How Mitochondria Control Your Metabolism | Dr. Jared Rutter
Huberman Lab
In this episode of the Huberman Lab Podcast, host Andrew Huberman sits down with Dr. Jared Rutter, a leading expert in biochemistry and mitochondrial biology from the
Key takeaways
- Metabolism is not a single system but the sum of trillions of individual cellular metabolic processes.
- Mitochondria are central to regulating energy production, cell growth, replication, and health—beyond just being 'powerhouses.'
Main topics
- Mitochondria as regulators of metabolism
- Cellular vs. organismal metabolism
Notable quotes
"Our body's metabolism is really the sum total of the metabolism of each one of our 30 trillion cells or so."
Conclusion
Mitochondria play a foundational role in health and disease far beyond energy production. Understanding
Transcript preview
Speaker 1 (0:00) There's a widely accepted hypothesis that mitochondria with excess energy leads to problems. Many people that are listening have probably heard of reactive oxygen species. This is forms of oxygen that become reactive and end up spinning out and damaging proteins and nucleic acids. And I think it is widely accepted that one of the contributors to that is mitochondria that have too much energy. Basically, the form that energy takes when it's extracted from the food we eat and before it's converted to ATP is powering the mitochondria. And when that mitochondria is overpowered, that leads to a state that is very susceptible to generation of these reactive species that end up damaging our genome, creating mutations and damaging proteins and creating many of the problems that we see. Welcome to the Huberman Lab Podcast, where we discuss science, Speaker 2 (0:54) and science-based tools for everyday life. I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. My guest today is Dr. Jared Rutter. Dr. Jared Rutter is a professor of biochemistry at University of Utah and an investigator with the Howard Hughes Medical Institute. He is one of the world's top experts in the biology of mitochondria and metabolism. Mitochondria are known as the powerhouse of the cell. But as you'll learn today, they do far more than just power our cells. They also determine how much energy goes into making new cells, to making sure that cells stay healthy and to fighting off disease. Today's conversation explains how mitochondria do that and clarifies what your metabolism really is. And in doing so, you will learn that you don't have one metabolism. Your metabolism, as it's called, is actually a reflection of the constellation of all the metabolisms of all the cells. in your body. So today's conversation will teach you the real biology of mitochondria, and it will provide a framework for you to make better decisions on the behalf of your health. So what follows is a conversation about mitochondria and metabolism, unlike any that you've heard from one of the world's premier experts in this topic. Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero-cost-to-consumer information about science and science-related tools to the general public. In keeping with that theme, today's episode does include sponsors. And now for my discussion with Dr. Jared Rutter. Dr. Jared Rutter, welcome. Speaker 1 (2:30) Thank you. Thanks for having me on. Speaker 2 (2:32) I have many questions about metabolism, mitochondria, and I know many people do as well. Most people hear the word metabolism and they think calories in, calories out. They hear the word mitochondria and they probably think the powerhouse of the cell. And that's all great. People are becoming more educated about cells and their bits and pieces and what they do. You have a very different perspective that is very important, I believe, for people to understand. Maybe we could start off by talking about how the metabolism of any one cell in our body relates to... what we call our metabolism, the collective metabolism of all those cells. And as you go, if you could take any liberties you want to tell us what we probably don't know about the quote-unquote powerhouses of the cell. Speaker 1 (3:19) You know, when we think about metabolism, as you say, I think all of us think about metabolism in terms of our body's metabolism, our metabolic rate, as you say, calories in, calories out. What that is really, our body's metabolism is basically the sum total. of what we ingest you know what we eat what we drink what we breathe That enters our body and gets processed. And the results of that processing are individual molecules, amino acids and sugars and so forth that then distribute throughout the body, go into individual cells and enter this process that we call metabolism, what we call cellular metabolism. And I think it's reasonable to think of cellular metabolism as almost like a map. There's an entry point, a molecule of glucose or sugar comes into a cell and that sugar can be chemically modified in a variety of ways to fulfill the needs of that cell. And then that cell does whatever it needs to do with the molecules it takes in to fulfill its particular functions. And then that leads to the release of waste products that we eliminate from our body. And that is sort of the organismal metabolism, the metabolism of our body. And as you allude to, I think something that maybe many people don't understand is that cellular piece of it. The metabolism of our body is really the sum total of the metabolism of each one of our 30 trillion cells or so. That's really where my passions lie are those individual cells and how they choose to take up certain nutrients. how they choose how to process them, turn them into other things, how they use them to fulfill their particular functions, and how that's regulated. The masterful coordination of each of those cells working together to allow us to be sitting here talking to one another and go out and run or whatever we do, it's a beautiful... orchestration, but that happens at the level of individual cells. And I think that's one of the fascinating things that is maybe a little bit less understood. If we were to just take the single cell view Speaker 2 (5:40) for a moment, and I know that aging isn't your specific area of interest, but one thing that's always intrigued me because my postdoc advisor once came down the hall and said, why do I have so much less energy than I used to? And he had a ton of energy. So that's like, I wonder what he used to be like. But it's a great question. He used to do this every once in a while. Like just ask these very basic questions that no one else on our halls at Stanford could really answer. Why does a kid have so much energy? And when we're older, we don't. People say, well, people are moving less. The tissues are wearing out. But at the level of energy production, are we aware as biologists at this point in history as to why a young cell, it could be muscle cell, it could be neuron, whatever, versus an older version of that? cell, why it either produces less energy, I don't know if it does, I'm guessing it might, but why the whole body just seems to have less get up and go. Do we have an answer for that? I Speaker 1 (6:36) think we have a partial answer for that. I think that's definitely a frontier of science is trying to understand exactly what goes wrong during aging. There's many aspects to it. As you alluded to, one of my passions also is the mitochondria. And I think it's almost universally the case. that mitochondria become less energized, less effective, let's say, as we age. And the reasons for that are to some extent clear, but I think largely unclear. But that is definitely a feature of the aging process. You know, there is this sort of aspect of accumulation of damage. Living in the world we live in, as I alluded to before, this orchestration of metabolism that happens throughout the body, that's hard. It's expensive. And it's expensive not only in terms of what we need to eat to fuel it, but it's expensive in terms of the damage that can come as a side effect of that. And the accumulation of that damage over time is certainly correlated strongly with aging. And I think there's some really nice... evidence in models where we can do genetics, you know, in animal models that suggest that that accumulation of damage is a big part of the aging process. And it's a huge area of interest in the field is trying to understand how you can decrease the onset of damage, how you can reverse damage that comes. One thing that I like about how you ask that question is thinking about that in the context of the cell, which again, I don't think we tend to think of aging. as a cellular phenomenon, but I think fundamentally it almost has to be. We are made up of cells and the processes that lead to aging are the accumulation of processes that happen at the level of individual cells. And I think in a way we're at the precipice of understanding a lot of this because of the tools that we are starting to have access to that will help us better understand cause and effect and the specific molecular features of the aging process. Speaker 2 (8:36) Let's talk about mitochondria. perhaps surprisingly i'm going to ask you why you study them with the caveat that they are incredibly interesting they are involved in energy production and metabolism but what specifically drew you to mitochondria versus all the other pieces of cells or parts of the body or organs that you could have worked on why the mitochondria what's so sticky about those is a place to i mean you devote a significant fraction of your life to them yeah Speaker 1 (9:04) It's an area of cell biology, an area of sort of the details of how life works. One of these things that is, in my view, just a brilliant example of taking chemistry of incredible complexity and making it work effectively inside of a living cell. Mitochondria are believed to have been the result of an endosymbiotic event where a bacterium, a free-living bacterium, was engulfed by another cell and in a way kind of domesticated. So why that's so think about holy Speaker 2 (9:43) while I'm sure people are following but in case there's somebody who's not What Jared is saying is that our cells? Basically were invaded by a bacterium and then that bacterium became part of our stable Genome going forward. It went into the what we call the germline and therefore was propagated from Parents to kids and so now mitochondria live in us, but they didn't start off living in us. That's right And we hear that about the gut microbiome. Like we have these trillions of bacteria that live in us and we colonize and we can recolonize, take antibiotics, then you need to replenish, eat your yogurt and so on. But the fact that the mitochondria made it stably into our genome and are transmitted from one generation to the next, we think of them as us. But you're saying there is solid evidence that they came from outside of humans. Speaker 1 (10:32) I think that's the only model that I think any of us as scientists have any good reason to believe. And, you know, that's fascinating history, right? That there was a bacteria and another cell that got together and together that combination could do things that any one of either of them on their own could not do. And that they worked together in some way to enable the evolution of complex life. You know, eukaryotes, which are the type of cell that resulted from that. combined situation that we were just talking about. These are all the organisms that we see around us. Plants, animals, fungi even, are all the result of these two cells getting together and making peace, so to speak, and teaming up to make this synergistic cell. Speaker 2 (11:24) Is it synergistic? Forgive me for interrupting, but when I think about viruses, I think viruses have their own sort of intelligence. They kind of... They hijack the genomes of cells and they either kill those cells or if they're really smart, they keep those cells alive and use those cells to continue to live and then propagate through like the behavior of an animal, like the rabies virus. Like, oh, let's get Speaker 1 (11:43) this animal aggressive Speaker 2 (11:44) so that it bites. And then, I mean, viruses don't think, but they have an intelligence. Do we know that the mitochondria? were benefiting the cells and the cells were benefiting the mitochondria? Or could have this been a takeover by the mitochondria? I Speaker 1 (11:58) mean, this is a bit of a philosophical question. Of course, we don't have a record of what exactly happened when and who benefited in real time. But one thing we do know is all of complex life resulted from cells that underwent that event one time or multiple times, but all of complex life evolved from that. And I think that tells us that more than likely, complex life could not result from a bacteria on its own or the archaea, the cell that became the host for that bacteria. So I think you can make a compelling argument that this was beneficial. And one reason it was beneficial, because it enabled a form of metabolism that wasn't possible before and enabled now a more complex cell. to be able to do things metabolically, to be more metabolically efficient and diversified, that it could enable, you know, again, complex life to evolve and totally fascinating history. But I think, as you alluded to, also has very interesting implications for life today. 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But what sets Juve Lights apart, and why they're my preferred red light therapy device, is that they use clinically proven wavelengths, meaning they use the specific wavelengths of red light, near infrared, and infrared light in combination to trigger the optimal cellular adaptations. Personally, I use the Juve whole body panel about three to four times a week, usually for about 10 to 20 minutes per session. And I use the Juve handheld light both at home and when I travel. If you would like to try Juve, they're offering up to $400 off select products for listeners of this podcast. To learn more, visit Juve, spelled J-O-O-V-V dot com slash Huberman. Again, that's J-O-O-V-V dot com slash Huberman. Today's episode is also brought to us by BetterHelp. BetterHelp offers professional therapy with a licensed therapist carried out entirely online. I've been doing therapy for a long time, and while it's not always easy, every time I do a therapy session, I come away feeling better and knowing that the time was well spent. With BetterHelp, they make it extremely easy to find an expert therapist who can help provide the benefits that come through effective therapy. And the data say it works. BetterHelp has an average rating of 4.9 out of 5 for its live sessions based on over 1.7 million client reviews. Also, because BetterHelp is done entirely online, it's extremely time efficient. If you would like to try BetterHelp, go to betterhelp.com slash Huberman to get 10 % off your first month. Again, that's betterhelp.com slash Speaker 1 (15:14) Huberman. Speaker 2 (15:16) Could we explore a little bit of how... mitochondria getting into these cells were able to make it stably into their genome and propagate. This isn't going to be a conversation about genetics per se, but maybe as just two points of background for people, like if any of our cells have something put into them, but let's say a physical object, like a splinter, little tiny piece of splinter stays in the cell. And then you procreate with somebody. You don't expect that child will have that Speaker 1 (15:41) little Speaker 2 (15:41) bits of splinter in their cells. But if the germline right so the the eggs or the sperm have something incorporated into them then potentially it could propagate that's why they call germline as opposed to somatic cells i think most people aren't aware of that it makes perfect sense once you hear it but you're talking about many many many years ago a cell having this bacterium go into it and then it was somehow able to stably represent itself in the genome so that that propagated forward and eventually it has to be in the germline of whatever you know primordial Homo sapiens were there. Otherwise. your kid's eye, you wouldn't have mitochondria in us. How do we think that might have happened? Speaker 1 (16:23) The main genome of the cell, the cellular genome, DNA contained typically in the nucleus of the cell. Mitochondria exist in the cytosol outside the nucleus. One of the interesting things about mitochondria, which I think is totally fascinating and has really interesting disease implications and worthy of talking about, we may or may not come back to it, is that mitochondria have their own separate genome that is sort of a relic of the bacterium that they are the descendants of. It's in a circle like the bacterial genomes, whereas the nuclear genome of a eukaryotic cell is linear chromosomes. And that genome performs very essential functions and codes very important proteins that enable our mitochondria to function. as the powerhouse of the cell, which we know them to be, to enable the extraction of usable energy from the food that we eat. So as you alluded to, those cytoplasmic mitochondria somehow make it from generation to generation. And one of the interesting features of them being cytoplasmic is they're completely inherited from the mom, from the egg. Because as you know, when the sperm invades the egg, the genome from the sperm gets into the egg, fertilizes it. The cytoplasm of the sperm does not. So the mitochondrial genome of you came completely from your mother. Mine came completely from my mother. And again, that has interesting implications for the inheritance of diseases that are. mitochondrial on origin but that's sort of how we think it works it basically propagates from the egg upon fertilization then it gets distributed to all the cells including the the germline that that fertilized embryo will have and then gets passed on to the next generation in the same way Speaker 2 (18:18) ratcheting toward the actual functioning of mitochondria maybe um you give a beautiful picture of the mitochondria not in the nucleus of the cell, but in the cytoplasm. So still inside the cell. And most people probably remember from their high school biology, a picture of a cell always looks round. I'm guessing you're going to tell us that the mitochondria can be distributed lots of places in the cell because a lot of cells aren't round. A lot of them look hairy or they have long extensions like neurons. Is it fair to say that you can find mitochondria everywhere in a cell? So no matter what shape it is, it's got mitochondria everywhere. And if so, what is the importance of having mitochondria distributed spatially through the cell? So maybe we go, so that people know where we're going. We'll talk about the spatial distribution because it turns out that's very important. We'll talk about the functioning. And then I want to talk about time as a factor. And that can be a little bit abstract for people. So we'll come to that. Speaker 1 (19:09) Yeah, spatially. You know, one of my scientist colleagues might call me on this, but to my knowledge, I can't think of a place that exists in cells where there aren't mitochondria. And I think, as you alluded to, it's a little bit dangerous for me to talk about neurons with a neuroscientist. I am not a neuroscientist, but one of the brilliant bodies of work that's been done on mitochondria has been done in neurons. It's fascinating, these neurons that have one meter long projections. Speaker 1 (19:41) mitochondria transit from the cell body down those projections. And as best we can tell, those mitochondria play essential roles at the ends of those projections, typically being able to generate, again, usable energy. They're extracting the energy from the food that we eat and powering the neurotransmission, the functions of those nerve terminals. And I think that's true of virtually every cell in our body. The extraction of energy, and turning it into a usable form, typically in the form of ATP, adenosine triphosphate. Obviously, that is the energy currency that's used by almost every cell in our body. And that is a key function of mitochondria. We'll probably come to functions of mitochondria that are outside of just extracting energy. But that is a critical function of mitochondria. And that ATP is needed in virtually every place of every cell. And by having local production, that makes it more efficient. So I think spatial distribution is a key part of that. It's fascinating. There's been beautiful work that's shown that when a cell is crawling, a cell sometimes do, you know, like an immune cell that sees something it's chasing. there will be a distribution of mitochondria towards that leading edge of the cell, which is very energetically expensive to crawl for a cell. It requires a lot of ATP. And mitochondria will congregate at that leading edge where that ATP is being consumed to make ATP right there so it can be used. I think it's a fascinating example of that local demand for energy. Speaker 2 (21:19) I'm asking some high-level questions, I realize, but is there any... reason to believe that a given mitochondria knows what cell it belongs to? Speaker 1 (21:28) Like Speaker 2 (21:29) are they different? Is the mitochondria in one cell type so very different than the mitochondria in another cell type? And are the mitochondria between like, let's say a neuron of the eye, let's get out of, since you're saying you don't want to talk neurons as a per se, like is it two adjacent skin cells? They're both skin cells. They have mitochondria in them, but do they know which cell they belong to? And do your mitochondria? I'm guessing because they came from your mom's genome. They know that they're different than my mitochondria, but how much identity do they have? Speaker 1 (22:00) I would say this is a topic that is at the frontier of what we know. You're asking some questions that are right at the edge of our current knowledge. Yeah, mitochondria are different. To a first approximation, you could say that virtually every cell in our body has slightly different mitochondria. that are particularly suited to the demands of that cell, a heart muscle cell, a cardiomyocyte. That cell kind of has one job, and that's to contract. Speaker 1 (22:31) Every second of every minute of every hour of every day for our entire life. And when it coordinates that contraction with the other cells in the heart, that enables our heart to beat. That's what its job is. Is Speaker 2 (22:43) there any turnover of those cells? We know neurons don't tend to turn over. Very little. Very little. That's reassuring. Very little. I'm glad to hear that. You can Speaker 1 (22:51) imagine that it would be hard to replace that in real time, right? I'm a hockey fan, and that's a change on the fly scenario. biblical proportions. So those cardiomyocytes, their mitochondria is wired to consume whatever it has available and make ATP because that ATP is going to be incredibly important to enable that contraction of that cell and the beating of the heart. Mitochondria and other cells, for example, like cells that line, that are the stem cells that enable our intestinal lining to be turned over. every five to seven days, which is amazing, by the way. Speaker 2 (23:31) Your whole gut. Speaker 1 (23:32) Your whole gut is turning over every five to seven days. The lining of that, of your gut. It is amazing. Those stem cells, ATP is not the major demand of those cells. They need to completely duplicate themselves constantly, every day or less. So their metabolic program is very different from a cardiomyocyte, which just needs to make ATP to a first approximation. They need to make a whole new cell. So we talked about, you know, the metabolism of the organism. The metabolism of those cells is very complex because it needs to replicate all the DNA, duplicate it to go into a new cell, duplicate all the proteins, duplicate all the membranes, the lipids, and that needs to happen rapidly. And so... that metabolic wiring is completely different. And again, the mitochondria are fundamental to that. So those mitochondria are wired in a way that enable them to produce. the biomass that's required to make a new cell, quite different from the mitochondria of a cardiomyocyte. And that distinction plays out in virtually all cells in our body, right? Every one of our cells has some particular purpose, some particular function that it serves for the body. And the demands of the mitochondria, therefore, of that cell are different depending on the unique functions and demands of that cell. And so it's a fascinating topic, this diversification of mitochondria. I think, again, that's something that we're learning about. One of the developments that's really been happening over the last few years, very much a frontier field, is you might imagine a cell that has a complex set of demands. There's actually evidence most prominently published recently by Craig Thompson at Sloan Kettering that showed that in one cell, You can have two different kinds of mitochondria that have two different functions, and they're distinct in one cell. Speaker 2 (25:37) What's each of them doing? Speaker 1 (25:39) Yeah, one of them tends to be more biosynthetic, maybe producing biomass, and one of them tends to be more energy extracting and producing ATP. That's an overly simplified but generally accurate way of thinking about it. It really emphasizes this unique function of mitochondria that can be adapted again for the needs of the cell. Speaker 2 (25:59) Okay, so I eat some food and that food's absorbed and I get glucose circulating in my bloodstream. I've got some stored energy in the form of glycogen, et cetera. And I'm curious, how greedy are the different mitochondria? Is the name of the game that every cell is trying to get as much energy as it can to produce as much ATP as possible? Or are they communicating and is energy being allocated in some way that's a little bit more democratic? Speaker 1 (26:25) That's Speaker 2 (26:25) one question then framed within that. I could imagine two scenarios. One, non-mutually exclusive, where like the vasculature just distributes the glucose very well to everything. So every cell gets access to some of this glucose and then is just greedily trying to make as much ATP as possible and the whole system works beautifully. I could also imagine a situation where there's some shuttling to important... structures like the brain, you know, to like keep your life, like breathing, heart, there's a prioritization of organs. I'm talking about under non-stressful conditions. So yes, how is energy allocated to cells and then how are cells divvying up the goods? Speaker 1 (27:03) Yeah, it's a brilliant question and a fascinating area of physiology. As you allude to, when we eat, our digestive system starts extracting the constituents of what we eat. Again, sugars, amino acids, fats. from that food, that then triggers signals of different kinds, GLP-1 being one, insulin being another. Those signals then are hormones. They get secreted and they go to many cells throughout the body. And that tells each individual cell, we just ate. And the implications of that are different from each cell. Some cells don't care. Some cells don't pay attention to that and they just keep on doing what they were doing. Some cells care a lot. Adipocytes, for example, these are the fat cells, the cells that make up our fat tissue. They care a great deal about that. And when they see insulin, what they do is they turn on a protein, they start making a protein that will cause glucose to be taken up into... that adipocyte, that fat cell. And that glucose will then be converted through a series of chemical reactions into a fat molecule. And then that fat molecule will be stored away in a way that is very safe and enabled to be stored for potentially a very long time. And again, it's a beautiful way for the organism to coordinate. I just ate, our energy status as an organism, as a body is great. It's very good. So let's squirrel away some of that energy in the form of fat that can be stored in our adipocytes, again, very safely, and can be then used when we go through a period of prolonged fasting, which... Doesn't happen for us all that frequently, but happened for our ancestors probably much more frequently. And those adipocytes full of fat from when we ate probably kept our ancestors alive when they went through the periods of prolonged fasting. Insulin has other effects on muscle and other cells throughout the body. But again, this is the brilliance of this coordination. The response of different cells to the fed state is different depending on the... the needs and functions of that cell. Again, some cells don't care at all. They're going to just go about and do their business. And some cells completely rewire their function depending on the metabolic state, the fed, fasted state of the organism. Speaker 2 (29:38) So the picture you just described leads me to conclude that basically every cell obviously knows its job. and is not greedily, but is diligently fulfilling that role. Speaker 1 (29:51) And Speaker 2 (29:51) somehow the whole thing is orchestrated so that like we work. Which I know, I think for some people it might be like, duh, but just like think about that. It's crazy. Like the liver cell isn't really talking to the brain cell in any kind of direct way about how much glucose it has access to. What you describe makes me really. understand for the first time the brilliance of having this hormone signal insulin, not just as a shuttle. Because I think most people, we think like insulin sensitive, most people who listen to this podcast or just existed in the world today, they're like, oh, you want to be insulin sensitive. You want yourselves to recognize this signal. But we've never actually talked on this podcast about what exactly that signal is. We think about insulin as a shuttle. Speaker 1 (30:29) But Speaker 2 (30:29) the size of that signal is saying what's... likely to be there. And I realized has all sorts of cool implications that can prepare the cell to like, oh, I'm going to go to work hard now to be the little squirrel that I am of a fat cell and like squirrel away as much as I can or be a brain cells. Like, let's go. I'm ready to fire action potentials if I need to. And some cells like the photoreceptors in the eye are just doing that. Speaker 1 (30:52) Eyes Speaker 2 (30:52) closed, they're firing. Eyes open, well, it's tricky, but they're more or less firing. It's not worth going into, obviously. But in every one of these cells, mitochondria are the ones that are essentially going to drive this ATP thing, right? And that seems extremely efficient too, to just have essentially one major cellular energy source. So if you could walk us through what happens as glucose gets into the cell and really what we've not done ever on this podcast, and I don't think I've heard elsewhere on any podcasts, maybe it's out there, but is... how you go from ATP to actually the cell being able to perform its roles. And I realize there's a lot of biochemistry there, but you've worked on some really linchpin molecules in that pathway that perform very specific roles. And so like, maybe we could really talk about what basically gets us from ATP to pyruvate. which might scare some people away, but you'll educate us as to why it's not scary. It's just super cool. And why it's so important to have these signals that aren't just like chemicals. They actually mean something for the cell. Because for me, forgive me for going a little long here, but then I'll shut up. I think if people can really internalize this idea that, yeah, like hormones go up, hormones go down. Chorazole goes