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.