Control of Cell Death: Videos & Practice Problems

Apoptosis, or programmed cell death, is a highly regulated process essential for maintaining cellular health. It balances cell division and death, preventing issues like cancer. Apoptosis can be triggered by intrinsic signals, such as DNA damage leading to cytochrome c release, or extrinsic signals from immune cells activating death receptors. Key proteins involved include caspases, which degrade cellular components. Inhibitors of apoptosis prevent unwanted cell death by blocking caspase activation. Understanding these mechanisms is crucial for comprehending cellular processes and their implications in diseases.

Overview

Hello, everyone. In this lesson, we are going to talk about regulated or programmed cell death, which is also called apoptosis. Okay, so cells, whenever they have been damaged in some way or aren't doing what they're supposed to be doing or if they are infected by a virus or something like that and they are told to actually commit suicide, this is apoptosis. And apoptosis is the process of regulated cell death. You'll also commonly see programmed cell death. It’s essentially the same thing. Programmed cell death and regulated cell death is apoptosis, and this is where the cell decides that it is going to basically commit suicide and it is going to break itself down into its parts and be destroyed. And this is a very extremely regulated process to ensure the health of the cells that surround the cell that is going through apoptosis. This is a really important process. You will definitely be asked about this process on your quizzes and your tests and it's really important because it balances cell division with apoptosis. So cell division and cell death need to be in balance or we're going to have things like cancer and tumors where cell division gets out of control and cell death is not working like it's supposed to. So apoptosis is controlled cellular death which is going to meet the same number as cell division. So we don't have too many cells in our body and we don't have things like growths and tumors. Now this is a very regulated death. It's neat and clean and the reason that it's neat and clean is so it doesn't damage other cells. If you think about cells and the different organelles that we've learned about, there are organelles like lysosomes which contain enzymes that are really dangerous because they break down things. Like lysosomes are the recycling and garbage center of cells. So they're going to have these enzymes whose main job is to destroy things, right? So if the lysosome is ruptured and then the cell ruptures, all of those enzymes whose job is to destroy are released into the body and enzymes whose job is to destroy are released into the body. And that's really problematic because then they start destroying things they're not supposed to be destroying. So apoptosis really gets a handle on this because it doesn't allow these dangerous components of the cell, things like lysosomal enzymes and stuff like that, to be released randomly into the body. So that's why we're gonna need this process because it's gonna be very neat and tidy and compartmentalized.

So what are some major things that are going to happen? Here are some of the major things. Obviously, not all of these steps of apoptosis are listed here. These are just some major steps. It is more complicated than this, but I want you to know that the cell is going to degrade into blebs. Yes, that is a scientific term no matter how much it sounds like it's not a scientific term. I'll show you a picture of a bleb in just a second. Basically, a bleb is where the cell, you know how usually a cell is nice and round kind of like this, an animal cell? A bleb is where the cell kind of starts to pinch off part of its body and then it's going to pinch off in a whole bunch of different places and basically this is going to be the main way that the cell is broken down into smaller components. Those blebs kind of push themselves out of the cell then they will be snipped off and then that will be a component and then it will be broken down in this way. So the cell is going to degrade into these compartments of plasma membrane and these different cellular compartments called blebs. Now, the nuclear envelope is also going to degrade. It is going to break down and then the DNA is going to be cut up and destroyed by different DNA processing enzymes. The cytoskeleton, the microtubules, actin filaments, and intermediate filaments are going to be broken down and going to be collapsed so that the cell can be compartmentalized, and then the cell is dismantled into apoptotic bodies. Whenever a bleb actually is released into this little component that is going to be the apoptotic body. And basically, you're going to see this big round cell be chopped up into all these little components called apoptotic bodies and that is going to be a bleb forms in an apoptotic body.

Now this whole process of apoptosis can be controlled in 2 ways, extrinsically or from the outside cell. Apoptosis is determined by cellular signaling as almost all things in the cell are. So the cell has to be given a signal to go into apoptosis. If it's extrinsic, it comes from the outside of the cell, meaning that an immune cell generally is telling that cell it needs to go through apoptosis. Generally, an immune cell will tell a body cell to do this if it's infected or if it's damaged in some some way or for whatever reason, the immune cell doesn't believe that cell is fit to do its job. It will give this extrinsic signal or signal from the outside, and then that signal will trigger apoptosis. Now intrinsically is where the cell itself recognizes that it needs to go into apoptosis, and it is going to have an internal signaling process that begins the process of apoptosis. Generally, this is gonna happen when problems occur with the mitochondria. If the enzymes inside of the mitochondria leak into the cytoplasm because the mitochondria might be damaged, then apoptosis is generally going to occur. There are some other ways that this can happen, but that's one of the most common. So something goes wrong, detrimentally wrong that cannot be fixed and the signaling process begins to happen inside of the cell and the cell goes into apoptosis. So those are gonna be the 2 signaling pathways that apoptosis can be triggered by. I'm gonna show you this image of apoptosis versus necrosis. Now I haven't talked about necrosis yet, but necrosis is gonna be different than apoptosis. It's not regulated cell death. Basically, necrosis happens when you have an injury or the cell is diseased in some way or something happens. So necrosis like if you fall and you scrape up your arm or something like that, those cells went through necrosis because they're physically damaged by an injury that is not controlled cell death, that is traumatic cell death. That's necrosis. It's messy. It's not clean. It's not compartmentalized, and it allows the cells to kinda just burst and then the body has to clean it up from there. So apoptosis is a lot nicer, a lot cleaner, more regulated. Necrosis is going to be a traumatic cell death that was not planned for.

Okay. So here's gonna be the process of cellular death. You can see the normal regular cell here that is going to begin cellular death. Here are those blebs I talked about that happen in both necrosis and apoptosis. You can see that they're kind of these little protrusions of the plasma membrane, and then they continue out here and get larger and larger until they become these apoptotic bodies. Now, this is very regulated. You can see that these little apoptotic bodies are membrane enclosed and they're closing off all of the things inside of those little bodies, so nothing gets out into extracellular matrix. That does not happen in necrosis. You can actually see in necrosis, the plasma membrane is broken right here, and you're gonna see all these cellular components enter into the extracellular matrix, which can be dangerous to the surrounding cells. So that's why the body chooses to do cellular death in the regulated way so the cells around the dying cell are not damaged. So those are going to be the different components of apoptosis. I'm gonna go down and we're gonna talk about the proteins that actually do this process.

Okay, so the proteins that are involved in this process are going to be the caspase proteins. And for apoptosis, caspases are the proteins responsible for degrading the different cellular components. I believe caspases are known to degrade or break down 600 different cellular components, which is a ton. Right? Now, caspases are gonna do the heavy lifting, but before they're actually activated, they're called procaspases. Procaspases are in their precursor form because, think about it. Do you want destroying proteins just roaming around the cell all the time? No. So in their procaspases form, these proteins are not degrading, not destroying anything. In fact, they have to be activated to turn into caspase proteins. Because we don't want these dangerous, degrading, destroying caspase proteins just roaming around the cell all the time. We only want them activated when apoptosis is triggered. So the procaspase must be activated via cleavage. So basically, you take the procaspase protein, cut some of it off, and it turns into a caspase protein, which is activated and ready to go. And then certain activated caspase proteins can be utilized to activate other caspase proteins.

So, some caspase proteins that I do want you to know are going to be 2 important types. The first one's going to be the initiator. Caspases. Initiator caspases, you can probably guess what they do. They're going to activate other caspases. They're gonna cause kind of like this chain reaction, activating caspases and other enzymes that are utilized for degradation and apoptosis. Now, the second type I want you to remember have a really great name. They are the Executioner caspases. You can probably guess what they are going to do. They are going to break down the cell. They are actually going to break down the cellular components and begin breaking down that cell. Now, initiator caspases are going to be activating other caspases including executioner caspases. Telling those executioner caspases to begin, basically, killing the cell and breaking down its different components. So those are some important caspases you should know.

Now, what if the cell doesn't want to go into apoptosis? Most of the time it doesn't, right? So how do we stop these processes from happening when the cell does not need to go into apoptosis? We're gonna use the inhibitors of apoptosis. These inhibitors bind to and inhibit the caspases. So either they're going to stop procaspases from turning into caspases, or they're going to stop caspases from functioning. So if procaspases cannot be cleaved or cut to activate them, they can't turn into degrading caspases. And inhibitors of apoptosis are also going to bind to already activated caspases and turn them off. So those are very important, especially when the cell does not want to go into apoptosis.

Now down here in this diagram, a lot of it I don't really need you to know. I just wanted you guys to look at these things that I'm gonna highlight here in blue. These 2 caspase or these 2 caspase proteins and the procaspase protein. So, procaspase 8 is obviously a procaspase. And, what do procaspases do? Well, remember they're going to cleave. They're going to be cut. And this arrow here is representing the cleavage event. This is where part of the procaspase is gonna be cut off. And you can actually see this cutting happening right here and part of the procaspase is removed. Now, what happens? What does it turn into? It turns into this caspase number 8. Well, what type of caspase is this? Can we determine this? Well, look, this caspase is interacting with another caspase. So, it must be some sort of initiator caspase. So, this is an initiator caspase. Caspase number 8 is gonna be an initiator caspase. Now, since this caspase is interacting with caspase number 3 we know that this is going to be an activation event represented by this arrow right here. Now, what does that mean? That means that caspase number 3 must be doing something else and you can see that caspase number 3 is leading to cellular death. So, what type of caspase is gonna be caspase number 3? It is going to be an Executioner caspase because it is going to be actually breaking down the different cellular components. So there is a procaspase that is cleaved and activated, turned into an initiator caspase which then activates the executioner caspases which bring on cellular death by degrading the different cellular components. So that is a great example of a chain reaction that occurs in these caspase based kind of cascades or pathways that lead to apoptosis. I know I went over a lot everyone but I hope it was helpful. Apoptosis is definitely something you're going to need to know. It's very highly tested upon. Just remember, apoptosis is going to be regulated and programmed cellular death that is highly controlled so that the other cells around the dying cell do not become damaged and it is going to utilize different proteins like caspases to begin degrading the different cellular components. Okay, everyone. Let's go on to our next topic.

Triggering Cell Death

Okay. So now, let's talk about how apoptosis is triggered. There are two ways: the intrinsic pathway and the extrinsic pathway, and we're going to go through both of them. So first, focus on the intrinsic pathway, which is going to regulate and trigger apoptosis based on intracellular proteins. The first one I want to talk to you about is the Bcl-2 family of proteins, and this family inhibits apoptosis. I'm going to walk through backwards what happens. So first, there's this molecule called cytochrome c, and we've talked about cytochrome c before. Do you remember when we talked about it? Right. So cytochrome c is important for oxidative phosphorylation. So where is it found? It's found in the mitochondria. But when cytochrome c is released from the mitochondria, that actually will trigger apoptosis because cytochrome c will bind to a bunch of cytosol proteins, which then will lead to apoptosis. So when is cytochrome c released from the mitochondria? Well, it's released due to DNA damage, which of course, if the DNA is just completely damaged, the cell is going to want to die, kill itself, so that that's not passed on through further generations. So when there's DNA damage, there are two proteins that are released. They're called BAX and BAD. And BAX and BAD act to release cytochrome c into the cytosol, which will then bind to proteins and stimulate apoptosis. So that's how apoptosis can be stimulated, but it can be inhibited by these Bcl-2 proteins, which bind to Bax or BAD and prevent cytochrome c release. So this is going to inhibit, and this is going to activate. So if we look at this pathway, what we get is we get some kind of stimuli, maybe DNA damage for instance, that tells the cell it needs to die. So then it can activate Bax; it can also activate Bax, and this will stimulate cytochrome c release. You can see here it's being released, which will result in apoptosis, or cell death. So that's how the intrinsic pathway works.

There is also an extrinsic pathway where extracellular proteins also play a role. They play a role through usually binding something called death receptors. Death receptors are receptors on the plasma membrane, and when they're activated, usually by binding some kind of ligand, they trigger apoptosis. An example of this is the Fas receptor. It can bind the Fas ligand, and when it's bound, it will actually activate this special complex called the DISC complex or the death-inducing signaling complex, which will stimulate apoptosis. Now, the opposite of that is going to be survival factors, which, when apoptosis needs to be suppressed, work by inhibiting the bad, which, remember, trigger the intrinsic pathway, and regulate the Bcl-2 families, which is also the intrinsic pathway. But these are the two main extracellular pathways. So, here we have the Fas receptor. So, here we have the Fas ligand and the Fas receptor. And you can see that once it's activated, it will form this DISC complex. And you don't need to know any of these proteins, but you can see here that it activates a lot of caspases through here, which will trigger, you know, cytochrome c release into the cytosol, but essentially, this will cause apoptosis. So that's how the intrinsic and extrinsic pathways work to trigger apoptosis. So now, let's move on.

Apoptosis can only be stimulated through intracellular signals.

• A. True
• B. False

Answer: (B)

In the intrinsic pathway of regulating apoptosis, Bcl2 controls what?

• A. It releases cytochrome C from the mitochondria
• B. It binds to cytochrome C and prevents its release
• C. It binds to Bad and Bax and prevents cytochrome C release
• D. It binds to Bad and Bax and triggers cytochrome C release

Answer: (C)

Here’s what students ask on this topic:

What is apoptosis and why is it important?

Apoptosis, also known as programmed cell death, is a highly regulated process where cells systematically dismantle themselves. This process is crucial for maintaining cellular health and homeostasis. It balances cell division and cell death, preventing the uncontrolled cell growth that can lead to cancer and tumors. Apoptosis ensures that damaged, infected, or unnecessary cells are efficiently removed without harming surrounding tissues. This 'clean' cell death prevents the release of harmful cellular components, such as lysosomal enzymes, into the extracellular space, which could damage neighboring cells. Understanding apoptosis is essential for comprehending how the body maintains cellular integrity and prevents disease.

What are the key differences between apoptosis and necrosis?

Apoptosis and necrosis are two distinct forms of cell death. Apoptosis is a regulated, programmed process that allows cells to die in a controlled manner, preventing damage to surrounding tissues. It involves cell shrinkage, chromatin condensation, and the formation of apoptotic bodies, which are then phagocytosed by immune cells. In contrast, necrosis is an uncontrolled, traumatic cell death resulting from injury or disease. It leads to cell swelling, membrane rupture, and the release of cellular contents into the extracellular space, causing inflammation and damage to neighboring cells. Understanding these differences is crucial for studying cellular responses to stress and injury.

How do intrinsic and extrinsic pathways trigger apoptosis?

Apoptosis can be triggered by intrinsic and extrinsic pathways. The intrinsic pathway is initiated within the cell, often due to DNA damage or mitochondrial dysfunction. Key proteins like Bax and Bad promote the release of cytochrome c from mitochondria, which activates caspases, leading to cell death. The extrinsic pathway is triggered by external signals, such as immune cells binding to death receptors on the cell surface. An example is the Fas receptor binding to its ligand, forming the death-inducing signaling complex (DISC), which activates caspases and induces apoptosis. Both pathways ensure that cells die in a controlled and regulated manner.

What role do caspases play in apoptosis?

Caspases are crucial proteases in the apoptosis process. They exist as inactive precursors called procaspases and are activated through cleavage. There are two main types: initiator caspases, which activate other caspases, and executioner caspases, which degrade cellular components. Initiator caspases, like caspase-8, trigger a cascade that activates executioner caspases, such as caspase-3. Executioner caspases then dismantle the cell by breaking down proteins and DNA. This cascade ensures that apoptosis is carried out efficiently and precisely, preventing damage to surrounding tissues. Understanding caspases is essential for studying how cells regulate their own death.

How do inhibitors of apoptosis work?

Inhibitors of apoptosis (IAPs) are proteins that prevent unwanted cell death by blocking the activation of caspases. They can bind to procaspases, preventing their cleavage into active caspases, or directly inhibit active caspases. This regulation ensures that apoptosis only occurs when necessary, such as in response to severe cellular damage or infection. By controlling caspase activity, IAPs maintain cellular homeostasis and prevent excessive cell loss. Understanding IAPs is crucial for studying how cells avoid premature death and how dysregulation of apoptosis can lead to diseases like cancer.