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0:06
Hi. My name is Jodi Nunnari. I'm a professor at the University of California at Davis, in the department of Molecular and Cellular biology. And in fact, I am a cell biologist and as such, I am dedicated to understanding how the insides of cells, especially our cells, which are eukaryotic cells, are organized and how the internal structures in those cells, help our eukaryotes, help our bodies function and exist and be healthy.
0:37
So, in particular, I'm interested in a sub-cellular organelle called mitochondria and that is the reason the title of my talk is "I Breathe for Mitochondria". I'm very passionate about this organelle, I have studied it my entire career and my fascination with the organelle began by thinking about how we came into being, in other words, how we evolved, as eukaryotes, as such complex organisms. So, I'm going to tell you a story
1:08
and I hope by the end of the talk that you will be as fascinated as I am about mitochondria. So, once upon a time, about 4 billion years ago, the first cell was born. And that cell was really simple and a lot of scientists think that that simple cell, and what do I mean by cell? A cell is a compartment enclosed by a membrane which is a lipid based structure that by its very nature is impermeable to water and other ions. So, it creates a barrier, or a protected environment.
1:44
That cell, a lot of scientists think, gave rise to the three major kingdoms of life that exist on earth now: bacteria, archaea and eukaryotes. Of course, we're eukaryotes. Now, bacteria and archaea are also known as prokaryotes. And they represent an amazing diversity of life on this planet and we wouldn't exist without them. They're simple cells in comparison to our eukaryotic cells, but they can actually exist, they can talk to one another,
2:18
they can aggregate and function in communities, but if you look inside them, they're relatively more simple than us eukaryotic cells. Eukaryotic cells, the hallmark of a eukaryotic cell is that inside of it, it contains a compartment that encloses our genetic material, or one of our major components of our genetic material, our nuclear chromosomes. It's called the nucleus, I'm sure you guys are all familiar with that.
2:47
That's the hallmark of a eukaryotic cell, but the eukaryotic cell has many more compartments than just that and these have all become specialized in a way that has enabled these cells to build complex multi-cellular organisms, like, for example, me. Who can talk and breathe and walk and so on. Now, as a, how did that happen? How can a eukaryotic cell do that and prokaryotes can't? Well, one of the answers lies in the fact that eukaryotic cells have expanded by almost 20,000 fold:
3:24
for example, their genetic material. And genetic material encodes the building blocks, or the map, of the cell. The proteins, all the regulatory mechanisms that allow us to respond to the environment. It expanded eukaryotes over prokaryotes, its genome, by that much. Now, as a consequence, they happen to be much larger cells, and if you look down here, to this image, this simple bright field image, you can see in white, the white circle, is a eukaryotic cell
3:57
and in the blue circle, and so is the red, two different types, a white blood cell and a red blood cell and in blue, that little itty bitty thing is a bacterium, so that's in the other kingdom. So, as a result of expanding the genetic material, these cells, our cells, are very much bigger and much more complex in size. So, how come bacteria, prokaryotes, haven't done that? In other words, what happened here, at this branch point in evolution, that enabled us to become as complex as we are?
4:33
Well, enter of course, my passion, which is mitochondria. And mitochondria are very unique in terms of eukaryotic organelles because they're derived from bacteria. Of course, the other organelle that's derived from bacteria, a bacterium, is the chloroplast, which defines the plant cell. But, in every single eukaryotic cell, has mitochondria or has had them and lost them along the way. So, how did they come into being?
5:03
Well, the thought is, evolutionary biologists think that an archaic type prokaryote engulfed a bacterium and they formed a symbiotic relationship that evolved during evolution to give rise to the modern day eukaryotic cell. Now, why do we think that? Well, mitochondria have a lot of features that are in common with bacteria and they're very, the genetic signature is there to indicate that. They have two membranes, as you can see here,
5:37
they have an outer membrane and an inner membrane, just like bacteria, and that inner membrane, those two membranes encapsulate two separate compartments, termed the intermembrane space and the matrix. Now, all four of these compartments are highly specialized in terms of their composition and their function, yet they all work together to work for us in the cell and that is to make energy through aerobic oxygen dependent production of energy
6:07
and of course, that's very advantageous, because we are on earth in a very oxygen-rich environment. And as a consequence of being derived from bacteria, they have their own genome, they have maintained their own genome, although it’s been modified in a very advantageous way for us. So, you can see from this image here of this electron micrograph that's been 3-dimensionally reconstructed, that the inner membrane, in contrast to what you'd see in bacteria,
6:41
is highly proliferated and differentiated to form these deep invaginations and this is exactly where energy is produced in this organelle. Highly specialized for energy production. So, as a consequence, maybe you weren't aware of this, but you actually have two genomes. You have your nuclear genomes, this happens to be the complement of chromosomes in the nucleus of a female, and you know, its 23andme, but you also have your mitochondrial genome.
7:14
And it is significantly smaller. So, the smallest chromosome is about 47 million base pairs that happens to be chromosome 21. And in contrast 3,000 fold smaller is the mitochondrial genome, which encodes only 13 proteins in addition to some regulatory RNAs, and those 13 proteins have been maintained and specialized for energy production. And they work together with the nuclear chromosomes to create energy for us in a very coordinated way. Even though that genome is small,
7:53
it's very mighty and in fact, in comparison to your nuclear chromosomes, which come from your mother and father, it only comes from your mother and it's present inside of us, in each cell, in many, many, many, many more copies than your nuclear chromosomes. And I hope you appreciate that each little circle is a mitochondrial chromosome, and that's how many of those are in a given cell in your body, in the background. And of course, they're maternally inherited.
8:25
So, the fact that that genome has been so reduced over the course of evolution makes it relatively energetically cost-efficient to maintain. It's still connected to the membrane that actually drives, is responsible, that inner membrane, for the synthesis of ATP and still encodes part of the key complexes in that membrane that give rise to energy. So, that small nature, the low energetic cost, yet, being still there so it can be coordinated with the nuclear genome,
9:05
makes it, makes mitochondria turn into an extremely highly efficient machine dedicated to energy production in a eukaryotic cell. And so back to evolution here, it's very tempting to speculate that the acquisition of mitochondria occurred at exactly the same time point that we branched off and become eukaryotes. And that the reason for that is that they allowed the energy that the cell required for the eukaryotic nucleus, the nuclear genome, to expand, as I mentioned before,
9:46
and that expansion allowed for the complexity, many more proteins to be synthesized, many more regulatory mechanisms exist, to exist for us, which allowed us to become multicellular, as you see here, so, I'd like to talk a little bit about how mitochondria makes energy for us because it is an amazing process. So, every day, we eat food, we are what we eat, literally, and that food in the form of protein, carbohydrates and lipids
10:18
are taken up by our body and metabolized by a complex network of intermediary metabolic pathways. And the background of this slide is a circuitry, the chemical reactions that occur inside our cells, that link all the possible metabolism, not only breaking them down, but building up building blocks that we need for life, like, for example, lipids, that get put into our membranes, that make us impermeable to water and protected. So, all those food sources break down in a way
10:55
that allows the production of simple carbon sources that flow through what is known as the Krebs, or TCA, cycle to produce reducing equivalents and these reducing equivalents that are captured from the TCA cycle and other pathways in the cell, funnel into a respiratory complex, a chain of macromolecular complexes in the inner membrane that shuttle electrons in exchange for transporting protons to generate chemical energy that, in a process that's dependent on molecular oxygen,
11:34
gets, that allows us to synthesize ATP. Now, ATP is the energy that our cells use and that energy is stored in the chemical bond in that molecule. And it fires all, a lot of these pathways that you see in the background here. And allows us to make building blocks, again, to create cells for our bodies and develop and exist. So, this seems a little daunting, this network in the background but it's fascinating in the sense that it really is who we are,
12:12
all our metabolism and in fact, exploring the relevance of these metabolic pathways is undergoing a renaissance in biological research as many investigators are beginning to realize that really understanding how these networks get changed, in pathogenesis, in states such as cancer, are key to curing these diseases. So, please don't be afraid of this network, it is life itself. So, let's take a closer look at what's happening inside mitochondria
12:45
to produce energy. Here you see a schematic depiction of mitochondria, the outer membrane, and the inner membrane, and here's the TCA cycle, and carbon sources are coming in, they're producing reducing agents, and those electrons are getting transported down an electron transport chain. And by that I mean, these are huge macromolecular complexes that are embedded in the membrane that move electrons and in doing so, can pump protons outside, from the inside of mitochondria, to the outside.
13:23
And that generates what we call a proton motive force, and this proton motive force is essential for producing ATP and drives many other processes that are essential in the mitochondrion and our eukaryotic cells. So, this proton motive force is harnessed by an ATP synthase complex, another large complex in the inner membrane to create ATP from ADP and phosphate. And a lot, in a fascinating way, many of these complexes have been looked at at the atomic scale
14:01
and actual, we can see what they look like at the atomic scale, and amazingly, they're fantastic machines. The first one is actually a piston driven machine, that pumps protons, and this one here, is especially elegant, it's a rotary machine, and you can see that when protons flow down the gradient, it drives the rotation of the head groups and produces conformational changes in those groups that are harnessed for the production of ATP.
14:39
And if you think about it, in the context of the fact that we consume and produce our body weight, every day, in ATP, you can imagine these engines running in our cells going full-bore, thank goodness. So, back to the fact that we have these two genomes, both the nuclear genome and the mitochondrial genome. And I've just hopefully convinced you how absolutely critical mitochondria are, not only for us to exist, that's why we breathe, for energy production,
15:16
and I think that's, that importance is underscored by the fact that mutations in both the nuclear genes and in the mitochondrial genome cause pretty severe and significant diseases. There's a spectrum, they can present in very young people, they can come to very old people, some of them are mild, some of them are extremely severe and fatal, and very unfortunate, but you can have mutations in both that cause these diseases. Both the nuclear and the mitochondrial genome.
15:47
And of course, if you have a mutation in your mitochondrial genome, you may not, it may not be present in every single copy of the genome in your cells and I've highlighted here, in blue and red, for example, just so you can think about it, those might be the copies in your cell that are mutated. Given that you inherit your mitochondrial DNA from your mother, the percentage of mutated forms she has and how that gets segregated
16:15
into your various tissues often determines the severity of the mitochondrial disease that you have. And often, mutations have different threshold levels in different tissues. And in fact, the next slide depicts kind of the array of disorders that present in mitochondrial diseases and you can see that you have effects from the very top of your head to the bottom of your body and most of the major organ systems are affected in mitochondrial diseases.
16:47
But of course, especially the ones, for example, like skeletal muscle, that rely quite a bit on the production of ATP. As I said, these diseases are often devastating, and unfortunately, there is no cure for these diseases, but I am hopeful that with the advent of new tools and genomics and large scale analysis, that we will begin, with these tools, to unravel what happens in these diseases, and to develop therapeutics, within the next 10 or 20 years or so,
17:21
that will hopefully be able to treat these diseases. In addition to mitochondrial specific diseases, mitochondrial disorders, mitochondrial dysfunction in many ways, is thought to contribute into many other diseases, such as cancer and even to how we age, how our bodies age over time. So, this is a fundamental organelle that's part of almost every cell that we have, that's absolutely critical to understand, which is why I'm devoted to the research that I am.
17:56
So, what I've told you so far, and hope to convince you of the importance of mitochondria, and why to be passionate about studying them, is that they're unique in that they're derived from bacteria, via an endosymbiotic event and that they're probably pivotal in the evolution of who we are today, specifically of eukaryotic cells. As a consequence of their origins, they have their own genome, and they're able to create a proton motive force in a very efficient manner because of their small genome
18:30
and their large inner-membrane surface area to synthesize ATP and to generate that for many other things that are important for our cells to exist. And they're also essential, of course, for human health. Now, even though they have been derived from bacteria, as I mentioned, their genomes are now much smaller, and as a consequence, they can't survive alone. If you took them outside of a cell, they can't exist, you can't build one, however, from scratch, you need to maintain them inside cells.
19:11
So, they're semi-autonomous, we refer to that as semi-autonomous. And this just really is a schematic depicting how different they are from their ancestors, which started with anywhere around 4,000 genes and now, present day mitochondria only have 12, so they've lost a lot of their genetic material, a lot of it is just gone, a lot of it has gone to the nucleus, and then, there are new innovations for mitochondria,
19:43
many new, different, and different from their bacterial origins, functions that they have, and in fact, one of those, of course, is the ability to import proteins that are synthesized in the cytosol as a consequence of genes being in the nucleus. And being able to import them inside the organelle, and actually properly sort them to all the various different compartments that they have. They also have evolved ways of importing lipids so that they can grow,
20:12
they self-template and grow inside cells. And they've also acquired dynamic behaviors, which is really, which are really important for them to integrate into the functions required in eukaryotic cells. And this just really makes the point in a visual way, of how different they are from their ancestors. So, on the bottom here, you see a bacterium, and it's a very solitary thing in this instance, very rod-like shaped, bean-like shape, and it's, this one is in the process of division,
20:47
in the bottom; on the top here is mitochondria in a eukaryotic cell. This eukaryotic cell is a single celled organism, the budding yeast Saccharomyces cerevisiae, which many of us use as a tool inside the labs, an excellent genetic tool to dissect the function and the biogenesis of the mitochondrial compartment, and other things. And what you see here is that in contrast to the bacterium, the mitochondria in this cell are very connected.
21:20
And the genome inside of them is distributed throughout this network that they have formed and in fact, you can see that really nicely on the next slide in this instance in time, in this eukaryote, this is a stereo pair, if you can cross your eyes, you can see it in three dimensions, and you can see that in this instant of time, the mitochondria's present in a single copy, but it's highly differentiated, it's branched, it's distributed very nicely all over the cell.
21:54
But if you look at the behavior of this organelle over time, and that's shown here, you can see events corresponding to mitochondrial fusion, in other words, coming together, and mitochondria dividing, and it turns out the machines, the molecular machines that mediate these processes are new inventions inside the cell. These organelles don't divide like their ancestors did. Now, why have they evolved these kinds of properties to be dynamic?
22:22
Well, first off, if you connect up mitochondria like this, you make a real efficient energy conductor and it's able to distribute ATP, for example, very efficiently through this cell. Secondly, this dynamic behavior, this fusing and dividing, allows both the organelle, in other words the lipid part of it, and the genome, to be nicely distributed also, which is key because you can't make these de novo. And then there's also content mixing, when two mitochondria fuse,
23:01
to become a single one, they can mix their compartments together, and so, for example, if you have a certain load of mutation in that organelle, because you have a mutated form of mitochondrial DNA, in a certain percentage, you can kind of buffer the effects of that with the rest, which is normal and wild-type. And then finally, this dynamic behavior, this constant changing, allows them to be a responsive system, responsive to the needs of the cell.
23:34
And in that context, you can see that this is harnessed nicely because if you look at mitochondria, where it is, what it looks like, inside diverse cell types, for example, skin cells, or skeletal muscle cells, these images are taken from a live zebra fish, which is a really great model, again, vertebrate model, for cell biologists, you can see that what the mitochondria look like, where they are, are very different in these two cell types.
24:06
Completely responding to the needs of those cell types for energy and other things. So, they're adaptable because of their dynamic behavior. And then, finally, dynamic behavior has been harnessed to kind of facilitate the communication of mitochondria with other compartments inside cells. So, let's go back to thinking about how we arose, the eukaryotic cells arose, and the other major endomembrane system inside the cell,
24:36
which is the endoplasmic reticulum. The endoplasmic reticulum is the compartment that encloses the chromosomes, the nuclear chromosomes, hallmarks of eukaryotic cells, the nucleus, and proliferates from there and spreads out throughout the cell to form a network that almost acts also as a structural component, as well as an entryway for the secretion of proteins outside the cells for communication. These two ancient endomembrane systems came together and have evolved ways to communicate
25:11
and that is shown here, in this movie, again, this is the simple eukaryote, budding yeast. And you can see in red are mitochondria and in green are endoplasmic reticulum and you can see how dynamic the behavior of both is, but you can also see, I hope, that in many places they're connecting and contacting and these are extremely important functional hubs where these two organelles are communicating and the endoplasmic reticulum is even aiding in how mitochondria divide and distribute,
25:43
so these two ancient endomembrane systems have evolved together and have evolved ways to communicate that are really important for the health of eukaryotic cells. So, in the second part of the talk, I wanted to point out that even though mitochondria are bacterial in origin, they have evolved many additional behaviors that make them amenable for our eukaryotic cells. They're dynamic behaviors that enable them to communicate with other cellular structures,
26:14
and most importantly, these dynamic behaviors, the mechanisms actually, that cause these dynamic behaviors, are all wired into to other signaling pathways that monitor the health status of cells. And so, this has allowed mitochondria to become integrated with cellular needs in a very nice way. So, I hope that I have convinced you that mitochondria are an absolutely fascinating organelle and I think the best is yet to come in terms of studying them.
26:52
As I said before, it's an exciting time in biology, where advances in proteomics, in other words, sequencing proteins, sequencing genomes, is now available, and we can take a system wide view of how this organelle functions within a cellular and organismal context to hopefully unravel its role in normal situations and also in disease situations. So, if I've tantalized you to delve further, here's three possible places where you could start.
27:28
These are three very accessible papers, go to the library and get them, and I encourage you, at some point in your life, to study mitochondria. Thank you.
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