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My name is Jared Rutter,
and I'm a Professor of Biochemistry
and an Investigator of the Howard Hughes Medical Institute
at the University of Utah.
And I'm gonna tell you today,
in the next 30 minutes or so,
some of the things that I find most fascinating about the mitochondria.
So, to give you a little bit of my background
and how we became interested in this organelle,
I did my PhD in the lab of Dr. Steve McKnight
at the University of Texas Southwestern Medical Center.
And at the time I joined Steve's lab,
he had just recently come back to academia
from a biotech company.
And as a result of that, the lab was relatively small,
and there weren't really ongoing projects.
Everything was brand new.
And Steve really encouraged us at that time
to really focus on doing something brand new,
focus on doing something unique,
make a discovery that no one else would ever make.
That's how we were taught to think about science,
and that's a teaching that has really influenced my career
and something that I've always aspired to.
This is really difficult.
We all like to stay in our comfort zones,
and this is a really difficult standard to hold ourselves to,
but I think it's very important for us as scientists.
So, after being in Steve's lab,
I eventually went to the University of Utah
and joined the Department of Biochemistry,
and was surrounded by a bunch of wonderful colleagues,
some of which worked on this organelle, the mitochondria.
Specifically, Janet Shaw and Dennis Winge
really inspired me with the work that they had done
to understand mitochondria and make important discoveries.
And I began to be kind of intrigued and thought that my lab
should maybe do something to try and understand this organelle better.
And I'll tell you, one of the things that really captured my attention
-- relating to how Steve taught us to think about science --
is the degree to which there were many things about mitochondria
that we just didn't understand well...
about this complex structure in cells.
So, what I'm gonna do is tell you about
a few features of this organelle
that I find really fascinating.
And some of the...
and I'll try and allude to those points
where I think there's really critical knowledge about the mitochondria
that we don't yet have,
and that we need to understand better.
And I will also tell you that
Jodi Nunnari gave an excellent talk about mitochondria
that's part of the iBiology series,
that talks about mitochondria
primarily from the perspective of evolution
and alludes to several features,
and I definitely encourage you to watch that.
And I'll try and cover some of the things that she didn't talk about
quite so much.
So, the five things... the five areas that I will allude to
regarding mitochondria are shown here.
First, about its origin.
It's clear, quite clear from how we understand mitochondria,
that they evolved as a result of an aerobic bacterium
becoming engulfed in what was a protoeukaryotic cell,
and essentially became domesticated.
Domesticated bacteria living in those cells
that eventually entered into a symbiotic relationship
that was of benefit both to that bacterium
and that cell.
And those bacteria have evolved and adapted
and have become today's mitochondria.
And when we think about that,
that we essentially have a domesticated bacterium
living in most of our cells,
I think that has big implications for how we think about cell biology.
And I'll allude to that a little bit later,
but that, I think, changes, in a way,
the relationship between mitochondria and the nucleus,
compared to other organelles,
where their origin is quite different.
So, the structure of mitochondria
is one of the most unique features of this organelle.
Unlike other organe... most other organelles
-- those in animal cells in particular --
mitochondria have two membrane compart...
two membrane systems.
There is an outer membrane that completely surrounds the mitochondria,
and everything is contained
within that outer membrane.
That outer membrane turns out to be
relatively porous to small molecules.
This inner membrane, however,
which encapsulates a protein compartment known as the matrix,
shown in blue...
this inner membrane is thought to be
completely sealed and is impermeable to ions,
except through specific transport processes
that are critically important for the function of mitochondria.
This inner membrane is highly invaginated
and leads to these folded structures
depicted here as cristae,
which will become important later.
But this also... this folding also creates a scenario
where the surface area of the inner membrane
is quite a bit larger than the surface area
of the outer membrane.
And again, that becomes important
because this inner membrane is the site
of much of the important work that is done in mitochondria.
And the mitochondrial matrix, I just want to point out,
is where a lot of the chemistry is done.
So, the enzymes that we consider to be localized to mitochondria...
the vast majority of them are localized
to the mitochondrial matrix,
which again is completely segregated from the cytosol
by virtue of this two-membrane system,
again the inner membrane being the dominant one
for conveying the separation.
So, where do the proteins come from
that perform the work in mitochondria?
99% of those proteins, roughly,
are synthesized in the cytosol on cytosolic ribosomes
and then imported into mitochondria.
But interestingly,
1% of the proteins found in mitochondria are actually synthesized there,
and they are encoded by the mitochondrial genome.
So, again, another very unique feature, for animal cells,
of mitochondria is the maintenance of this mitochondrial genome,
which is a relic, we believe,
of the ancestral bacterial genome
that was first brought into this protoeukaryotic cell.
This mitochondrial genome only encodes 13 proteins,
but those 13 proteins
are critically important for the respiration functions of mitochondria.
And those 13 proteins...
all of them co-assemble with other nuclear-encoded
cytosolically synthesized proteins
into large protein complexes,
which creates very interesting and important challenges of coordination
that we'll talk about later.
So, metabolism... metabolism is
easily the most famous function of mitochondria.
That's what we think about typically
when we think about mitochondrial function.
This metabolic function of mitochondria
can be broken down into several flavors of function.
The most well known and most well studied, probably,
is the catabolic function of mitochondria,
the processes by which mitochondria
consume the food that we eat
and enable the production of ATP.
And we're gonna go through that in a lot of detail.
But mitochondria also play very important biosynthetic functions,
in building the molecules that our cells need
for duplication and repair.
And there are also very important functions of mitochondria
in controlling redox balance,
which I won't talk about in great detail
but are clearly very important.
So, this system by which mitochondria consume food and make ATP
is truly amazing, truly incredibly important,
especially in those cells that consume a lot of ATP,
like cardiomyocytes -- heart muscle cells --
and neurons, which have enormous ATP demand.
The vast majority of that ATP comes from mitochondria.
How does that work?
This is just a brief summary of that
from the perspective of a carbohydrate like glucose.
When glucose is brought into the cell,
it's converted to pyruvic acid in the cytosol,
which generates a little bit of ATP
-- two molecules of ATP.
To fully capture the energy of glucose, however,
that pyruvate is taken into the mitochondria,
carbons are extracted and released as CO2,
electrons are extracted and conveyed to the electron transport chain,
which enables very efficient ATP production,
leading to a much...
in an idealized setting, 38 molecules of ATP.
That is the way to generate ATP highly efficiently.
But as I mentioned, in that context
the carbon is lost as CO2.
So, if that carbon needs to be used to build something,
like DNA or proteins or lipids,
one can't fully oxidize glucose to carbo... to CO2.
And so that balance between anabolic and catabolic functions
of mitochondria is one I'll come back to later,
but it appears to be critically important.
It's clearly important in normal physiology,
and it appears to be critically important in disease.
So, this is an overall summary of how this happens.
So... of how ATP synthesis
is managed by the mitochondria.
So, how does this actually work?
In very simplistic terms,
one of the key features of this
is that the energy of food
is used to enable the pumping of protons
through this respiratory system,
which we'll talk about in much more detail,
from the mitochondrial matrix into the cristae space,
the intermembrane space between those two membranes.
And then, as those protons flow back down their gradient,
the energy from that is captured to make ATP.
And that is the process
by which food energy is used to fool...
fuel ATP production.
And we'll talk about both the proton pumping
and the ATP production aspects of that
in a little bit more detail.
So, again, this is a zoom-in of this system.
Again, food molecules are used to feed the TCA cycle,
the citric acid cycle or Krebs cycle.
The carbon is lost as CO2,
but the electrons are extracted
and passed to the electron transport chain,
which then, in conjunction with pumping...
with passing electrons,
pumps protons from the matrix to the intermembrane space.
And then as those protons
then flow back down their gradient
in an energetically favorable process,
that energy is captured -- very elegantly --
by this beautiful machine, the ATP synthase,
and coupled to the synthesis of ATP.
And again, we're gonna talk about each of those processes
in more details.
So, unlike combustion or an explosion,
where the energy from a fuel is lost as heat or light,
this process... the mitochondria capture that energy
by virtue of it being conveyed
in very small, very discrete steps,
not unlike how a turbine -- a series of turbines --
captures water flowing downhill through gravity,
or flowing through a dam via gravity.
That energy is captured and converted into...
and stored in a way that it can then be used
to generate ATP that our cells will use
to fuel their pro... their... the processes that they need to power.
So, this is how mitochondria do it.
It's by capturing that energy
in very discrete processes.
And it is done primarily through the pumping of protons.
So, this is a depiction of the electron transport chain.
And again, this complex I, or NADH dehydrogenase,
captures the electrons that have been held in
the NAD cofactor pool
and then conveys those electrons to ubiquinone,
and in... and in the process of doing so,
pumps protons from the matrix to the intermembrane space.
The quinone pool passes those electrons
again, to complex III, or cytochrome c reductase,
which again pumps protons as those electrons
are eventually then conveyed to cytochrome c,
which again passes its electrons to cytochrome c oxidase,
which pumps protons in conjunction
with electrons being carried to oxygen,
and then enabling the formation of water.
So, this process, this series of
many, many electron transport reactions,
is coupled to the pumping of protons.
And this depiction is inappropriate in a way,
because it belies the massive complexity of these complexes.
So, I just want to focus on complex I.
So, this is a structure of complex I
that was solved a few years ago.
44 different proteins are required for the function of this complex,
make up this complex,
which exists both in the... in the... mit...
in the membrane, which is about here,
the membrane piece of complex I,
and then this matrix arm of this complex.
And these are all required for the conveyance
of electrons from NADH,
through a series of cofactors
that sequentially capture those electrons
and pass them on down the chain,
eventually reaching the quinone,
where they are deposited.
That then takes them, as I said before,
to the next complex in the chain.
And that conveyance of electrons
is coupled to the movement of specific helices
in this membrane...
in this membrane arm
that enable the pumping of protons
from the matrix to the intermembrane space.
How that exactly works, we don't really know.
We know some of the features of it,
and we're trying... the field is trying very hard
to understand this in more detail.
But it's a very elegant process
by which these two functions of electron passage and proton pumping
are coupled through this very complex,
44-subunit enzyme system.
So, how does this proton gradient
then get used to make ATP through ATP synthase?
So, I want to show you an animation
that I think illustrates this very nicely,
based on actual structural data of this complex.
So, the ATP synthase molecule is shown...
or... complex is shown here.
It's composed of two different motors
-- a motor in the matrix and one in the... in the membrane --
that use the proton gradient,
as you see here.
High in the matrix.
You see low proton availability in the IMS.
Those protons flow through this complex,
and that flowing is coupled with ATP synthesis.
And these two motors...
the F0 motor that exists in the membrane
captures those electrons
and couples their flowing through the...
to the rotation of this rotor.
And the F1 motor makes ATP.
So, protons come in through this rear channel,
bind to this F0 rotor,
go all the way around,
360 degrees around this rotor,
and then are released through this front channel
into the matrix.
And that powers the rotation of this F0 motor.
That rotation is conveyed to the F1 motor
through this central stalk,
which rotates in the middle of this F1 motor
and causes -- sequentially, as it goes around --
conformational changes that
convey energy to the production of ATP
from ADP and phosphate.
And this goes around and around,
coupled with the pumping of protons,
with the flowing of protons from the IMS...
from the intermembrane space to the matrix,
and coupling that with ATP synthesis.
It's a really beautiful motor system
to convey the potential energy of the proton gradient
to the production of ATP that can be used
for energetically demanding processes in the cell.
I wanted to talk a little bit about the anabolic functions of metabolism...
of the mitochondria as well.
So, this is a complex slide,
and I just want to point out a few things.
So, again, glucose comes into the cell.
It's converted to pyruvate in the cytosol.
That pyruvate is transported into the mitochondria
and enters the TCA cycle.
That TCA cycle not only extracts electrons
to fuel the electron transport chain
but also provides intermediates, like citrate,
that can then be exported to the cytosol
and are critically important
for the synthesis of lipids, like fatty acids and cholesterol.
So, mitochondria actually contribute
to the building of molecules
as well as their destruction,
like this... in this case with lipid synthesis.
Oxaloacetate, another TCA cycle intermediate,
is also used in the building of amino acids like aspartate,
which contribute to nucleotide biosynthesis.
So, again, very important
biosynthetic functions of mitochondria,
in addition to the catabolic, ATP-producing functions
that we tend to focus on mostly.
Interestingly, many pathways are actually shared
between the cytosol and the mitochondria,
or the mitochondria and another organelle.
Phospholipid biosynthesis is one example.
One example is also shown here, which is particularly interesting,
like this SHMT enzyme,
which interconverts glycine and serine.
There's actually an isoform in the cytosol and an isoform in the mitochondria
that do the same reaction.
And it's interesting to speculate
that perhaps that enables the function of this pathway
-- and others like it --
to exist... to be functional in different metabolic states,
where the cytosol and the mitochondria might be differentially optimized
for this chemistry in one condition versus another.
Something that we really need to understand better
is how the cytosolic and mitochondrial metabolic functions
are coordinated.
And in addition, one other type of coordination
that is clearly important
is the coordination between the anabolic functions of mitochondria,
as shown here,
and the catabolic functions, which we just talked about.
Clearly, those are both very important,
and the mitochondria conducts all of them.
How does it coordinate them?
How does it decide whether it's more important
to generate ATP
or more important to generate building blocks
for cell growth and proliferation and repair?
It's something that we don't understand very well just yet,
but it's something very critical for human...
normal physiology and for disease.
So, I want to talk about the challenges
that arise for protein homeostasis
because of the unique structural constraints
provided by mitochondria.
So, this is, again, another depiction
of the mitochondrial electron transport chain
and the TCA cycle.
And I just want to point out again
that the electrons are extracted from acetyl-CoA,
passed to this system through these very complex
electron transport chain complexes...
and eventually conveying the electrons to oxygen to make water,
while pumping protons.
As I described, this is critically important to eventually enable ATP synthase
to make ATP by using that proton gradient.
A beautifully elegant system, fantastically complex.
And that complexity brings several challenges
that eventually end up being protein homeostasis challenges.
So, just focusing on the...
just the protein components of these complexes.
So, just complex I, for example,
as I alluded to, has 44 different subunits,
7 of which are encoded by the mitochondrial genome,
37 by the nuclear genome.
And these proteins all have to find one another,
in the right stoichiometry,
to make an intact complex I.
It's impossible for the cell to manage that in complete...
with complete control.
And the results have to be that
too much of one subunit or too little of another is there.
And that leads to a degradation problem,
where those excess subunits have to be degraded.
And this is happening throughout this complex.
That's an important problem that the mitochondria have to deal with.
In addition to that, all of these complexes
also have redox active cofactors
that need to be managed very carefully.
And when they're not managed carefully,
that leads to the production of reactive oxygen species
that create damage to the mitochondr...
to mitochondrial proteins.
Again, those proteins that are damaged
have to be degraded,
and recognized as being damaged,
and degraded.
And... so, this is a massive protein homeostasis problem.
And this is made worse by the fact that
this is all happening in a place
that is inaccessible to the proteasome,
which does most of the protein degradation in the cell.
So, that creates a challenge for how do proteins...
how are proteins recognized and degraded in the mitochondria?
And this is one depiction of the...
the complexity of systems that do that.
This system includes several proteases in the matrix,
in the inner membrane,
and in the intermembrane space
that, through mechanisms we mostly don't understand,
recognize proteins that need to...
need to be degraded and degrade them.
There are also proteins on the outer membrane
that need to be degraded,
extracted from the outer membrane,
and typically presented to the proteasome for degradation.
How are they recognized as being aberrant is...
still remains to be determined.
And interestingly, it's becoming clear
that the mitochondria is a common destination
for the mislocalization of proteins
that should be somewhere else
but end up mislocalizing to the mitochondrial outer membrane.
How are they then recognized and degraded?
It's a very important question that is clearly important for human disease.
We really don't understand it very well.
But sometimes, even all this complexity of systems
trying to maintain mitochondrial quality
doesn't work well enough,
and mitochondria need to be degraded.
And there's a very interesting process known as mitochondrial autophagy,
or mitophagy,
that manages the degradation of whole organelles.
This is mediated... one part...
one pathway toward mitophagy is mediated
by this PINK/Parkin system,
which targets mitochondria for autophagy.
Parkin is so named because mutations in the Parkin...
the gene encoding Parkin cause, also, Parkinson's disease,
a devastating neurodegenerative disorder,
just emphasizing the importance of mitochondrial quality,
both in terms of protein degradation
as well as mitochondrial degradation,
for maintaining the normal function of healthy cells
and healthy organisms.
Finally, I want to just allude to some of the interesting communication
that happens from mitochondria out to the rest of the cell,
to the nucleus and the cytosol.
There is also, of course, very interesting and important communication
happening going in to mitochondria.
I won't talk much about that.
But one of the obvious ways that mitochondria communicate with the rest of the cell
is through providing metabolites, as we just talked about.
And several of the metabolites that are produced by mitochondria
have very important signaling and regulatory roles,
like acetyl-CoA, alpha-ketoglutarate, ATP itself.
They all play very important roles in controlling cell biology.
And that's one of the key means whereby mitochondria
communicate to the rest of the cell.
Another is the redox state of mitochondria.
Because of its ability to put electrons into oxygen,
this is... provides what is normally a very safe way to dispose of electrons.
And when mitochondria don't have...
when the cell doesn't have access to oxygen
as an electron acceptor, through mitochondria,
the cell has to adapt and find other ways
to dispose of those electrons,
or to not generate as many electrons.
This is a very important part of mitochondrial function,
by controlling redox homeostasis,
that we don't think about as much but is clearly important in several disease settings.
We talk about reactive oxygen species, typically,
as being signs of damage, when things go wrong.
But it's clear that hydrogen peroxide and other oxidants
play normal signaling roles,
and we're just starting to understand the means
whereby that signaling happens.
What are the targets of that signaling?
And how does it control cell biology? But it's interesting to speculate that that might be
a very interesting sentinel of how mitochondrial function is going,
by virtue of the production of hydrogen peroxide.
Calcium signaling is...
mitochondria play a very important role in calcium signaling,
both by virtue of their storing some calcium
as well as controlling the release of calcium from other sites.
And that... and obviously, calcium signaling is critically important
in many excitable cells.
Mitochondria directly contact almost every other organelle,
and probably we'll come to know that they
contact every other membrane system in the cell.
And by virtue of those contacts,
that enables efficient transport of metabolites between organelles,
and it's clear that there is also regulatory information
conveyed by those interactions as well,
and this is a very active area of research currently.
One of, I think, the most interesting features of mitochondria
is their connection with the immune system.
Again, this harkens back to the...
to the history of mitochondria as a...
as a bacterium that became engulfed by a eukaryotic cell.
It's interesting to know, now,
that many features of the immune system
have particular relationships with mitochondria.
Some systems of the innate immune response
actually reside on mitochondria all the time,
are centered there.
And it's interesting to think about the implications of that,
given its origin as a bacterium.
And there are very interesting responses to the exposure of mitochondrial DNA
to the cytosol.
And again, that's quite interesting,
given the history of that mitochondrial genome
as the descendant of what was once a bacterial genome.
And the net effect of this is
mitochondrial functions don't just make ATP.
They don't just make metabolites.
They significantly influence the behaviors
that cells make.
And those behaviors, when they become aberrant...
it's very clear have profound impacts on disease.
And so, I think one of the most interesting areas of future research for us
is to understand how mitochondria communicate,
through these and other mechanisms,
to control the behaviors of cells.
And I'll talk in much more detail about that
in the second part of this series.
So, this leads us back to my story of
why we became so interested in mitochondria.
I think I told you about all the mysteries that I think
are still contained within this organelle.
And this was brought home to me, quite clearly,
by the elegant work of Dave Pagliarini and Vamsi Mootha
when they defined the mitochondrial proteome in humans,
several years back now.
And it became clear that about
a third of the proteins found there
were completely uncharacterized.
For this organelle that's been so well studied,
about a third of the... about a third of the proteins found there
have no known function.
They likely are doing something.
And that likeliness that they're doing something
is really illustrated by the fact that many of those proteins
are found throughout all eukaryotes,
implying conservation across many, many years of evolution.
So, that function that they're doing
is not important just for yeast, or just for humans,
but throughout all eukaryotes.
So, we decided in my lab to take a stab at understanding
the functions of some of these uncharacterized,
highly conserved mitochondrial proteins.
And initially... initially characterized that group,
32 protein families,
that we set out to just go find the functions of,
going one by one.
And that's led us into many different areas of mitochondrial biology,
some of which are shown here,
along with the protein functions that we've identified.
And I'll focus in Parts 2 and 3 of this series
on two stories that emerged from this project,
where we, by taking... by taking an approach to try
and go into the mysterious features of mitochondria
and take what was unknown,
and really try and understand the functions that those proteins have,
that's led us into some very interesting of areas
of mitochondrial biology.
And I'll tell you more about that in Parts 2 and 3,
and thank you for listening.
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Jared Rutter (U. Utah, HHMI) 1: Mitochondria: The Mysterious Cellular Parasite

80 Folder Collection
劉源清 published on February 5, 2020
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