the most common congenital malformation of the limbs and occurs in 1 in 3000 live births. It is a condition in which two or more digits remain fused together after birth, due to a failure of apoptosis. Syndactyly of the most medial and lateral digits is treated at an early age, to avoid curving of the digits towards each other with growth