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  • Hi.

  • 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,