In Our Time - Mitochondria

Episode Date: June 29, 2023

Melvyn Bragg and guests discuss the power-packs within cells in all complex life on Earth. Inside each cell of every complex organism there are structures known as mitochondria. The 19th century scientists who first observed them thought they were bacteria which had somehow invaded the cells they were studying. We now understand that mitochondria take components from the food we eat and convert them into energy. Mitochondria are essential for complex life, but as the components that run our metabolisms they can also be responsible for a range of diseases – and they probably play a role in how we age. The DNA in mitochondria is only passed down the maternal line. This means it can be used to trace population movements deep into human history, even back to an ancestor we all share: mitochondrial Eve. With Mike Murphy Professor of Mitochondrial Redox Biology at the University of CambridgeFlorencia Camus NERC Independent Research Fellow at University College Londonand Nick Lane Professor of Evolutionary Biochemistry at University College LondonProducer Luke Mulhall

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I hope you enjoy the programme. Hello, inside each cell of every complex organism, There are structures known as mitochondria. The scientists who first observed them in the 19th century thought there were bacteria who'd somehow invaded the cells they were studying. We now understand mitochondria are the power packs of cells. They take components from the food we eat and convert them into energy. Mitochondria are essential for complex life.

But as the components that run our metabolisms, they can also be responsible for a range of diseases, and they probably play roles in aging. The DNA in mitochondria is only passed down the maternal line. This means it can be used to trace population movements deep into human history, even back to an ancestor we all share mitochondrial Eve. With me to discuss mitochondria of Lawrence Camus, NERC Independent Research Fellow at University College London, Mike Murphy, Professor of Mitochondrial Redox Biology at the University of Cambridge,

and Nick Lane, Professor of Evolutionary Biochemistry at University College London. Nicolaine, mitochondria are found in all complex cells. What do we mean by a complex cell? There are cells that we are made of and that plants are made of and fungi and algae and things like amoeba. So they're compared to bacteria, which are incredibly tiny. You could get, I don't know, how many on a pinhead. And there's all kinds of things inside.

We have a nucleus where we pack our DNA. We have all kinds of membrane systems, all kinds of moving parts, and we have these mitochondria, the power packs of cells, which ironically were bacteria once. Those early pioneers were right, they were bacteria. When was once? About 2 billion years ago, so 2,000 million years ago. That's in the middle age, if you like, of our planet.

So life started around about 4 billion years ago, around 2 billion years ago, these complex cells appeared for the first time. Quite abruptly, we still argue between ourselves as scientists about quite how they arose. What do you mean by eukaryotic cells? Well, eukaryotic cells literally means true kernel or true nucleus, and the nucleus is where we pack our DNA. And all complex, when I say complex cells, I really am talking about eukaryotic cells. So these are the cells that have mitochondria and a nucleus and so on.

When things are so numerous and so small, how do you get near them? to describe them? Well, we can see them under microscopes, but it is very difficult to imagine. It's very difficult for scientists to imagine as well. And we've been able to see them since late Victorian times, and they look and behave like bacteria. And for a long time, people were trying to culture them

as if they were bacteria, and it never worked. And it doesn't work because it turns out that although they do have genes of their own, most of them went to the nucleus instead. And so we have this kind of split personality of a cell that has got two genomes. There is no such thing as the human genome. We all have two genomes. We have the mitochondrial genes and the nuclear genes.

Can we go through a bit more about what role they play in the cells, mitochondria? So they're often called power packs. You could think of them as little batteries. They are electrically charged. It doesn't sound like much of a charge. It's around about 150 or 200 millivolts. But if you were to shrink yourself down to the cell. size of a molecule and stand next to that membrane, the electrical field that you would

experience is about 30 million volts per meter, which is like a bolt of lightning. And now, if you kind of iron out all of the membranes in the mitochondria in our own bodies, there would be about four football pitches of these membranes with a charge like a bolt of lightning across all of this surface area, and that is what keeps us alive. And this is happening, all four of us now as you speak. Absolutely, and everybody in the world, yes. All complex life. It's extraordinary, isn't it? Can I tell to you, Mike Murphy, what are ATP molecules and what function do they have?

When we're thinking about mitochondria, what we're thinking about is how those organelles, those parts of the cell, make energy available to the rest of the cell to do the work. What we have is a currency of energy called ATP. It's a small molecule with a bunch of phosphates attached to it. And this is kind of a universal energy currency. So energy comes in the form of food or come in the form of light of photosynthetic organisms or other forms of minerals that could be used for some bacteria that can rely on minerals in the environment. In all cases, we've got to convert that energy into a form that can be used to do the basic work of the cell. That could be to make new cells, for a muscle cell to contract, for a neuron to transmit ions and transmit neuronal signals.

In those situations, what we do is convert all the food energy or whatever other sort of energy into this universal currency called ATP. And so we build up a large amount of ATP inside the cell. So formerly, the ATP concentration is that store of energy. And if you were at equilibrium, if your ATP went down to zero, then you would be dead. So continually life is holding that away from equilibrium, storing the energy in the ATP concentration, more formally in the ratio of ATP to, its products, but that's kind of the way we store the energy that does everything in our bodies. I'm in the position of finding it astonishing, and you seem to take it for granted that this is what goes on. It is astonishing, and if I sit back in the garden at the end of the day and have a think

about what I've been working on, it is completely mind-boggling. Of course, on the day-to-day basis when you're doing the work and you're in there, sometimes you lose track of that and just becomes a job, but it's important to distance ourselves and bear in mind how astonishing it is that we have these bacteria inside our cells doing these processes, providing the ATP, and they're working away inside us all the time. Do you have any figures to tell the listeners about what scale this is on?

It's huge. If we think about the amount of oxygen that we breathe in, well, that oxygen is being used to burn the food we consume, so we'd consume food as sugars or fat. That gets broken down and goes to our mitochondria. Then about 95% of the oxygen we breathe is used by the mitochondria to burn up that food and that will produce a whole way of converting that energy into ATP and probably inside

our bodies we're making maybe 70, 80 kilos, our whole body weight in ATP is being turned over every day. So that's happening continuously. We're making and using that all the time, even though the actual amount is quite small. Do we know how that came about? We know how that process is called oxidative phosphorylation, which sounds a bit complicated, but all it means is that because we have phosphates on ATP and because we use oxygen to release the energy, we have a process inside the mitochondria, which Nick alluded to that we have this huge inner membrane, and that's a key part of how mitochondria work. This was discovered by a person called Peter Mitchell, which you may come back to a bit later on, and it's a process called chemoasmotic coupling. What happens is that we take

the food, we break that down and react it with oxygen, and then it goes to the mitochondria, and there we use this to actually pump protons, the things that we see in acid, like in vinegar, the protons are what give it its acidity. We pump those protons across this huge, huge membrane, the four football fields in area that Nick alluded to earlier. That each of us has. Each of us have. And that huge amount of charge and concentration across that membrane, this lightning bolt that we store there, is then stored as an intermediate energy form. And it's only transient, though, and that gets used, the protons,

come back through these astonishing machines called the ATP synthase, the structure which was determined by John Walker in Cambridge, and what was absolutely amazing about the ATP synthase, is it's like a tiny turbine. The protons come flying back through the ATP synthase, and it rotates maybe a couple hundred times a second. As it rotates like a turbine, it's using the energy that was temporarily stored in this proton gradient,

these lightning bolts that Nick was alluding to, and then it's making the ATP. So we're continually replenishing the ATP as this kind of like a dynamo system inside. And the idea that inside our mitochondria on this huge area of membrane, all the time we have these tiny little turbines whizzing around a few hundred times a second. It's astonishing, really. Thank you. A great. Flow come here.

It contains DNA. True, it does. But it's different to DNA found in the nucleus. How is it different? As Nick was saying earlier, we have two genomes inside of ourselves. So most of our DNA is stored in the nucleus. It's about, in humans, it's about 16,000 genes that do all sorts of functions. But the mitochondria has a really, really small genome.

It's like a little circle, and it only encodes, it only has 13 of these genes, protein coding genes, and they are responsible for making products of this energy factory, the oxidative phosphorylation system. In what way does the responsibility demonstrate itself? So it's the, it's a structural component. So if we think about the mitochondria, it's got the little energy factories making all of this ATP through the turbines. The factory needs the building blocks. And so some of the building blocks are produced in the mitochondrial genome. And some of the other building blocks are produced in the nucleus.

And so I like to use the analogy of components of two different manufacturers have to come together to build this energy factory to produce all of this ATP that we use. So it's an incredible cooperation between these two systems that generates all life. So each of us is walking around it with a massive industry inside us. That's correct, yes. Pumping away the entire time. Pumping away, exactly. Yeah, yeah, it's incredible. I can't get my head around it.

I just keep saying how extraordinary. But I'm going to pluck on saying it's extraordinary, and you'll tell people exactly why it's extraordinary. What does the DNA in mitochondria actually do? Can you just go back to Bacius? With the DNA, what does it do there? So DNA is our genetic makeup. It is the building blocks of who we are. It's a blueprint. And so it has all the instructions on how these proteins should be made.

So the DNA in the mitochondria has the instructions on how to make these components for the energy factory in the mitochondria. DNA stands for deoxyribonucleic acid. And it's all the genetic information that we have in our body. to generate who we are as a person. The only timeline we've got at them up to is a mere two billion years ago. But do we know what you are talking about, how and when it was assembled? When these complex cells arose in the world, that's when interaction between the mitochondria and the nuclear genome started.

So the endosymbiotic theory is a theory that states that this partnership started. So you have a pre-ukaryotic cell. that was swimming along and it found this bacteria and it engulfed it. And so the bacteria ended up being the mitochondria and this pre-ukaryotic cell ended up being our nucleus. So this is the start of this wonderful friendship between the mitochondria and the nucleus. And through billions of years, genes started being lost in the mitochondria and being brought into the nucleus.

So this bacteria that once was functioning bacteria started losing control of itself and the control in terms of the genes got moved into the nucleus. So now the nucleus has a lot of control over what the mitochondria does. Nick, Nick Lane, it was first observed by scientists in the 19th century.

What did they observe and what did they make of it when they first? Well, it was a guy called Richard Altman. He, actually, he died in rather tragic circumstances because nobody believed him and they mercilessly made fun of him. What didn't that mean? Well, they didn't believe because he had discovered what he said were the elementary organisms. So he'd used a dye. At the time they were using dyes that would allow you to see the chromosomes in the nucleus. So you could see the cell division.

It's marvelous dance of the chromosomes as a cell divides and they all line up and then segregate into the daughter cells. And he was not interested in that. He was interested in the rest of the cell, and he used a different dye that effectively dissolved all the cell, apart from these elementary organisms that he could see, that were kind of long sausage-shaped things, but actually there were partly threads and partly granules, and mitochondria literally means threads and granules.

And he thought that the cell was a kind of corral, and the mitochondria were like cattle in this thing, and the nucleus he thought that was a food dump for them. and so these were the elementary organisms and they constructed all of life. And you can imagine it didn't go over particularly well. But why didn't it? You've explained it very clearly.

Why didn't it go over very well? The rest of the field had already figured out that most of the action was happening in the nucleus with whatever those chromosomes were, this was the dance of life to the rest of the field. And the mitochondria, nobody knew what they were. It wasn't until about the 1940s, late 1910, that it was first shown that this is where energy is being generated in the form of ATP,

as Mike was saying. He came to a side end, didn't he this butcher? He killed himself, yes. Because nobody would believe him and made fun of him and heck with him and said, you're wrong. It happens in science too, I'm afraid. How awful. Mike Murphy, you mentioned Peter Mitchell earlier and said you'd come back to him and here we are back to him. What did he propose?

What did he do? Describe briefly this idea called. the chemoasmotic coupling hypothesis, which sounds a bit complicated, but it's how... This is a 20th century, so. Yeah, this was all happening in the 1960s. Yeah. At the time in the 1960s, Peter Mitchell proposed this theory where we had these protons moving across a membrane, coming back in, driving this ATP turbine, and then making the ATP

available. That sounds fine, that's a theory. But at the time, what people really thought was that they understood how ATP was being made by a different process called substrate-level phosphorylation. All that means is that it was a normal chemistry, like you put molecules into a test tube, you shake them up, they react, that made ATP. And that was how other processes like the simple breakdown of sugar works. So that's what people thought was going on in mitochondria. And a lot of quite big personality, should we say, were invested in these ideas.

Which big personality? People like Ephraim Racker, E.C. Slater, Britain chants. These are all very eminent scientists at the time. Did wonderful work. but they all really wanted to be the person winning the Nobel Prize to give the fundamental idea about how is energy transduced within ourselves. Turns out that those big names were wrong and Peter Mitchell turned out to be right because that's how nature works.

Peter Mitchell was very interesting in ways beyond just being right about how this works. He was at a PhD in Cambridge and he moved to Edinburgh, set up a research unit there. But for various reasons, he decided he's a research unit there. was going to move out of academia. Luckily, he was very wealthy and set up his own laboratory in a house called Glen House in Bodman in Cornwall and did the basic experiments with a colleague called Jennifer Moyle to actually uncover and show that this mechanism worked for how mitochondrically made ATP. Then he was building on this, this idea, which was very different because it involved

both vectorial ideas, as he called, in other words, moving things in and out across membranes, as well as scalar things like normal reactions in a mess and a test tube. And that idea was hugely influential. What he was able to do was, though, he wasn't very good at explaining it in clear ways. He just wrote it up as books. In 1966 and 68, he produced his books, which were called the Little Grey Books, a bit like the Little Red Books from Mao.

And in some more cynical terms, they said these were the Little Grey Books of Chairman Mitchell. Because these ideas were quite difficult to understand because biologists weren't able to understand them. It took other people like David Nichols, for example, to really explain and sort of proselytize around. And also, of course, what happens is that younger people came up and were able to grow up with those ideas and we used to them and then pass them on. So Jennifer Moyle was mentioned there as well. And she was really a lifelong scientific collaborator with Peter Mitchell. And I don't think that she's really got the credit that she deserved because she was the one who was doing the experience.

Mitchell himself apparently was cack-handed in the lab. He would tend to get bored and wander off and do something else. And it was really Jennifer Moyle who did a lot of the experiments that made the rest of the world, made people like Ephraim Racker take it seriously and do experiments themselves. But Mitchell and Moyle published not only the little gray books that was Mitchell alone, but there were a number of papers in journals like nature in the 1960s, which were Mitchell and Moyle together. And I was reading these. again recently. And I was quite struck by how modern they are in their tone. And it's because Moyle was the experimentalist and she was explaining the experimental approach and I think they, I genuinely think that she didn't get

the credit that she deserved. Flo, endosimbiosis. What is embossimbing? And how is it relevant to mitochondria? Well, endosimbiosis, the word symbiosis means partnership. I got that bit, but the

The endo is inside, right? And so with the mitochondria, it's this partnership. The mitochondria being sort of a little almost parasite, let's say, inside of our cells. But they work together to produce all the energy that we need. So endo, it's inside, and then the symbiosis. It's a partnership between both nucleus and mitochondria. How would you say that was relevant to what we're talking about? Well, if it wasn't for this great partnership, we wouldn't be able to produce all of this ATP and energy that we need to survive.

Right. It's really, to make energy, you really need these two manufacturers, these two genomes, to work well with each other. If there is any complications in terms of, let's say you have a mutation in one genome that makes this communication or this sort of marriage not work properly, then you have. have catastrophic effects when it comes to producing the energy because things just don't physically work. Nick, you want to come in? Yes, there's been a lot of change over the last five or six years about who were the partners in this relationship, who was the host cell and who were the end of symbioniont the bacteria that got inside.

And it's become increasingly clear that the host cell were really simple cells themselves. They were what's called archaea. They look a lot like bacteria. ago, they're relatively complex. But in effect, they didn't have anything. They didn't have a nucleus. They didn't have any of these membranes. They didn't have really anything that are a eukaryotic cell, these complex cells that make up you and me. They had none of that. And then if you think about the makeup of complex cells, you look at a plant cell and if you look at it under a microscope, it's got exactly the same structures that our cells have. And an amoeba has exactly the same

structures as well. And you wonder, why would a plant cell which sits in the sun and photosynthesizes have all the same equipment, if you like, there's an animal cell or a fungal cell which have got completely different lifestyles in completely different environments? And there's an argument, which is a beautiful one. It's certainly not proved. But actually, they were not adapting to a way of life in an outside world. They were adapting to the pesky ender symbionion that was living inside them, the bacteria, which itself wants to grow and potentially eat. It's somewhere between being a parasite and being a genuine symbiont wants to eat its host. And so a lot of this complexity in the world may have been driven by, effectively, the

conflict between the host cell and the ender symbionance, and then various forms of conflict resolution, which drove complexity, a kind of a nuclear arms race, you may say, in early evolution. My. Following up on what Flo and Nick have said, the history of endosymbiosis and how it was adapted and understood is also very fascinating as well because early on, as we discussed before, the microscopists suggested something similar that the mitochondria and also chloroplast might be bacteria. This was then found to be ridiculous at the time for various reasons, which turned out

not to be correct, then later on when people discovered mitochondrial DNA and that pointed to the history of mitochondria and chloroplasts endosimbionts, Limurgulis in particular in the the late 1960s pushed that forward. And she was famous for establishing the endosumboiosis. And really the current understanding of endos symbiotic origins of mitochondrial and chloroplasts comes from her work in the 60s, which built on discoveries of mitochondrial DNA and chloroplast DNA. Can we ask Nick, then does mitochondria play any other roles in cells, apart from energy production?

Many, in fact. And we've become almost blinded to some of them by our fascination with the energy. energy side. But if we go back to some of the earlier bacteria that preceded mitochondria very early in the earth, before there was any oxygen at all, they were behaving like mitochondria, you may say. And what they were doing is running the machinery backwards. And instead of burning food in oxygen to generate energy, they were actually taking the components that we breathe out, which is to say water and CO2. The water is, first of all, What we're really doing with the water is we're pulling hydrogen out of food

and burning it in oxygen to make the water. Now, what these early bacteria were doing was taking hydrogen bubbling out of the ground in places like hydrothermal vents and reacting with carbon dioxide to make these organic molecules the building blocks of life. And this is in what's called the Krebs cycle, which is effectively feeding the hydrogen in the mitochondria to generate this charge and this is what's driving everything. It turns out now in diseases like cancer, they start to behave almost like those early bacteria that sometimes the Krebs cycle starts going in reverse.

And what they're doing in effect is instead of generating energy or as well as generating energy, they're making more building blocks. They're making more nucleic acids to make DNA. They're making more lipids to make the membranes. They're making more amino acids to make the proteins and so on. they're driving growth and cancer and so on. So they've become over the last 10 years or so, almost notorious in cancer. It's much more ambiguous than simply they're providing energy.

They're also providing the building blocks for growth, and it's become very important in medicine now. Mike, you do you come in? Building on those ideas that mitochondria have many metabolic roles, which Nick was describing there, they also have other roles by the nature of just being kind of slightly foreign X-bacteria inside the cell. It means they now seem to coordinate a lot of processes such as cell death. We understand that cell death sounds like a bad thing, but many times you

want to kill the cell. The cell would rather die if it's virally infected or if it's become cancerous. You want their cell to die cleanly and go away. Mitochondria turn out to be central for that. They release some components, which activates a very clean way of killing off the cell. They also enable the cell to respond to things like inflammatory signals. So there could be an infection because some of the bacterial components that would trigger an infection are a bit like some of the things that we have in mitochondria. So they came to converge on similar signaling pathways. And also viral infections also enable the cell to respond to viral infections

and respond to kill off viral infections and the cell might die. And a lot of those are coordinated on the surface of mitochondria as well. So as if we use the fact that mitochondria are slightly foreign and we encompass them and lock them away, but we can occasionally release them, and they can trigger the cell to die or respond to infections. So we tell that mitochondria,

it's only passed down the maternal line. That's correct. Could you discuss that? So unlike our nuclear genome, so we all know that we get half of our DNA from mum and half of our DNA from dad, and that's what makes all of us, right? Every living individual, every sexual,

living in individual. What we get from mum and mum alone is the mitochondria. So we get everything that surrounds. Do we know why? I think it's a process. It's the process of how sexual reproduction works. When the sperm meets the egg, the sperm head is just a tight, compact bundle of nuclear DNA and the male sperm doesn't pass anything else on. Actually, the mitochondria, DNA, and gets actually destroyed inside of male sperm, which there's sort of theories as to why that that is. But yes, we only get mitochondria from our mums. What consequences does that have?

So that has, from an evolutionary perspective, that has really interesting consequences. I study a lot this hypothesis called the Mother's Curse hypothesis. It's got a flashy name, but it's basically because the mitochondria is inherited from mothers to all of the offspring. The mitochondria only see females, right? And so if there is a mutation that is bad for females,

selection will get rid of it, because that's what selection does. It gets rid of bad mutations. But if it's a mutation that is good for females but bad for males, selection can't touch it because it's only inherited from mother to offspring. And so the mother's curse hypothesis predicts that male mitochondrial DNA, well mitochondrial DNA males,

has a lot of mutations that are harmful for them just because of a byproduct. At what stage, at what stage, all this activity, which you're often talking about in contesting this, that and the other, become something that was leading to life as we know it? As soon as bacteria get inside another cell,

then effectively the number of them is enormously decreased. You can no longer have millions and millions of them. In our own cells, we may have a few thousand in an oocyte and an egg cell. That's as many as we get. There's about half a million in an oocyte. But what that means is, you know, it's not like having billions of people or billions of bacteria or something. And the strength of selection depends on population size.

So as soon as you live inside another cell and you have a small population and you begin to degenerate and lose genes. And that process of gene loss in the mitochondria is why they ended up losing almost all their genes. And they've kept a few, and those few that they've kept in mitochondrial DNA are really necessary for respiration to work. So anything that lost them dies in effect. So we keep this handful of genes. All of this is actually a process of almost degeneration. And yet somehow those are losing their genome. But they're still making ATP.

they're still making energy. And because instead of having 4,000 genes like their bacterial ancestors had, now they've got 13 genes that code for proteins and maybe some that code for other things as well like RNA. So they're down to only 37, 38 genes left. And they can make as much ATP as they always could, but they're overheads making this ATP. Instead of having to run 4,000 genes, they've just got a few.

And so actually this process of degeneration gave the host cell an enormous. power to almost do what it wanted, to swell up, to become larger. And so it's almost an unforeseen consequence of trivial trapping in a population inside other cells that leads to a step change in what evolution is capable of. In what way, was there any way in which we could say in the compass of the way we speak that they knew about what was happening? Was this done by... We're not allowed to say that. This is teleology. and evolutionary biologists are not allowed to engage in teleology. But in effect, no, they have no foresight.

They don't know what's going to happen. They simply are. So the whole thing is accidental haphazard? Yes. But it doesn't sound haphazard when you talk about it. There are principles that govern what can happen. And things like the strength of selection depends on the population size. These kind of things are principles that govern what may or may not happen.

But they're loose and they give so much scope for other, expected outcomes. I think the closest analogy in my mind to the way that natural selection works is probably the way that's a banking sector works or something. If there's a loophole in the law, they're going to find it somewhere and they're going to exploit it. And this is how natural selection works as well. I guess the issue, of course, is that we've only done the experiment once that we're aware of. So the idea of finding life on other planets would be so exciting to see how it originated, does it have similar. We predict there'd be similar systems involved and we'd predict there would be a strong push through selection to come to something more complicated.

But let's see what we find when we go out to look for it. What do we know about disease? So mitochondrial diseases are very interesting because we know, from what we've been saying, that mitochondria are very important for the basics of basic processes of life. So you need the mitochondria to break down food to make energy available. So you might expect then that if mitochondria weren't able to do that, we'd be in trouble. So as you might expect, we've talked about mitochondrial DNA. If we get mutations from our mother in our mitochondria, our mitochondria can't work that well. Under those

circumstances, energy dependent cells like muscle cells, brain cells will show up as not working well and will get usually childhood diseases will arise. This is similar for many of the maybe 1,000 plus genes in the nucleus that also help assemble mitochondria. Those will also lead to metabolic defects. But in addition, of course, because mitochondria is so central to life in general for the methods, for the reasons that I alluded to a wee bit earlier, anything that goes wrong mitochondria is going to contribute to all sorts of other diseases, what we would call, say, secondary mitochondrial disease. They don't have a genetic origin, but things like neurodegeneration, diabetes, aging associated processes, all of these will also have a component of mitochondrial dysfunction.

Is there any sense in which the systems you've been talking about are developing, are refining themselves as we speak? Well, mutation is a random process, right? So we think you have our nucleus and our mitochondria and they're making energy in our cells and it's all going well. But we have mutations occurring all the time in our bodies and our cells and mutation is a random process. So sometimes these things appear and within generations, as an evolutionary biologist, I'm not just thinking in minutes or hours or days.

You think across several generations or thousands of generations, things are about to pop up. And mutations will arise either in the mitochondrial DNA or in the nuclear DNA that prevent this talking with each other. And so this is how it's a bit of an arms race. Mutations will arise and then the other genome has to compensate somehow for this miscommunication. So we're not in a stable place all the time. The question you raised, Melton, alludes to the idea that, well, it seems that we're still in the process of the post-cell adapting to having the mitochondria there. Some of the questions that are raised is why do mitochondria still have mitochondria DNA? Why couldn't they get rid of most of it to the nucleus?

And that's far more efficient. Because in the mitochondria, you've got all this machinery to keep the mitochondrial DNA going. Why? We don't really know. Some of the ideas which I find very not convincing at all are that the mitochondria DNA is still in the process of being moved to the nucleus. I don't think many people believe that. I think the idea is that there's a reason for retaining mitochondrial DNA. I think in the simplest of terms

we need it to govern this huge electrical charge as I mentioned earlier on 30 million volts per meter if you get that wrong you sizzle yourself you need those genes right there to control this process in real time

we're breathing all the time we're burning this all the time we need those genes there if you lose them and there are various conditions where if you have a mutation in the mitochondrial DNA it can play havoc

and it's not just in one organ it tends to be worse in, say, the brain or in the muscle because those are the most energy-dependent organs, but it's actually the whole body. Everything that we do depends not just on energy, but on these building blocks. And we think about a condition as well, like long COVID, for example,

or any viral infections. Viruses are, they're notorious for, they can cause cancer, but their interest is similar to, is similar to a cancer cell's interest in that it wants to grow. It wants to make copies of itself. It wants to take over the production system of cells and make copies of itself. And to do that, they want the mitochondria.

They want to switch the gearing of the mitochondria effectively to make more viruses. And there's some interesting work suggesting that some of the problems with long COVID with dreadful lack of energy and inability to really do anything. anything very much, are linked effectively to the viruses having manipulated mitochondrial function, and it's the whole body which is affected by this. But are they instrumental in fighting disease as well? Yes, I mean, having good mitochondrial function and having a lot of energy in our reservoirs, it's always good to help combat any diseases or illnesses that we might have, of course.

This thing has cropped up in the last year or two about a child with three parents. Yes. How does that involve mitochondria? So for people that, for mothers especially, that suffer from mitochondrial diseases, if they know that they have a mutation in their mitochondria that can possibly get passed on to their child, right?

So what they do is that they get an embryo so that they get the nucleus from the mom and dad where the mum has the mitochondrial disorder, and they get a donor embryo. And what they basically do is that they remove the nucleus from the donor embryo, and they put the nucleus from the mother and father that want to have the child, and they place it in there. And so the mitochondria comes from a donor parent,

but most of the genetic information comes from the mother and the father that suffer from this condition. Is this commonplace now, or is it... The UK passed the law to legalise this practice, I would think, 2016 or 2017. And in the news, it was a couple of weeks ago, I think that the first child was born from this procedure.

I think they've only been about five births worldwide from this procedure. What role is it playing aging, mitochondria? Well, the whole process of aging really Nobody can agree about it, that's the first thing to say But in effect, the engines wear down, I suppose you can say in the broadest sense

And the engines are the mitochondria So we've known for a long time that they play a role in ageing But the question is what kind of a role exactly And I suppose the simplest way to imagine it And again, this is an evolutionary question because different animals have different lifespans. And it boils down to how much investment do you want to have to maintain a system in relation to when do you want to have offspring.

And so small animals like rats will produce a lot of offspring in a short period of time and an elephant obviously much slower and much fewer. And these are trade-offs in evolution. And if you think about if we wanted to keep our own minds alive for hundreds of years, we would need to invest quite a lot in making sure that the neurons are maintained in a working state. And if you simply replace them and you think that a single neuron may have millions of synaptic connection, or tens of thousands of synaptic connections, then are you going to rewire all of those, or are we going to lose our memories in doing that?

The amount of investment in trying to kind of refashion a mind from within is very difficult to do. And so that trade-off in evolution effectively said, well, 70, 80, 100 years, that's enough, you produce your offspring and this is your lifespan. And so it's been very difficult to help people live, say, more than 120 or something. That's often called a maximal human lifespan. Some people think we can do it. Some people think we should never do it. I think it'll be quite difficult to get much beyond there.

And it's because of this trade-off. Mike. What Nick was showing very nicely there is that we've got kind of two ways of looking at aging. First is the evolutionary one, which is the key one, that once you've reproduced, evolution doesn't care about you anymore. If you wear out, it doesn't matter. Normally you'd have died from other events by that stage during most of human evolution.

But then that means, even in that context now, where we have a very good environment for most of us, why do we still wear out? Why do we still age? It's something like that mechanism of aging, what's going wrong, what's falling apart. Mitochondra clearly involved in that. But the simple idea is that it was just mutations, accumulation,

or oxidative damage you to free radicals, the more we look at all those simple theories, the more it's clear they're not sufficient to explain. So we sort of have the mystery about what is it that's going wrong. If we live beyond when evolution stops caring about us, what's the details of going wrong? It's still very tricky. If we can understand those a bit,

we might be able to enhance lifespan or health span a bit better. And often it's the way that we handle energy, handle food, seems to be partially involved with those. And if we get addressed some of those, like caloric restriction, can mimic some of these. We can live a little bit longer. But even then, we don't live another 100 years. We live another 10 years maybe, or we stay healthy a bit longer. So there's huge amounts about aging we just don't understand.

Aging is a very big, unanswered question, right? And we don't know why we age. And to me, I think the diet and the interaction of diet and the mitochondrial state is quite important. So there's been a lot of work done, showing, for example, that if you eat a lot of protein, that you tend to die really quickly. Although protein at the moment is a diet trend. It's extremely complicated, and we still don't know. There's two views about protein.

It's a good for you, me it's bad for you. Correct. Almost with any diet. It's like that. There's one nice point. The flow touched on earlier on about mother's curse. My mitochondria are a dead end. it doesn't matter how good or how bad they are, they're going nowhere.

And that means selection can't act on them. And so men can accumulate mutations in mitochondrial DNA over multiple generations that aren't good for them. This is the idea of Mother's Curse. And there's a beautiful idea that this could be one of the reasons why there's a difference in life expectancy between men and women. Women will often live five, six, seven years longer than men. Why is that?

It's probably not only Mother's Curse, but it's an interesting way of thinking about the question. Well, I think that's terrific. Thank you very much. Thanks, Mike Murphy, Nick Lane and Flo Cammu, and to our studio engineer, Jackie Marjoram. Next week, Sophocles' tragedy, Oedipus Rex, Aris Sottle, thought it the greatest play ever written.

Thanks for listening. And the In Our Time podcast gets some extra time now with a few minutes of bonus material from Melvin and his guests. So what would you like to have said that we had in time in our order? scientifically what intrigues me and I think is going to be very important for all aspects of mitochondria is how mitochondria are integrated into the cell, how they talk to each other within a cell, and how they talk to the nucleus, because I think there's a lot of feedback between the mitochondria and the nucleus. This could be by metabolites affecting what are called epigenetic marks within the nucleus.

There are also ideas that mitochondria might be signaling from cell to cell, from mitochondria and related cells. So all these ideas that we have this pool of mitochondria inside our cells talking to each other and talking to mitochondria in other cells as a very intriguing aspect. You're saying that I get a bit confused because talking to seems these millions and millions of them chattering away to each other. You're just using that as a metaphor. Yeah, they're not using sound waves obviously,

but they might be using... They may be using waves, though. They might be using waves, electrical waves. They could be using waves of small metabolites that they're sending around chains in pH. changes in ions like calcium. There's lots of ways that they can talk, well, I'm using inverted commas here,

but not good on radio, but what they're talking to each other, using all sorts of signals that they can communicate with each other would have been a better phrase. I mean, one area that I'm becoming fascinated in, and it's on the boundaries of respectable science, I would say, but fascinating. It turns out that anesthetics interfere with electron transfer to oxygen,

so they interfere with respiration. and I mentioned that the mitochondria generate these very powerful electrical fields, but we also now know that their structure means that we have a lot of oscillating current happening, and that should generate electromagnetic fields. And the role that electromagnetic fields play in this talking between different mitochondria or talking to the plasma membrane and so on, I say it's on the bounds of respectable science right now, but there's been some beautiful work in the last few years

that show that electrical charges really, do influence development in things like flatworms and so on. And there's some work where you just manipulate the charge on the membranes that will mean that flatworms develop two heads of strange things like that. So there's scope for understanding this electrical talk. So I'm quite interested in mitochondria from an evolutionary and ecological perspective. So a lot of my work revolves around trying to understand how the mitochondria has helped. organisms adapt to different environments. For instance, I work on little fruit flies in Australia, and we have shown that the fruit flies in the north, tropical Queensland, right? They have a different

mitochondrial DNA, and it's this DNA that has helped them adapt to this sort of hot rainforest conditions. But the ones in Melbourne, which is very similar climate to London, quite temperate, they have a different mitochondrial DNA, and that DNA helps them adapt to more colder conditions. So it's not just looking at mitochondria in terms of a medical and biochemical lens, but also looking at how it impacts a lot of other big evolutionary questions as well. Is there any way that people like you can, as it were, intervene or interfere with this to make it more effective for human purposes?

That's very interesting because a lot of the work I'm trying to look at is what we might call mitochondrial medicine, developing drugs that are targeted to go to mitochondria, to manipulate them. Partly some of the work that goes on in my institute in Cambridge, colleagues like Mikal Minchuk is trying to make ways of targeting proteins to mitochondria so they could repair damages, damage mutations in mitochondria DNA. Much of the work I've been involved in is small molecule, small drugs, trying to manipulate mitochondria, and trying from that to develop treatments for things

such as heart attack and stroke. Also, the idea about how could we intervene in chronic diseases like neurodegeneration, target mitochondria, and try to improve the outcome. So those would be another area that we think has got huge scope and huge potential for the future, but we're just scratching the surface, I would say, of thinking about mitochondria as a way to treat disease.

Nick? So mitochondrial diseases, which are often, degenerative conditions that can attack very young babies, often in the first six months, usually within two years. Sometimes they take longer. It depends on the specific mutation. But with mother's curse in particular, the mutation is not harmful to the mother or to women in general. They're only harmful to men because mitochondrial function cannot be selected for in men because mitochondria do not pass down the male line. So it's an interesting idea. It's quite subtle because the genes in the nucleus can compensate for that

and effectively can force the mitochondria to behave in a male way, if you like. But it's, but it really does mean that men have about twice the risk of mitochondrial diseases on average. Do you anticipate great changes in the way your study hitherto has been going? I think there's a big change happening now. which I suppose the way that medicine has been structured over hundreds of years has been focused on specific organs and degeneration of particular organs. And of course that's true. But there's also, you know, a lot of diseases like diabetes or Alzheimer's disease or cancer. They are linked with being older, their age-related diseases.

And there's something about the process of aging and the role of mitochondria in aging that mean that instead of it being as organ-specific, which goes back to Vesalius in Renéning. Nissance Italy. It's really about the system as a whole. So it's a different way of conceptualising how medicine works and how we should approach medicine. And this is a change I think that's happening now slowly, but it's going to be a big revolution in how we perceive it. So we change the perspective. At the moment we're looking from the body up down through the organs, but if we go back to the original cell and that's a community of the endosomyos mitochondria and the rest of the cell and look from that up, how that community operates in different organs, how they interact. That could be a very fruitful way of thinking about human health.

If you follow that through and got what you aim to get, what difference would it make? It could be that instead of thinking purely of neurodegeneration as neuronal cells dying or being damaged, it could be thinking in the whole context of the mitochondria throughout the body, affecting all of these processes and how they proceed with aging. but the reality is we don't know how it will progress. We're just diving in and seeing where it takes us at the moment. One area that's quite exciting at the moment is effectively mitochondrial transplants and we don't really know where this is going.

But if you have a cell culture and you effectively sprinkle mitochondria on that culture, then they will be taken up very quickly within an hour or two. They'll have all been kind of guzzled up. And it seems that this happens in the body as well, that mitochondrial will move around from one cell to another cell. cell. And there's some potential dangers there because if you're effectively transplanting mitochondria with its own DNA and it's the wrong kind of DNA, then it could be that there are, there could be a penalty for that. We don't really know. But at the moment, it looks as if you can regenerate

somewhat cells by effectively giving them young mitochondria. Philo, do you want to come in here? Well, I'm quite interested in the future with what we talked about before with the mitochondrial replacement therapy or the three parents. It's a really new technique and I think it has the potential to help a lot of people. We don't really know at the moment what some of the consequences are but I think it's some revolutionary techniques that will help a great number of people. Well thank you all very much. You were brilliant. I was staggering to keep up but you were extremely helpful. Thank you very much indeed.

Would everyone like a cup of tea? That would be nice. That would be really nice. Thank you. That was terrific. I was. It's completely absorbed in this. Hi, I'm Ryland, and I'm here to talk about men. Because in recent years, we have all seen the man in Britain undergo radical change as the rule book has been well and truly ripped apart. So I'm going to talk to a range of prominent figures and celebs who have each got their own diverse and contrast intakes

on what it means to be a man today. I want to prize open the fault lines of modern masculinity and get to grips with the changing landscape and try to get some answers so that we can want. Passamon to the next generation. This is Ryland, How to Be a Man, from BBC Radio 4. Listen on BBC Sounds.