Do Mitochondria Talk to Each Other? A New Look at the Cell’s Powerhouse
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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.

Martin, would you tell us a little bit about who you are and where you work? 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 mind-mitochondria connection, how energy and those little living creatures that populate our cells

how they actually feed our lives and allow us to be and to think and to feel and to experience life. Well, before we get into the details, you know, 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? Yes, 1957, the powerhouse of the cell. That was momentous. That shaped generations of scientists. And now the powerhouse analogy has expired. So it's time for a new perspective. Really, mitochondria 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, you know, the 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, inner 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. Well, I definitely want to get into what you said about the powerhouse analogy not working anymore, because 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. 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 kind of drive and determine things.

And we know now to be misleading and it forces us to think that a lot of what we experience, a lot of health or diseases is actually determined by our genes. The reality is a very small percentage, whether we get sick or not and when we get sick is not driven by our genes, but it's driven by emergent processes that interact from our

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 utility is dwindling down. So the powerhouse analogy powered a few decades of science.

And then what started to happen as scientists discovered all of these other things that mitochondria do, we kept getting surprised. And when you feel surprised about something, like it's because your internal model of what that thing is, it was wrong. Right. Right. And when there's a disconnect between your internal model and reality, then that feels like surprise. And I grew up over the last 15 years as an academic scientist. And like every month there's a paper that's published, mitochondria do this, mitochondria make hormones.

Surprise, 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 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. I fell in love with mitochondria, I think is what happened. 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? You know, what surprises have you encountered about these organelles? One of the first things that I saw that actually changed my life was seeing the first physical evidence that mitochondria share information with one another. The textbook

picture and the powerhouse analogy suggests that mitochondria or these like little beans

and that they kind of float around and they just make ATP, adenosine triphosphate, which is cellular energy currency. And once in a while, they reproduce more mitochondria that come from mitochondria that can grow and then divide. So that's kind of what the powerhouse predicts. And then what we found was that if you have a mitochondrion here and another mitochondrion here, inside the mitochondria, there are these membranes. They're like little lines. And healthy mitochondria look like radiators, like parallel arrays, etc.,

And it's in these lines that the oxygen that we breathe is consumed and that the little charge, the food that we eat is converted into this electrical charge. These are called Christie.

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 looks healthy. And then if you look at mitochondria in a diseased organ or in a diseased cell, often the cristae are all disorganized and 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 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 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 mitochondria that had beautifully organized Christie is all where that mitochondria was touching other mitochondria. 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. And the Christie of one mitochondria were bending out of shape.

that's not thermodynamically favorable to bend the lipid membrane. So there has to be something that is 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. And this was not what I learned or this was not what I thought or that I'd read. So this was very surprising. First time we saw this, we had this beautiful video in three dimension. I was with my colleague, Megan McManus.

And then she realized that the cristae were actually aligning. We did some statistics and it became very clear mitochondria care about mitochondria around them. 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 the magnet.

Sprinkle iron filings into a 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. 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 60s, but that's not something that most biologists think

think is possible. And this was showing me maybe the powerhouse thing is not the way to go. Did you face any pushback or just general surprise from your colleagues? About the Christie alignment? Yeah. I did a lot of work. I took a lot of pictures and did a lot of analysis to make sure this was real. So I think when I presented the evidence, you know,

It was clear. This was real. Whether this is electromagnetic, and I think that's where people have kind of a gut reaction that can be real, that can be true. The Chrissy alignment is real. No questioning this. But whether there's a magnetic field underlying this, we don't have evidence for that. It's speculation. But I think it hits some people, especially the strongly academically trained people that have been a little indoctrinated. I think that

tends to happen in science. I think if we wrote a grant to NIH to study 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. What it means then, I think, is more work to be done towards that. If we were seeing an electromagnetic field, what would the implications of that be?

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, 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. 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 all sorts of other means of communication with technology. A lot of information can be carried through Bluetooth waves, right? Fields or through light. We use fiber optic very effectively to transfer a lot of information very quickly. And it seems like biology has evolved to harness these other ways of non-molecular 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, I think, against evidence in some cases for a while. Nobody can propose a rational, plausible molecular mechanism to explain what would organize Christie like this across mitochondria. The only plausible mechanism seems to be that there's some field, some organizing electromagnetic field that would bend the Christie and organize them, you know, across organelles, if that's true. Right. It was a bit of a...

of an awakening for me and it turned me into a mitochondriac because it made me realize that this is 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. Yeah. 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 energy flowing through your body? And if you go down 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 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 physical structure, you still are you. 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 yourself. When you're hangry, you haven't eaten and you're like also you're not the best version of yourself. This is an energetic change, right? Yeah. Many people now who have experienced severe mental illness like schizophrenia and bipolar disease and who are now treating their symptoms.

and finding full recovery in some cases from changing their diets. 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. Yeah. So if we, you know, look at this social relationship between mitochondria, what are in your mind the most like direct connections

obvious implications for our health and well-being. 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, 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

kind of understanding makes it clear that the key to health is really the coherence between every cell. 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, 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 into the picture 1.5 billion years ago, before endosymbiosis, the origin of multicellular life. So cancer in a way is cells that have broken the social contract,

right? Exited the social collective and then they 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 support it. And then the same thing we think happened at the level of mitochondria, right? So the molecular machine perspective is that mitochondria are a lot of powerhouses and they're kind of slaves to the cell. If the cell says, I need more energy than the mitochondria provide, and they kind of obey rules. The mitochondria

perspective 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. Most people will know apoptosis, programmed cell death, which is a normal thing that happens. The main path to apoptosis 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 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

of signals, hormones and metabolites and energy levels and temperature. And they basically act like a mini brain inside every cell. And then once they have an appropriate

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 the nucleus and then their 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 the lab, you can prevent a cell from,

staying alive, 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. And if mitochondria don't provide the right signals, the stem cell is never going to differentiate into a specific cell type.

If mitochondria exist as a social collective, then what it means for health is that what we might want to do is to promote sociality, right? To promote crosstalk between different parts of our bodies. And I suspect this is why exercise is so good for us. Yeah, that's a great segue to my next question, which is how do you think we can foster that sociality? Yeah. When times are hard, right, then people tend to come together to solve challenges.

Exercise is a big challenge for the organism, right? You're pushing the body, you're like contracting muscles and you're moving or 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. And if you're crazy enough to run a marathon to push your body for like three, four hours,

This is like a massive challenge. 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 have been strong evolutionary forces

that have pushed biology to evolve 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 have 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 and 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.

They don't release hormones or they release some hormones, but not like the liver, right? And the liver feeds the rest of the body and the liver is really good at this, but the liver is 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 feeding the rest of the body. So every organ specializes

And this is the reason we're so amazing. This is the reason complex multicellular animals that have bodies with organs can do so many amazing things because this whole system has harnessed this principle of division of labor, the sociality between cells and mitochondria and organs that really make the whole system thrive. So exercise does that. So when you exercise and you start to breathe harder, the reason you breathe harder is

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, the body says, next time this happens, I'll be ready.

And it gets ready, it mobilizes this program, this preparatory program, 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 organs are talking to one another. Then when you go and you rest and you go to sleep, you lose consciousness. 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 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 your muscle. That's really cool. Yeah. And this seems to happen in other parts of the body as well, including the brain. 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?

The ability of mitochondria to flow energy supports basic cellular functions, but it also powers the brain and powers the mind.

or best understanding now of what is the mind, and consciousness researchers have been debating this for a long time, 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 of the brain. There are 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's what people report when 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 mental illness in many people get better. So 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. And I know that mitochondria have kind of a weird, fascinating evolutionary backstory. Could you just summarize that a little bit for us? 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, single cell organism. And then some bacteria, they're 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 alpha proteobacterium, 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. Yeah. And animals became possible. And somehow this acquisition from the perspective of the larger cell enabled 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.

Yeah. And that was really controversial when it was first proposed, right? Yeah. Lynn Margulis, who is like a fantastic scientist, she proposed this. And I think her paper was rejected 14 times. Wow. Probably by nature and then by a bunch of other journals. 14 rejections. And then in the end, she published it.

And now this is a cornerstone of biology. So kudos for persistence for Lynn Margulis. And mitochondria have just been shaking things up for decades, I guess. Yeah, there have been several Nobel Prizes specifically for the powerhouse function of mitochondria.

The field of mitochondrial medicine was born in the 80s. Doug Wallace, who was my mentor as a postdoc trainee, discovered that we get our mitochondria from our mothers. The motherly nourishing energy is passed down through mitochondria. There's something beautiful about that. 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. Thank you. My pleasure.

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. Yeah, really.

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Science Quickly is produced by me, Rachel Faltman, along with Fonda Mwangi, Kelso Harper, Naima Marci, and Jeff Dalvisio. This episode was edited by Alex Sagiara. Shaina Poses and Aaron Shattuck fact-check our show. Our theme music was composed by Dominic Smith. Subscribe to Scientific American for more up-to-date and in-depth science news. For Scientific American, this is Rachel Faltman. See you next time. ♪