Mitochondria, apoptosis, and oxidative stress

- [Presenter] The mitochondria is probably most well known for metabolic pathways like the Krebs cycle and the electron transport chain that allow our cells to produce ATP. And that's probably why it's commonly referred to as the energy powerhouse of the cell. But in this video I want to talk about one of its other functions, and specifically the role that it plays in apoptosis, which is defined as programmed cell death. Now when we're talking about cell death, there is another type of cell death that you might have heard of called necrosis. And before we jump into apoptosis, I just want to take a minute to talk about the distinction between these two. Notably, there's still a lot of active research going on to elucidate the mechanisms behind necrosis and apoptosis, and to be honest, in some cases, it's hard to classify a particular case of cell death as strictly apoptotic or a due to necrosis. And so we often say it sometime lies along a spectrum between necrosis and apoptosis. But in any case, just painting broad strokes, we generally classify apoptosis as more of a controlled type of cell death. Whereas necrosis is more of an uncontrolled type of cell death, that usually is in response to extreme stress. Like in an extreme infection, or extreme trauma. Apoptosis on the other hand, as its definition kind of implies here, it's a programmed type of cell death, has usually some big purpose. And often can confer some advantage to the organism. And one example of this is actually in embryological development, and specifically the development of our fingers and our toes. So let's take for example, the development of our hands. So early on in our development, when we're still a fetus, our hand looks something like a paw. And through apoptosis, the tissue between our digits eventually dies off, and that purposeful, controlled death of this tissue ultimately allows us to produce a hand with five separated digits that we call fingers. And with that in mind, we can actually brainstorm some other advantageous reasons that a cell might want to undergo cell death. So here I've kind of drawn a cell, and because I mentioned earlier the mitochondria plays a big role in apoptosis, I'm gonna go ahead and draw kind of a massive mitochondria in here. Remember that the mitochondria has two membranes, I've drawn the outer membrane. And here I'm drawing the infoldings, or the cristae of the inner mitochondrial membrane. Now we just talked about one type of signal that induced a cell to undergo apoptosis, and that was a signal that was given during our embryological development. But there are also other things that can induce our cell to undergo apoptosis as well. And I want to touch on several of these factors right now. First off, turns out that DNA damage can induce cell death. And I should mention that our cells have repair mechanisms in place that can deal with DNA damage, but in some cases the DNA damage might be quite extensive or our repair mechanisms are simply not equipped to repair DNA damage from some reason or another, and so the kind of last, fail-safe mechanism to deal with this, is to induce programmed cell death. And of course, this is advantageous for our organism, because we wouldn't want a cell with damaged DNA to pass that damaged DNA down to its offspring cell. So this is a way that we can essentially get rid of those damaged cells. In addition, infection, especially by viruses, because viruses like to hang out inside of our cells, can also induce programmed cell death. And in this case, often times it's immune cells, that remember, are kind of our army against infection that see that there are specific proteins on cells that have been infected by viruses. And our immune cells can recognize theses proteins and send signals from the immune cell to our infected cell, to tell our cell to undergo cell death. Additionally, environmental stress can also induce apoptosis or programmed cell death. So this is anything from the deprivation of oxygen or nutrients, to even the deprivation of the cell's connection to other cells. It turns out that in order to continue surviving, the cell needs to get a signal that it's attached or in close proximity to other cells around it. And so if these cell to cell connections are somehow disrupted, it could signal the cell to undergo apoptosis. And I'll also mention that many cells are constantly receiving signals from growth factors, which are specific molecules, often times hormones, that are sending signals to these cells to proliferate and divide. And so if those are somehow taken away, for some reason or another, then cells might see that as a sign to undergo cell death as well. Of course the big theme here is that cells have a way to undergo some type of controlled, programmed cell death if their environment isn't very hospitable. And finally, I want to mention that, reactive oxygen species, which are often referred to as ROS can also induce cell death. Now these reactive oxygen species are exactly what they sound like. They are oxygen species that have acquired often times, an unstable number of electrons, and that makes them very reactive. And some examples of these, include the super oxide anion, which is an oxygen molecule that has essentially acquired an extra electron here, making it negatively charged. In addition we have a neutrally charged hydroxide molecule, which is usually called a hydroxide radical, 'cause it only has one electron. And also hydrogen peroxide is an additional reactive oxygen species that can be formed inside of our cells. Now recall that oxygen is important because it's the final electron acceptor in the electron transfer chain of the mitochondria. Which is important for producing all of that ATP for our cells. But it turns out that up to 4% of that oxygen is improperly reduced, only partially, and that's what leads to the production of these reactive oxygen species. Now in order to prevent unwanted reactions between these highly reactive species and important things in our cells, like lipid membranes, and DNA, and proteins, our cells have come up with some enzymes to try and convert these to less reactive species, as well as some antioxidant molecules that try and trap these reactive oxygen species. But of course, if the extent of this oxidative damage is too high, and our repair mechanisms can't work, our cells will undergo programmed cell death. Now even though the pathways by which these diverse signal communicate to the cell that it needs to undergo apoptosis, may be slightly different from one another, one common endpoint is that they all have an effect upon the mitochondria which plays a large role in initiating apoptosis. In fact, one of the early findings in apoptosis is that this outer mitochondrial membrane here, becomes more permeable than it was before. And notably, the proteins that regulate the permeability of this outer mitochondrial membrane are part of a family of proteins called the BCL-2 family of proteins. And this name comes from where these proteins were first discovered, which was in a B cell lymphoma, which is a type of cancer of B cells, which are immune cells in your body. But the important thing to take away here is that there are two types of proteins in this BCL-2 family There are proteins that are pro-apoptotic, which means they want to push the cell towards apoptosis. Or their anti-apoptotic, in which case they oppose apoptosis Ultimately what that means, is that when the cell is healthy and it's not receiving any of these apoptotic signals, the balance of these proteins is in favor of these anti-apoptotic proteins, which essentially inhibit and prevent this mitochondria from initiating apoptosis. On the other hand, when the mitochondria receives signals downstream from any of these apoptotic signals, this balance shift to be in favor of these pro-apoptotic proteins, which then facilitate this increased permeability of the outer mitochondrial membrane. Now the purpose of increasing the permeability of this outer mitochondrial membrane, is to allow a particular molecule that's normally found within the inter membrane space, and actually it's often loosely associated with this inner mitochondrial membrane here, but when this permeability increases it allows this molecule to exit the inter membrane space, and enter the cytoplasm. And the name of this molecule is cytochrome C. And notably it also happens to be a member of the electron transfer chain, specifically it helps shuttle electrons between the third and fourth complex of the electron transport chain. So it kind of has a dual role here, it does that, but it also plays a role in apoptosis. Specifically, these cytochrome C molecules activate a family of enzymes inside of the cytoplasm called caspases, and the name caspase actually tells us a lot about the function of this family of enzymes. I'm going ahead and writing this name out suggestively here to explain to you that this caspase is a type of protease, which remember is a type of enzyme that breaks down proteins. And it specifically breaks down proteins after the aspartate residue, which is a type of amino acid, and it breaks these proteins down with a cystine residue, which again is a type of amino acid that's located in its active site, hence the C at the beginning of the name caspase. Of note, if we come full circle back to the beginning of our discussion when we were talking about the difference between necrosis and apoptosis, one of the major differences in terms of the mechanism of these two pathways, is that apoptosis is caspase mediated It uses these caspase enzymes, but necrosis does not utilize these enzymes. And what's special about these caspase enzymes is that they have a controlled cascade of action. So the one caspase that was activated by the cytochrome C can go on to activate another type of caspase, and essentially control and orchestrate the degradation of proteins that way. In addition, it also can activate other types of enzyme in the body, like nucleases, that can break down DNA. And so all together, the eventual result is that there is basically a whole scale degradation of all the kind of large polymers inside of this cell. And one unique thing about apoptosis is that the degradation of all of these polymers inside this cell, can be recycled to surrounding cells. So surrounding cells can kind of phagocytose, or eat up those degraded polymers to kind of reuse all of those amino acids and nucleotide bases in their own cells.