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Programmed cell death, also known as apoptosis, is a normal process that occurs in cells when they reach the end of their life cycle. It involves a series of biochemical events that result in the death of the cell. Apoptosis is different from necrosis, as it is a regulated process that the body needs to make room for new cells and eliminate aging cells. There are two pathways involved in apoptosis: the intrinsic pathway, which is initiated by mitochondria inside the cell, and the extrinsic pathway, which is activated by factors outside the cell. There are various reasons why a cell might undergo apoptosis, including stress, depletion of nutrients, infection, and an increase in calcium concentration. Abnormal apoptosis can be associated with certain diseases. The activation of caspases, specialized protease enzymes, plays a crucial role in the apoptotic process. Both the intrinsic and extrinsic pathways ultimately lead to the activation of caspases. In addition to caspase-dependent apop Chapter 10 Programmed Cell Death and Autophagy The end of a cell's life involves a process known as apoptosis or programmed cell death. Normal human and mammalian cells undergo only a certain number of cell divisions before finally becoming unable to divide any further. At some point, a signal is given to the cell to not only cease dividing, but to die off. Another process related to this is called autophagy. In this process, the cell has mechanisms to get rid of cellular debris and parts of the cell that are no longer needed. Both of these topics are the subjects of this chapter. Apoptosis Apoptosis is another name for programmed cell death, as mentioned. It is a process that almost all cells of the human body go through at the end of the life cycle and after the cell has divided for a pre-programmed number of times. During apoptosis, a series of biochemical events occur in the cell that result in the shrinkage of the cell, fragmentation of the nucleus, DNA fragmentation, mRNA decay, leaving of the cytoplasm, and condensation of the chromatin. About 50 to 70 billion cells in the human adult die every day through this process. Apoptosis happens in children as well, with about 20 to 30 billion cells dying every day. Apoptosis is different from necrosis. In necrosis, a cell dies because of a traumatic event that kills the cell. Apoptosis is highly regulated and is actually something the human host needs to have happen to make room for new cells and to get rid of cells that are aging. Apoptosis also happens in embryos. For the fingers to separate into separate digits in embryonic development, some cells must die through apoptosis to leave behind normal tissue. The end result of apoptosis is the formation of small cell membrane-enclosed apoptotic bodies that are recognized as such by phagocytic cells that go to the site of the apoptotic cell and devour the contents of these apoptotic bodies before they can be taken up by nearby cells, which would damage these cells. Once apoptosis begins, it doesn't stop. There are basically two pathways involved in apoptosis, which will be discussed later in this chapter. Both pathways ultimately result in the death of the cell through the activation of caspases, which are specialized protease enzymes that degrade the cellular proteins. While apoptosis is a normal phenomenon, there is evidence that some diseases are directly related to abnormal apoptosis. Too much apoptosis might cause diseases that have atrophy as their major phenomenon, while too little apoptosis might be related to the inability of cells to die, as can happen in cancerous cells. As part of this chapter, we will also discuss those aspects of the cell that either promote or inhibit this apoptotic process. The beginning of apoptosis is activation. Some type of mechanism needs to be in place to activate the process that, as mentioned, will continue unabated until the cell dies. There are two known pathways that activate apoptosis. The intrinsic pathway initiates apoptosis through the action of mitochondria inside the cell and depends on the release of proteins by mitochondria that begin the apoptotic process. The extrinsic pathway is activated by factors outside the cell. It is believed that there are extracellular ligands that bind to the cell surface leading to what is known as the death-inducing signaling complex on the cell membrane. This complex triggers the death of the cell. There are a number of reasons why a cell might go through apoptosis. There may be stress placed on the organism that causes cells to start the apoptotic process. There may be external factors such as depletion of nutrients, infection by viral organisms, hypoxia, corticosteroid binding to the nucleus, or an increase in the cytoplasmic calcium concentration that trigger intracellular signals that ultimately lead to apoptosis of the cell. All of this is highly regulated. There are several intracellular enzymes that get activated in the process of apoptosis such as poly-ADP ribose polymerase which are regulatory enzymes in this process. Apoptotic intrinsic pathway Scientists understand that there is an intrinsic pathway in the cell that begins the process of apoptosis. It ultimately begins with the mitochondria. The mitochondria are the energy makers of the cell and when they cease to function, the cell has no energy and begins to die. It is believed that there are apoptotic proteins that directly attach to the mitochondria making pores in the mitochondrial membrane. This causes the mitochondria to swell or at least may cause the mitochondrial enzymes to leak out of the organelle triggering cellular apoptosis. Nitric acid may be part of this process because it is known to adversely affect the membrane potential of mitochondria resulting in swelling of this organelle. When the mitochondria swell and leak out their components, they can no longer work. In addition, they may leak out activators that trigger apoptosis. There are specialized mitochondrial proteins known by the long name of second mitochondrial-derived activator of caspases or SMACs that are released through pores in the damaged mitochondria into the cytoplasm that bind to apoptosis inhibitory proteins causing their deactivation. This prevents these proteins from keeping the cell alive so that apoptosis begins. These inhibitory proteins normally suppress the caspases and cysteine proteases in the cell but without their activity, these enzymes begin to degrade the cell. A specific channel forms as part of the intrinsic pathway in the membrane of the mitochondria called the mitochondrial apoptosis-induced channel. It releases cytochrome c that enters the cell and binds to ATP and apoptotic protease activating factor 1 or APAF1, which together bind to procaspase 9. This creates a larger protein complex called an apoptosome. The apoptosome cleaves procaspase so that it becomes caspase 9. This, in turn, causes the activation of caspase 3, which is a potent protease. Extrinsic Pathway of Apoptosis There is more than one theory as to how the extrinsic pathway causes apoptosis. The first is known as the TNF-induced model and the second is known as the fast-fast ligand-mediated model. While these differ slightly, both involve the tumor necrosis factor receptor group of receptors as they relate to signals outside of the cell destined to become apoptotic. According to one theory, tumor necrosis factor alpha, or TNF-alpha, is the extrinsic molecule that stimulates apoptosis by the extrinsic pathway. This molecule is made and released by activated macrophages, which are responsible for the cellular degeneration of pathogens in the normal human. Most human cells have two separate TNF receptors, TNF-R1 and TNF-R2. Both bind to the TNF-alpha molecule. It is believed that the binding of TNF-alpha to the TNF-R1 receptor is the thing that starts the apoptotic cycle by activating caspase. As is typical in cellular processes, the binding of TNF-alpha to its receptor doesn't directly activate caspase, but instead has two mediators. The mediators are known as the TNF receptor-associated death domain, or TRAD, and the FAS-associated death domain, or FAD. Interestingly, if there is binding to the second TNF receptor called TNF-R2, there is activation of transcription factors that promote cell survival. Therefore, apoptosis depends on the binding of TNF-R1 and not on the binding of TNF-R2. Too much TNF-alpha in the body poses a medical problem and is believed to lead to a number of medical conditions that result in cellular apoptosis, particularly autoimmune diseases. According to another theory involving the extrinsic pathway, there is a FAS receptor called the first apoptosis signal receptor, which is a transmembrane protein that is part of the TNF family of receptors. It binds to the FAS ligand outside of the cell, causing the development of a protein complex known as the death-inducing signal complex, or DISC. Some components of DISC include caspase-8, caspase-10, and the FAS-associated death domain, or FAD. This complex is highly proteolytic and starts a cascade of reactions that ultimately lead to the release of pro-apoptotic factors normally held within the mitochondria as well as the activation of the proteolytic enzyme caspase-8. When this happens, apoptosis cannot stop. Both theories involve the binding to a type of tumor necrosis factor receptor, and both theories involve the direct increase in permeability of the mitochondria. Whether the intrinsic pathway is used to induce apoptosis or the extrinsic pathway, both require that the mitochondria become permeable and that they release certain caspase activators such as cytochrome c and SMAC. There are inhibitors of these activators that could keep the cell alive, but through reasons that aren't yet known, they are not active, so caspases become activated. Regardless of the theory or pathway used to induce apoptosis, the result is the activation of a series of caspases, which have intense proteolytic activity. There are a number of caspases made by the cell, some of which have initiator activity, while others have effector activity. For the initiator caspases to become active, they need to bind to an activator protein. When this happens, the effector caspases become more active, and it is these enzymes that carry out the apoptotic process. There is an apoptotic pathway that doesn't involve caspase called the caspase-independent apoptotic pathway. It is mediated by another factor called the apoptosis-inducing factor or AIF. AIF causes condensation of chromatin and fragmentation of DNA. In the mitochondria, this factor oxidizes NADH and is found embedded in the membrane of mitochondria. When the mitochondria become damaged and more permeable, AIF is released and goes to the nucleus where it destroys DNA. Interestingly, AIF is necessary for normal mitochondrial function. Up to a third of human mitochondrial diseases, all of which are genetic in nature, have been found to be related to a deficiency in complex I, which depends on AIF to function. It may be that infants born with complex I deficiency diseases actually have a mutation in their AIF, leading to a cluster of diseases that cause blindness, seizures, deafness, and other significant birth defects. So far, it is known that caspases and AIF contribute to apoptosis, but to have cell death, the messenger RNA must be degraded so that proteins aren't made by the cell. In fact, messenger RNA degradation happens very quickly in apoptosis, but no one knows the exact mechanism behind this phenomenon. As apoptosis progresses in a cell, this cascade of events is known to occur. The cell begins to shrink and takes on a rounded shape because the cytoskeleton, which is mostly made from proteins, is degraded by caspases. The organelles pack tightly together, causing an increased density of the cytoplasm. The chromosomes become denser and form compact patches that abut against the nuclear envelope or membrane. This process is called pycnosis and is necessary for apoptosis to occur. The DNA fragments in the nuclear envelope breaks down. The fragmentation of DNA is referred to as karyorexis. The cell's nucleus breaks down into nucleosomal units containing degraded DNA fragments. The cell membrane forms blebs that result from budding of parts of the membrane that take some of the cytoplasm with it. The entire cell degrades into several small vesicles called apoptotic bodies. Phagocytes engulf and destroy the apoptotic bodies. Ultimately, the apoptotic bodies need to be removed. The process by which this happens is called epherocytosis. It is triggered by the presence of phosphatidylserine, which is expressed on the membrane of the dying cell. It is a molecule that is normally found on the interior of the cell, but a protein called scramblase takes the interior phosphatidylserine and makes it an exterior molecule, marking the cell and the apoptotic bodies that come from the cell for phagocytosis. All of this happens without generating an inflammatory response, even though phagocytes are involved in the process. Part of this process involves the separation of the cell's DNA and RNA for reasons that aren't clear. Apoptosis and disease. There is ongoing research as to the effect apoptosis has on disease, and in particular, what can happen to block the apoptotic process. The process is long and involves a lot of steps, and any dysfunction of these steps can lead to a cell that lives past its intended death date. This can mean that the cell will continue to divide and have cancerous potential, or at least some potential for disease. This has been discovered in one particular example. A type of lung cancer known as NCI H460 involves an inhibitor of the apoptosis protein. When this particular protein, called XIAP because it is an X-linked genetic problem, is overexpressed in certain cells, it blocks the activity of cytochrome c, which is necessary for apoptosis. The result is a cell that doesn't have the capacity to undergo apoptosis and a propensity of the cell to become cancerous. While this is just one example, there are likely hundreds of similar examples that aren't yet known, which might lead to cancerous diseases and other diseases involving an overproduction of certain cells. In theory, anything that blocks apoptosis could lead to cancer, viral diseases, inflammatory diseases, and autoimmune diseases. It was originally thought that whenever cells build up unnecessarily, it was from an increase in cell division. Now it is thought that the problem is more likely to be that of a lack of appropriate cell death. There are likely a number of gene mutations that interfere with the cell death process, causing or contributing to any one of the previously mentioned diseases. There are other diseases that are believed to be caused by too much apoptosis. Certain diseases that cause tissue degradation, neurodegenerative diseases, and some hematological diseases in which cells unnecessarily die may be related to excessive apoptosis of cells. It is already known that neurons unnecessarily die off in Alzheimer's disease and in Parkinson's disease. Even HIV disease is linked to apoptosis that has gotten out of control. In the case of HIV disease, the problem is a lack of CD4 plus lymphocytes. The reason there is this lack of lymphocytes is that they are triggered to die off through apoptosis in the bone marrow by the infection. It is believed that viral infections play a role in apoptosis and the effect of the virus can go either way. There are viruses that can cause apoptosis and viruses that inhibit apoptosis. Viruses can infect a cell by binding to a receptor, activating enzymes, interacting with human DNA, or expressing viral proteins that become attached to recognition proteins on a cell's surface. When this happens, the body's immune system is triggered to recognize the cell as foreign, inducing the infected cell to begin the process of apoptosis. Other viruses encode for proteins that block apoptosis. They encode for proteins that are similar enough to inhibitory proteins in the cell that normally inhibit apoptosis. Viruses that do this include the Epstein-Barr virus and the adenovirus. Other viruses encode for proteins that directly inhibit caspases, such as cowpox. Still, other viruses are known to interfere with tissue necrosis factor and FAS so that apoptosis doesn't occur. The gene p53 is necessary for apoptosis to happen in any cell, and viruses that block this gene also block apoptosis. The hepatitis B virus and a strain of adenovirus do exactly this function, inhibiting apoptosis. An added advantage to the virus that promotes apoptosis is that the virus can remain intact inside the small apoptotic bodies that are made at the end of apoptosis. The virus particles are engulfed along with the apoptotic body, and if the phagocyte can't kill off the virus, it will spread the virus, allowing the virus to take hold and infect other cells. Autophagy is a cellular process in which there is controlled destruction or disassembly of components of a cell that are not considered necessary. Not only are unnecessary parts of the cells disassembled, the process involves the recycling of the components of these unnecessary parts so the cell can reuse them. The process of macroautophagy goes on in cells. It involves taking large segments of cytoplasm and any organelles contained within it and forming a double-membraned vesicle called an autophagosome. In an orderly fashion, this vesicle fuses with a lysosome in the cell, which contains the necessary enzymes to degrade the contents of the autophagosome. The different types of autophagy include microautophagy, chaperone-mediated autophagy, macroautophagy, and mitophagy. In general, autophagy is believed to be a positive thing which helps an organism adapt to stress, but it may, in cases of starvation, cause cellular death and disease. Besides macroautophagy already described, there is microautophagy, in which the lysosome just takes up material from the cytoplasm without any autophagosome being created. Chaperone-mediated autophagy, or CMA, is more complicated. It relies on a protein complex to bind to a protein forming a bigger complex. The proteins together travel to the lysosome, where it is recognized by the lysosome. The chaperone delivers the protein to the lysosome, where it is degraded. This differs from other autophagy procedures because the lysosome is selective about what it will degrade and what it won't, and proteins get degraded one by one. In mitophagy, only a mitochondrion is degraded, and it is only degraded if it is defective or stressed in some way. This is the cell's way of getting rid of poorly functioning mitochondria that might be damaging to the cell. Some research indicates that even healthy mitochondria can be engulfed and degraded by this process. Autophagy has been implicated as a factor in Parkinson's disease. Some patients with Parkinson's disease have mutations in the genes that code for proteins necessary for the digestion of abnormal mitochondria in the mitophagy process. Autophagy results in a buildup of abnormal mitochondria, oxidative stress to the brain cell, and a buildup of abnormal proteins that can't be digested. The histological findings include cells that have swollen and depolarized mitochondria. No one knows the implications of this, nor has any mechanism for altering this abnormal pattern in a therapeutic way been discovered. Key Takeaways Apoptosis is the process of programmed cell death of cells that are diseased or old. There are certain diseases that are directly related to an excess of apoptosis or a lack of appropriate apoptosis. In cancer, apoptosis doesn't occur, and the cancerous cells keep dividing without cell death programmed into the cell's DNA. Autophagy involves the taking up of abnormal substances in the cytoplasm and digesting them through the use of lysosomes. Quiz Question 1 Multiple things happen to a cell as part of apoptosis. What biochemical or physical event is not part of this process? a. mRNA decay b. Receptor induction c. DNA fragmentation d. Cytoplasmic blebbing Answer b. All of the above things happen in apoptosis except for receptor induction. Receptors most likely get removed as part of the blebbing process as they would come off the cell when the cell membrane is used for blebbing. Question 2 Apoptosis happens all the time in the adult human as part of normal metabolic activity. About how many human cells die every day through this process? a. 10 million b. 1 billion c. 50 billion d. 1 trillion Answer c. About 50 to 70 billion cells die every day as part of the apoptotic process in the adult human. Question 3 What is the main difference between necrosis and apoptosis? a. The cell nucleus is preserved in apoptosis but not in necrosis. b. The cell doesn't actually die in necrosis but is repaired, and this doesn't happen in apoptosis. c. They are basically the same thing and happen in the same way. d. Apoptosis is programmed, while necrosis is uncontrolled and happens through trauma to the cell. Answer In both cases, the cell dies, but in necrosis, the process is uncontrolled and happens through trauma to the cell. Apoptosis is a programmed and controlled thing that happens as a natural process. Question 4 Which molecule is believed to bind to the mitochondrial membrane resulting in the swelling of the organelle and leakage of its contents? a. ATP b. Mitochondrial protease c. Nitric oxide d. H2O2 Answer c. It is believed that nitric oxide may play a role in apoptosis by binding to the mitochondria in the cells, resulting in mitochondrial swelling and release of the contents inside the organelle, triggering apoptosis in the intrinsic pathway toward programmed cell death. Question 5 The mitochondria are believed to release SMACs, which are also called second mitochondrial-derived activators of caspases. What do they do in the apoptotic process? a. They cleave a pro-caspase enzyme making it more active. b. They inhibit proteins that normally block the activity of caspase and other protease enzymes. c. They break down the nuclear envelope so an increased DNA transcription of caspases happens. d. They begin to degrade the mitochondrial lipid bilayer, further increasing mitochondrial permeability. Answer b. SMACs are known to inhibit proteins that normally block the activity of caspase and other protease enzymes that can now be free to degrade intracellular proteins. Question 6 In the intrinsic pathway of apoptosis, an apoptosome is created by the combination of intramitochondrial components and cytoplasmic components. What does the apoptosome do? a. It starts degrading enzymes and proteins within the cell. b. It inhibits proteins that normally promote cellular division. c. It bores through the nuclear envelope, disrupting DNA in the cell. Or d. It cleaves procaspase to make caspase-9. Answer d. The apoptosome is a protein complex that is part of the intrinsic pathway of apoptosis. It cleaves procaspase to make caspase-9. Caspase-9, in turn, activates caspase-3 and the process of protein degradation begins. Question 7 Independent of caspase, there is an apoptosis-inducing factor or AIF pathway that also contributes to apoptosis. What role might AIF play in the development of apoptosis? a. It damages mitochondrial enzymes. b. It degrades DNA. c. It degrades membranes on the organelles. Or d. It is another protease that attacks cellular proteins. Answer b. AIF or apoptosis-inducing factor contributes to apoptosis by degrading DNA and causing condensation of the chromosomes, which also add to the cellular death process. Question 8 The phenomenon of pycnosis needs to occur as part of cell death. What happens during pycnosis? a. The rough endoplasmic reticulum condenses and becomes smooth. b. The cell cytoskeleton breaks down. c. The organelles become denser. Or d. The chromatin becomes denser and forms patches on the nuclear envelope. Answer d. In pycnosis, the chromatin or chromosomes of the cell become denser and form patches that abut against the nuclear envelope or membrane. Question 9 In the apoptotic cascade, a variety of things happen that result in the death and total destruction of the cell. What is the very last step in the apoptotic cascade? a. The cell membrane forms blebs. b. Apoptotic bodies are phagocytosed. c. The nuclear envelope forms nucleosomal units. Or d. The chromatin is disintegrated by AIF. Answer b. The final step in the apoptotic process is the phagocytosis of the apoptotic bodies, which are small vesicles created by the dying cell's membrane as it breaks down. Question 10 What is the key difference between mitophagy and macroautophagy? a. In mitophagy, the lysosome doesn't degrade the damaged material. b. In mitophagy, smaller amounts of material are digested. c. In mitophagy, only selective proteins are digested by the lysosome. Or d. In mitophagy, the mitochondria in particular get digested by the lysosome. Answer d. In mitophagy, the mitochondria in particular get digested, where macroautophagy involves the digestion of just about anything in the cytoplasm.
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