 In this video, we are going to discuss when the cells can die and how they die. They can die either when they become badly damaged like they can get infected, injured or even poisoned or they can die more of a natural death where the death is important for the normal functioning of the body. The death death occurs when they are infected, injured or poisoned is known as necrosis. While the natural death that occurs due to signals from within the cell or even from outside but where the cell death is a part of process of normal functioning of the body, it is known as apoptosis. Now in layman terms if we use we can say that necrosis is like a cell murder which the body does not want but the cells have become so badly damaged that the cell dies while apoptosis is known as cell suicide. Where the signal comes from within the cell or from outside which is part of the plan of the body. So this is kind of a program decided. Now in necrosis what happens that cells which have become damaged they swell and rupture so that their contents are released outside and what happens that these contents can actually act on other normal cells and they can cause inflammation. However this apoptosis which the cells suicide it is a kind of a silent death where the cell dies virtually unnoticed and the contents are not released into the surroundings. So there is no inflammatory reaction and morphologically what happens that the cell shrinks in size instead of swelling necrosis we saw that the cells swell. The cells shrinks in size condenses and starts getting fragmented and form small small blips. Now these blips start falling off. Actually apoptosis literally means falling off. So cell membrane and its contents fall off as small particles or blips which are phagocytosed by macrophages. So how does this apoptosis occur? A cell survival actually depends on growth factors which promote cell survival. So the sustainings of life there are certain growth promoting factors. Now when these growth promoting factors are present it causes cell to survive to divide and to mature but when these factors are not present it will tilt the balance towards death opposite. When example if I tell you that in case of nerve injury we see the atrophy of the muscle also which it supplies. So why this is happening is that this nerve when it is intact it releases certain growth factors also which are maintaining the survival of these muscle cells. When there is this nerve injury occurs there is automatically this absence of the growth promoting factors for the muscle and it leads to apoptosis that leads to atrophy of the muscles. So this is an example where apoptosis becomes clinically relevant. Now other way when the cells will die is that the cell may receive a death signal. So the absence of the growth promoting factors or the presence of the death signal both may lead to apoptosis. Now this death signal may come either from inside the cell or from outside the cell. The death signal from inside may be needed when there is a cell which is not formed properly or there are certain damages going on inside the cell say suppose the DNA is damaged or there is damage of the endoblasmic reticulum or mitochondria any other organelles or there is accumulation of misfolded protein. That means that cell is fundamentally functionally not required so that death signal will come from inside the cell. From outside to the death signal comes when sometimes the cell becomes infected say suppose viral infection is there what happens that cell starts expressing on its surface certain receptors and these receptors are recognized by our immune system. So it's an infected cell and it is kind of signaling the immune system to come and give a death signal to me so that I die unnoticed. Otherwise if I am severely damaged the contents of the release outside will cause severe inflammation. So this signal is coming from outside that means our immune system. Now this balance between life and death we can also state in molecular terms. Now basically this absence of growth promoting factors or the death signal what it does it changes the milieu inside the cell in terms of certain proteins. Now these proteins and family of proteins known as proapoptotic proteins or antiapoptotic proteins. So if we express this the balance between life and death in molecular terms we can write it as balance between antiapoptotic protein concentration inside the cell and proapoptotic proteins. So when there is presence of growth promoting factors or absence of death signal there is more antiapoptotic proteins in the cell promoting life. On the other hand if there is absence of growth promoting factors or presence of a death signal it leads to increase in the proapoptotic protein in the cell. So what are these antiapoptotic and proapoptotic proteins in the cell? Now under antiapoptotic come two proteins mainly BCL2 and BCLXA and under proapoptotic there are BAPs and BAP proteins. So what do these proteins do? For understanding the function of these proteins let us consider a schematic diagram of a cell. Now this cell has both antiapoptotic and proapoptotic proteins. Now one of the most crucial organelles for apoptosis is mitochondria. Let us take one mitochondria. Right now in between the two membranes of mitochondria there is very important protein cytochrome C. Cytochrome C is a mediator of apoptosis. If cytochrome C enters into the cytosol apoptosis is going to occur. Now what happens that this BCL2 and BCLXL proteins they form dimers and they are present on the outer membrane of the mitochondria. Plus these BAPs and BAP proteins they also form dimers and they are also present on the outer membrane of the mitochondria. So green one we are seeing as antiapoptotic and red ones as proapoptotic the dangerous. Now what happens normally this antiapoptotic proteins keep this proapoptotic proteins under check right. So they keep these inhibited. Now when they keep them inhibited whenever there is presence of growth factors. So growth factors are released by other cells so these growth factors are present and then they act on the receptors which are present on the cell membrane. So these growth factors bind to their receptors plus certain downstream events cause activation of this BCL2, BCLXL which keeps the proapoptotic proteins under check. When these growth factors are absent you can yourself deduce that this check will be effective. So we see how the proapoptotic proteins are becoming important when growth factors are absent. Second thing which may occur as we have seen earlier that when there is DNA damage or endoblasmic reticular damage when signal comes from inside there are certain sensors in the cell. So these sense the damage and the signal comes from inside which again acts on these proteins causing decrease in the check on the proapoptotic protein. So again this is intracellular death signal which is coming. So what are the further events which occur when the check on these proapoptotic factors is not present they form dimers and it is kind of a channel which is inserted on the outer membrane of the mitochondria. Now when this happens the cytochrome C which is present in between the membranes of the mitochondria leaks out and comes into the cytochrome. So as I already told that cytochrome C is a triggering factor which causes a cough process. Now when cytochrome is released it binds with another protein A-path 1. So this complex of cytochrome C and A-path 1 now activates certain gas phases. Now there are different numbers which are given to different gas phases in case of these signals that is the absence of the growth factor or the internal death signal the gas phases which activate is gas phase. Now remember even though here it is written outside but actually whatever events are happening they are happening inside the cell. So these gas phases nine inside the cell which were previously in individual forms they are present as pro gas phases now become active in us gas phases. So basically what has happened that either the absence of growth factor or presence of intrinsic death signal has led to release of cytochrome C from the mitochondria which has in turn activated gas phases nine. Okay before we spoke about one another death signal that is coming from the outside. Now if a cell has become virus infected then it will express certain receptors known as fast receptors. So on its membrane it expresses fast receptors. These are recognized by T lymphocytes which express fast ligand. So when the fast receptor and fast ligand bind with each other it activates a sequence of events in the cell leading to activation of another gas phases not gas phase nine gas phase eight. So there is a mechanism by which there is activation of gas phases nine and there is another mechanism that is when there is an external signal for the activation of gas phases eight. So let us summarize what they have seen till now. There is an extrinsic signal which is due to fast fast ligand and it leads to activation of gas phases eight. Now this pathway the first one where there is either absence of growth factor or presence of intrinsic death signal it is known as an intrinsic pathway for activation of a pop process. While the other pathway is known as extrinsic pop. Now despite both leading via different mechanisms different proteins are involved ultimately both lead to activation of the common gas phase gas phase three. This gas phase three leads to activation of other proteases nucleases which ultimately lead to a pop process. Now what do these proteases and nucleases do? Proteases cut down various cytoskeletal proteins of the cell which are maintaining the cell shape like microtubules, micro filaments, intermediate filaments and nucleases break down the nucleic acid. So without DNA the cell cannot survive and because of these proteases and nucleases the cell starts forming the plebs which then fall off from the cell and are recognized by macrophages and lead. Okay so we have seen that what are the signals for a pop process and whatever various pathways for a pop process but one thing remains that how do these macrophages know that they have to eat these fragments. Now when this pop process is occurring the various changes that are occurring what happens that there is a change in membrane properties also. So these blebs which are forming one example is that there is a lipid phosphatidyl serine which is present on the cytoplasmic side of the membrane that is the inner side of the membrane. Now during the process of a pop process it flips and comes to the outer side of the membrane and it is this lipid which is recognized by the macrophages which come and engulf. So only the death signal is not important. When the cells start dying it is also important the macrophages eat them very fast. Now because of this only even though day in and day out cells are dying but it is hardly detectable on histology that means you take any cut section everywhere in the body cells are dying but you won't detect these dying cells on histology.