Could Mitochondria Be Rewriting the Rules of Biology?

Scientific American

21-05-2025

Rachel Feltman: Mitochondria are the powerhouse of the cell, right? Well, it turns out they might be way more complicated than that, and that could have implications for everything from diet and exercise to treating mental health conditions.
For Scientific American's Science Quickly, I'm Rachel Feltman.
Our guest today is Martin Picard, an associate professor of behavioral medicine at Columbia University. He's here to tell us all about our mitochondria, what they do for us and how they can even talk to each other. If you like to watch your pods instead of just listening, you can check out a video version of my conversation with Martin over on our YouTube page. Plus, you'll get to see some of the aligning mitochondria we're about to talk about in action.
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Martin, would you tell us a little bit about who you are and where you work?
Martin Picard: Sure, I work at Columbia University; I'm a professor there, and I lead a team of mitochondrial psychobiologists, so we try to understand the, the mind-mitochondria connection, how energy and those little living creatures that populate our cells, how they actually feed our lives and allow us to, to be and to think and to feel and to experience life.
Feltman: Before we get into the details, most people know mitochondria as the 'powerhouse of the cell'—which, fun fact, Scientific American actually coined in the 1950s—but what are mitochondria, to start us off with a really basic question?
Picard: [Laughs]Yes, 1957 is the ' powerhouse of the cell.' That was momentous.That shaped generations of scientists, and now the powerhouse analogy is expired, so it's time for a new perspective.
Really, mitochondria are, are small living organelles, like little organs of the cell, and what they do is they transform the food we eat and the oxygen that we breathe. Those two things converge inside the mitochondria, and that gets transformed into a different kind of energy. Energy is neither created nor destroyed, right? It's a fundamental law of thermodynamics. So mitochondria, they don't make energy; they transform the energy that's stored in food from the plants and from the energy of the sun and then the oxygen combining this, and then they transform this into a little electrical charge. They dematerialize food—energy stored in food—into this very malleable, flexible form of energy that's membrane potential, so they become charged like little batteries and then they power everything in our cells, from turning on genes and making proteins and cellular movement; cellular division; cell death, aging, development—everything requires energy. Nothing in biology is free.
Feltman: Well, I definitely wanna get into what you said about the powerhouse analogy not working anymore 'cause that seems pretty huge, but before we get into that: you recently wrote a piece for Scientific American, and you referred to yourself as, I think, a 'mitochondriac.' I would love to hear what you mean by that and how you got so interested in these organelles.
Picard: Yeah, there's a famous saying in science: 'Every model is wrong, but some are useful.' And the model that has pervaded the world of biology and the health sciences is the gene-based model (the central dogma of biology, as it's technically called): genes are the blueprint for life, and then they drive and determine things. And we know now [it] to be misleading, and it forces us to think that a lot of what we experience, a lot of, you know, health or diseases, is actually determined by our genes. The reality is a very small percentage [is].
Whether we get sick or not and when we get sick is not driven by our genes, but it's driven by, you know, emergent processes that interact from our movement and our interaction with other people, with the world around us, with what we eat, how much we sleep, how we feel, the things we do. So the gene-based model was very powerful and useful initially, and then, I think, its, its utility is dwindling down.
So the powerhouse analogy powered, you know, a few [laughs] decades of science, and then what started to happen, as scientists discovered all of these other things that mitochondria do, we kept getting surprised. Surprise is an experience, and when you feel surprised about something, like, it's because your internal model of what that thing is, it was wrong, right?
Feltman: Right.
Picard: And when there's a disconnect between your internal model and the, the reality, then that feels like surprise. And I grew up over the last 15 years as a academic scientist, and, like, every month there's a paper that's published: 'Mitochondria do this. Mitochondria make hormones.' Surprise! A, a powerhouse should have one function: it should make, or transform, energy, right? This is what powerhouses do. Mitochondria, it turns out, they have a life cycle. They make hormones. They do transform energy, but they also produce all sorts of signals. They turn on genes; they turn off genes. They can kill the cell if they deem that's the right thing to do.
So there are all of these functions, and, and I think, as a community, we keep being surprised as we discover new things that mitochondria do. And then once you realize the complexity and the amazing beauty of mitochondria and their true nature, then I think you have to become a mitochondriac [laughs]. You have to, I think, be impressed by the beauty of—this is just a—such a beautiful manifestation of life. I fell in love with mitochondria, I think, is what happened [laughs].
Feltman: Yeah, well, you touched on, you know, a few of the surprising things that mitochondria are capable of, but could you walk us through some of your research? What surprises have you encountered about these organelles?
Picard: One of the first things that I saw that actually changed my life was seeing the first physical evidence that mitochondria share information ...
Feltman: Mm.
Picard: With one another. The textbook picture and the powerhouse analogy suggests that mitochondria are these, like, little beans and that they, they kind of float around and they just make ATP, adenosine triphosphate, which is the cellular energy currency, and once in a while they reproduce: there's more mitochondria that come from—mitochondria, they can grow and then divide. So that's what the powerhouse predicts.
And what we found was that when—if you have a mitochondrion here and another mitochondrion here, inside the mitochondria, they're these membranes ...
Feltman: Mm.
Picard: They're, like, little lines. They look, in healthy mitochondria, look like radiators, right? It's, like, parallel arrays. And it's in these lines that the oxygen that we breathe is consumed and that the little charge—the, the food that we eat is converted into this electrical charge. These are called cristae.
And in a normal, healthy mitochondria the cristae are nicely parallel, and there's, like, a regularity there that's just, I think, intuitively appealing, and it, it looks healthy. And then if you look at mitochondria in a diseased organ or in a diseased cell, often the cristae are all disorganized. That's a feature of 'something's wrong,' right?
And I've seen thousands of pictures and I've taken, you know, several thousands of pictures on the electron microscope, where you can see those cristae very well, and I'd never seen in the textbooks or in articles or in presentations, anywhere, that the cristae could actually, in one mitochondrion, could be influenced by the cristae in another mitochondrion.
And what I saw that day and that I explained in the [laughs], in the article was that there was this one mitochondrion there—it had beautifully organized cristae here, and here the cristae were all disorganized. And it turns out that the part of this mitochondrion that had beautifully organized cristae is all where that mitochondria was touching other mitochondria.
Feltman: Mm.
Picard: So there was something about the mito-mito contact, right? Like, a unit touching another unit, an individual interacting with another individual, and they were influencing each other ...
Feltman: Yeah.
Picard: And the cristae of one mitochondrion were bending out of shape. That's not thermodynamically favorable [laughs], to bend the lipid membrane, so there has to be something that is, you know, bringing energy into the system to bend the membrane, and then they were meeting to be parallel with the cristae of another mitochondrion. So there was these arrays that crossed boundaries between individual mitochondria ...
Feltman: Wow.
Picard: And this was not [laughs] what I, I learned or this was not what I was taught or that I'd read, so this was very surprising.
The first time we saw this, we had this beautiful video in three dimension, and I was with my colleague Meagan McManus, and then she realized that the cristae were actually aligning, and we did some statistics, and it became very clear: mitochondria care about mitochondria around them ...
Feltman: Yeah.
Picard: And this was the first physical evidence that there was this kind of information exchange.
When you look at this it just looks like iron filings around a magnet.
Feltman: Mm.
Picard: Sprinkle iron filings on the piece of paper and there's a magnet underneath, you see the fields of force, right? And fields are things that we can't see, but you can only see or understand or even measure the strength of a field by the effect it has on something. So that's why we sprinkle iron filings in a magnetic field to be able to see the field.
Feltman: Right.
Picard: It felt like what we were seeing there was the fingerprint of maybe an underlying electromagnetic field, which there's been a lot of discussion about and hypothesis and some measurements in the 1960s, but that's not something that most biologists think is possible. This was showing me: 'Maybe the powerhouse thing is, is, is, is not the way to go.'
Feltman: Did you face any pushback or just general surprise from your colleagues?
Picard: About the cristae alignment?
Feltman: Yeah.
Picard: I did a lot of work. I took a lot of pictures and did a lot of analysis to make sure this was real ...
Feltman: Mm.
Picard: So I think when I presented the evidence, it was, it was, you know, it was clear [laughs].
Feltman: Right.
Picard: This was real.
Feltman: Yeah.
Picard: Whether this is electromagnetic—and I think that's where people have kind of a gut reaction: 'That can't be real. That can't be true.'
Feltman: Mm.
Picard: The cristae alignment is real, no questioning this, but whether this—there's a magnetic field underlying this, we don't have evidence for that ...
Feltman: Sure.
Picard: It's speculation, but I think it, it hits some people, especially the strongly academically trained people that have been a little indoctrinated—I think that tends to happen in science ...
Feltman: Sure.
Picard: I think if we wrote a grant, you know, to, to [National Institutes of Health] to study the magnetic properties of mitochondria, that'd be much harder to get funded. But there was no resistance in accepting the visual evidence of mitochondria exchanging information ...
Feltman: Yeah.
Picard: What it means, then, I think, is more work to be done to—towards that.
Feltman: If, if we were seeing an electromagnetic field, what would the implications of that be?
Picard: I think the implications is that the model that most of biomedical sciences is based on, which is 'we're a molecular soup and we're molecular machines,' that might not be entirely how things work. And if we think that everything in biology is driven by a lock-and-key mechanism, right—there's a molecule that binds a receptor and then this triggers a conformational change, and then there's phosphorylation event and then signaling cascade—we've made a beautiful model of this, a molecular model of how life works.
And there's a beautiful book that came out, I think last year or end of 2023, How Life Works, by Philip Ball, and he basically brings us through a really good argument that life does not work by genetic determinism, which is how most people think and most biologists think that life works, and instead he kind of brings us towards a much more complete and integrative model of how life works. And in that alternate model it's about patterns of information and information is carried and is transferred not just with molecules but with fields. And we use fields and we use light and we use, you know, all sorts of other means of communication with technology; a lot of information can be carried through your Bluetooth waves ...
Feltman: Mm.
Picard: Right? Fields. Or through light—we use fiber optic to transfer a lot of information very quickly. And it seems like biology has evolved to, to harness these other ways of, of nonmolecular mechanisms of cell-cell communication or organism-level communication.
There's an emerging field of quantum biology that is very interested in this, but this clashes a little bit with the molecular-deterministic model that science has been holding on to [laughs]—I think against evidence, in, in some cases—for a while. Nobody can propose a rational, plausible molecular mechanism to explain what would organize cristae like this across mitochondria. The only plausible mechanism seems to be that there's a—there's some field, some organizing electromagnetic field that would bend the cristae and organize them, you know, across organelles, if that's true.
Feltman: Right.
Picard: It was a bit of an awakening for me, and it turned me into a mitochondriac because it made me realize that this is the—this whole thing, this whole biology, is about information exchange and mitochondria don't seem to exist as little units like powerhouses; they exist as a collective.
Feltman: Yeah.
Picard: The same way that you—this body. It's a bunch of cells; either you think it's a molecular machine or you think it's an energetic process, right? There's energy flowing through, and are you more the molecules of your body or are you more the, the energy flowing through your body?
Feltman: Mm.
Picard: And if you go down this, this line of questioning, I think, very quickly you realize that the flow of energy running through the physical structure of your body is more fundamental. You are more fundamentally an energetic process ...
Feltman: Hmm.
Picard: Than the physical molecular structure that you also are. If you lose part of your anatomy, part of your structure, right—you can lose a limb and other, you know, parts of your, of your physical structure—you still are you ...
Feltman: Right.
Picard: Right? If your energy flows differently or if you change the amount of energy that flows through you, you change radically. Three hours past your bedtime you're not the best version of your, the best version of yourself. When you're hangry, you haven't eaten, and you, like, also, you're not the best version of yourself, this is an energetic change. Right?
Feltman: Yeah.
Picard: Many people now who have experienced severe mental illness, like schizophrenia and bipolar disease, and, and who are now treating their symptoms and finding full recovery, in some cases, from changing their diets.
Feltman: Mm.
Picard: And the type of energy that flows through their mitochondria, I think, opens an energetic paradigm for understanding health, understanding disease and everything from development to how we age to this whole arc of life that parallels what we see in nature.
Feltman: Yeah, so if we, you know, look at this social relationship between mitochondria, what are, in your mind, the most, like, direct, obvious implications for our health and ...
Picard: Mm-hmm.
Feltman: And well-being?
Picard: Yeah, so we can think of the physical body as a social collective. So every cell in your body—every cell in your finger, in your brain, in your liver, in your heart—lives in some kind of a social contract with every other cell. No one cell knows who you are, or cares [laughs], but every cell together, right, makes up who you are, right? And then together they allow you to feel and to have the experience of who you are. That kind of understanding makes it clear that the key to health is really the coherence between every cell.
Feltman: Mm.
Picard: If you have a few cells here in your body that start to do their own thing and they kind of break the social contract, that's what we call cancer. So you have cells that stop receiving information from the rest of the body, and then they kind of go rogue, they go on their own. Their purpose in life, instead of sustaining the organism, keeping the whole system in coherence, now these cells have as their mind, like, maybe quite literally, is, 'Let's divide, and let's make more of ourselves,' which is exactly what life used to be before mitochondria came in ...
Feltman: Mm.
Picard: Into the picture 1.5 billion years ago, or before endosymbiosis, the origin of, of multicellular life. So cancer, in a way, is cells that have broken the social contract, right, exited this social collective, and then to go fulfill their own little, mini purpose, which is not about sustaining the organism but sustaining themselves. So that principle, I think, has lots of evidence to, to support it.
And then the same thing, we think, happens at the level of mitochondria, right? So the molecular-machine perspective is that mitochondria are little powerhouses and they're kind of slaves to the cell: if the cell says, 'I need more energy,' then the mitochondria provide and they kind of obey rules. The mito-centric perspective [laughs] is that mitochondria really drive the show. And because they're in charge of how energy flows, they have a veto on whether the cell gets energy and lives and divides and differentiates and does all sorts of beautiful things or whether the cell dies.
And most people will know apoptosis, programmed cell death, which is a normal thing that happens. The main path to apoptosis in, in our bodies is mitochondria calling the shot, so mitochondria have a veto, and they can decide, 'Now, cell, it's time to die.' And mitochondria make those decisions not based on, like, their own little powerhouse [laughs] perception of the world; they make these decisions as social collectives. And you have the hundreds, thousands of mitochondria in some cells that all talk to each other and they integrate dozens of signals—hormones and metabolites and energy levels and temperature—and they integrate all this information; they basically act like a mini brain ...
Feltman: Hmm.
Picard: Inside every cell. And then once they have a, a—an appropriate picture of what the state of the organism is and what their place in this whole thing is, then they actually, I think, make decisions about, 'Okay, it's time to divide,' right? And then they send signals to, to the nucleus, and then there're genes in the nucleus that are necessary for cell division that gets turned on, and then the cell enters cell cycle, and we and others have shown in, in, in the lab, you can prevent a cell from staying alive [laughs] but also from differentiating—a stem cell turning into a neuron, for example, this is a major life transition for a cell. And people have asked what drives those kind of life transitions, cellular life transitions, and it's clear mitochondria are one of the main drivers of this ...
Feltman: Hmm.
Picard: And if mitochondria don't provide the right signals, the stem cell is never gonna differentiate into a specific cell type. If mitochondria exists as a social collective, then what it means for health [laughs] is that what we might wanna do is to promote sociality, right, to promote crosstalk between different parts of our bodies.
Feltman: Hmm.
Picard: And I suspect this is why exercise is so good for us.
Feltman: Yeah, that was—that's a great segue to my next question, which is: How do you think we can foster that sociality?
Picard: Yeah. When times are hard, right, then people tend to come together to solve challenges. Exercise is a, a big challenge for the organism, right?
Feltman: Mm.
Picard: You're pushing the body, you're, like, contracting muscles, and you're moving or, you know, whatever kind of exercise you're doing—this costs a lot of energy, and it's a big, demanding challenge for the whole body. So as a result you have the whole body that needs to come together to survive this moment [laughs]. And if you're crazy enough to run a marathon, to push your body for three, four hours, this is, like, a massive challenge.
Feltman: Sure.
Picard: The body can only sustain that challenge by coming together and working really coherently as a unit, and that involves having every cell in the body, every mitochondria in the body talking to each other. And it's by this coherence and this kind of communication that you create efficiency, and the efficiency is such a central concept and principle in all of biology. It's very clear there, there have been strong evolutionary forces that have pushed biology to be evolved towards greater and greater efficiency.
The energy that animals and organisms have access to is finite, right? There's always a limited amount of food out there in the world. If there's food and there are other people with you, your social group, do you need to share this? So if biology had evolved to just eat as much food as possible, we would've gone extinct or we wouldn't have evolved the way we have. So it's clear that at the cellular level, at the whole organism level, in insects to very large mammals, there's been a drive towards efficiency.
You can achieve efficiency in a few ways. One of them is division of labor. Some cells become really good at doing one thing, and that's what they do. Like muscles, they contract [laughs]; they don't, you know, release hormones—or they release some hormones but not like the liver, right?
Feltman: Sure.
Picard: And the liver feeds the rest of the body, and the liver is really good at this. But the liver's not good at integrating sensory inputs like the brain. The brain is really good at integrating sensory inputs and kind of managing the rest of the body, but the brain is useless at digesting food or, you know, feeding the rest of the body. So every organ specializes, and this is the reason we're so amazing [laughs]. This is the reason complex multicellular animals that, you know, that, that have bodies with organs can do so many amazing things: because this whole system has harnessed this principle of division of labor. So you have a heart that pushes blood, and you have lungs that take in oxygen, and that's the main point: [it's] the cooperation and the teamwork, the sociality between cells and mitochondria and, and organs that really make the whole system thrive.
So exercise does that.
Feltman: Yeah.
Picard: It forces every cell in the body to work together. Otherwise you're just not gonna survive. And then there are other things that happen with exercise. The body is a predictive instrument, right ...
Feltman: Mm.
Picard: That tries to make predictions about what's gonna happen in the future, and then you adapt to this. So when you exercise and you start to breathe harder the reason you breathe harder, the reason, you know, you need to bring in more oxygen in your body, is because your mitochondria are consuming the oxygen. And when that happens every cell has the ability to feel their energetic state, and when they feel like they're running out of energy, like if you're exercising hard and your muscles are burning, your body says, 'Next time this happens I'll be ready.' [Laughs] And it gets ready—it mobilizes this program, this preparatory program, which, which we call exercise adaptation, right—by making more mitochondria. So the body can actually make more mitochondria after exercise.
So while you're exercising, the mitochondria, they're transforming food and oxygen very quickly, making ATP, and then cells—organs are talking to one another; then you're forcing this great social collective. Then when you go and you rest and you go to sleep, you lose consciousness [laughs], and then the natural healing forces of the body can work. Now the body says, 'Next time this happens I'll be ready,' and then it makes more mitochondria. So we know, for example, in your muscles you can double the amount of mitochondria you have ...
Feltman: Wow.
Picard: With exercise training. So if you go from being completely sedentary to being an elite runner, you will about double the amount of mitochondria in, in your muscle. And ...
Feltman: That's really cool.
Picard: Yeah. And this seems to happen in other parts of the body as well, including the brain.
Feltman: I know that your lab does some work on mitochondria and mental health as well. Could you tell us a little bit more about that?
Picard: The ability to mitochondria to flow energy supports basic cellular functions, but it also powers the brain [laughs] and powers the mind, and our best understanding now of what is the mind—and consciousness researchers have been debating this for a long time—I think our, our best, most parsimonious definition of the mind is that the mind is an energy pattern. And if the flow of energy changes, then your experience also changes. And there's emerging evidence in a field called metabolic psychiatry that mental health disorders are actually metabolic disorders ...
Feltman: Hmm.
Picard: Of the brain.
There's several clinical trials—some are published, many more underway—and the evidence is very encouraging that feeding mitochondria a certain type of fuel, called ketone bodies, brings coherence into the organism. And energetically we think this reduces the resistance to energy flow so energy can flow more freely through the neurons and through the structures of the brain and then through the mitochondria.
And that—that's what people report when they, they go into this medical ketogenic therapy: they feel like they have more energy, sometimes quite early, like, after a few days, sometimes after a few weeks. And then the symptoms of, of mental illness in many people get better. The website Metabolic Mind has resources for clinicians, for patients and, and guidance as to how to—for people to work with their care team, not do this on their own but do this with their medical team.
Feltman: And I know that mitochondria have kind of a weird, fascinating evolutionary backstory.
Picard: They used to be bacteria, and once upon a time, about two billion years ago, the only thing that existed on the planet that was alive were unicellular, right, single-cell, bacteria, a single-cell organism. And then some bacteria—there were different kinds—and then some bacteria were able to use oxygen for energy transformation; that was—those are called aerobic, for oxygen-consuming. And then there are also anaerobic, non-oxygen-consuming, bacteria that are fermenting cells.
And then at some point, about 1.5 billion years ago, what happened is there was a small aerobic bacterium, an alphaproteobacterium, that either infiltrated a larger anaerobic cell or it was the larger cell that ate the small aerobic bacterium, the large one kept it in, and then the small aerobic bacterium ended up dividing and then became mitochondria. So mitochondria used to be this little bacterium that now is very much part of what we are, and what seems to have happened when this critical kind of merger happened is that a new branch of life became possible.
Feltman: Yeah.
Picard: And animals became possible. And somehow this acquisition, from the perspective of the larger cell, enabled cell-cell communication, a form of cell-cell communication that was not possible before. And this seems to have been the trigger for multicellular life and the development of, initially, little worms and then fishes and then animals and then eventually Homo sapiens.
Feltman: Yeah, and that was really controversial when it was first proposed, right?
Picard: Yeah. Lynn Margulis, who is, like, a fantastic scientist, she proposed this, and I think her paper was rejected [15] times ...
Feltman: Wow.
Picard: Probably by Nature and then by a bunch of [laughs] ...
Feltman: [Laughs] Sure.
Picard: A bunch of other journals. Fourteen rejections and then in the end she published it, and now this is a cornerstone of biology. So kudos for persistence ...
Feltman: Yeah.
Picard: For Lynn Margulis.
Feltman: And mitochondria have just been shaking things up for, for decades [laughs], I guess.
Picard: Mm-hmm, yeah, there've been several Nobel Prizes for understanding how mitochondria work—specifically for the powerhouse function of mitochondria [laughs].
The field of [molecular] mitochondrial medicine was born in the '80s. Doug Wallace, who was my mentor as a postdoc, discovered that we get our mitochondria from our mothers. The motherly nourishing energy [laughs] is passed down through mitochondria. There's something beautiful about that.
Feltman: Yeah. Thank you so much for coming in. This was super interesting, and I'm really excited to see your work in the next few years.
Picard: Thank you. My pleasure.
Feltman: That's all for today's episode. Head over to our YouTube page if you want to check out a video version of today's conversation. We'll be back on Friday with one of our deep-dive Fascinations. This one asks whether we can use artificial intelligence to talk to dolphins. Yes, really.
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