Mitochondria, apoptosis, and oxidative stress | Cells | MCAT | Khan Academy

December 27, 2019

– [Voiceover] The mitochondria
is probably most well-known for metabolic pathways
like the Krebs cycle and the electron transfer chain that allow ourselves 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 due to necrosis. And so, we often say it sometimes 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 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 an embryological development, and specifically the development of our fingers and our toes. Let’s take for example the
development of our hands. 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 in foldings or the crysti 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 intensive 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 a damaged DNA to pass that damaged DNA
down to its offspring cells. 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,
oftentimes 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 these proteins and send signals from the
immune cell to our infected cell to tell our cell to undergo a cell death. Additionally, environmental stress can also induce apoptosis
or programmed cell death. This is anything from the
deprivation of oxygen or nutrients to even a 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. I’ll also mention that many cells are constantly receiving
signals from growth factors which are specific molecules
oftentimes 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 oftentimes an unstable number of electrons and that makes them very reactive. And some examples of these
include the superoxide 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 because 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 if the pathways by
which these diverse signals 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 BCL2 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 BCL2 family. There are proteins that are pro-apoptotic which means they want to push
the cell towards apoptosis, or they’re 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, the balance shifts 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 intermembrane 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 intermembrane space and enter the cytoplasm. And the name of this
molecule is cytochrome c. 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 transfer chain. It kind of has a dual role here. It does that but it also
plays a role in apoptosis. Specifically, the cytochrome c molecules activate a family of enzymes inside of the cytoplasm called caspases. 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 the type of enzyme that breaks down proteins. It specifically breaks down proteins after the aspartate residue which is a type of amino acid, and it breaks these proteins down with a cysteine 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. 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 mechanisms
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 actions. 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 enzymes in the body like nucleases that can break down DNA. And so, altogether the eventual result is that there’s 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 the cell can be recycled to surrounding cells. The 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.

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