- [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.