Mitochondria & mental health: Dr Martin Pichard

Transcript

0:00 Introduction to Dr. Martin Picard 3:16 What Are Mitochondria and Where Are They? 9:04 Ecosystem of Mitochondria 10:25 Mitochondria and Disease 16:38 Genetics and Mitochondria 19:18 Lifestyle Choices for Poor Mitochondrial Health 22:08 Impact of Psychological States on Mitochondria 25:55 Medications and Mitochondrial Dysfunction 32:12 How to Improve Mitochondrial Function 52:29 Conclusion ==================================\0 Welcome back to Metabolic Mind, a nonprofit initiative of Baszucki Group where we focus on the intersection of metabolic health and mental health. 0:06 Today we're going to talk about mitochondria, all things mitochondria, the powerhouse of the cell, but it's so much more than that. 0:13 So my guest is Dr. Martin Picard, who really is one of the worldwide experts on mitochondria. Now, Dr. Picard has a PhD in mitochondrial biology 0:22 from McGill University and he's an associate professor of behavioral medicine in psychiatry and neurology at Columbia, 0:28 where he runs the Mitochondrial Psychobiology Lab. 0:33 Hearing Dr. Picard talk about mitochondria is really inspiring. He cares so much about it and he's so passionate about it. 0:40 And you can tell if you go to his Twitter profile, which is @MitoPsychoBio, 0:45 his picture is a huge mitochondria drawn in the sand, which just shows how passionate he is about mitochondria. 0:51 And he talks about it so well. And we start with the basics because a lot of people really don't know what mitochondria are. 0:58 You can't see them with your naked eye. You can't touch them. They're hard to sort of conceptualize. So we talk about what they are, 1:03 how involved in our bodies they are, how they're on every cell, and how they're involved in so many disease processes, 1:09 but also how they're involved with health. So it's not just all about disease, it's also about promoting health. And what can we do to improve mitochondrial function 1:17 and mitochondrial health. So we go through this whole journey in this interview with Dr. Picard talking about mitochondria. 1:23 So if you're wondering about mitochondria, you're wondering about their role in health, specifically mental health and mental illness, 1:29 but really any organ system disease process, mitochondria have a role. This is the podcast. 1:34 Dr. Picard is the guy for you to listen to because not only does he know it well and research it, 1:40 but he's so good about communicating about mitochondria. So I hope you enjoy this interview about mitochondria 1:46 as much as I did with Dr. Martin Picard. But before the interview, please remember our channel is for informational purposes only. 1:52 We're not providing individual group healthcare or medical advice. We're not providing a doctor-patient relationship. 1:59 Anythings we discuss could be potentially harmful have done on your own without clinical supervision. So never change any of your medications or your lifestyle 2:07 to treat a medical condition without consulting your healthcare provider first, right? So let's get on with the interview with Dr. Martin Picard. 2:13 Well, Dr. Picard, thank you so much for joining me on Metabolic Mind, so we can really sort of dig into and better understand what are mitochondria. 2:21 So thank you so much for joining me today. - Yeah, my pleasure. - Yeah, so I want to start with a little funny story. 2:26 So I'm helping my son, this was a little while ago, a few months ago, I was helping my 10 year old son 2:31 prepare for this little science competition. And one of the things he had to learn about were all the different organelles in the cells. 2:38 So we're looking at Golgi bodies and endoplasmic reticulum and, of course, mitochondria. And like any 10 year old, 2:43 he says, why do I have to learn this? This is so stupid. These are so tiny little things, what are they? 2:48 And I said, "Hold on." And I ran and I got Chris Palmer's book and I told him about mitochondria in the book and I told him about the work you're doing 2:54 and his eyes glazed over and he didn't really care. But I felt good that I had some like concrete example 3:00 to explain to him why he had to learn about mitochondria. Now, you study mitochondria, you research mitochondria, 3:06 but I think a lot of people still don't really understand what are mitochondria and why are they so important 3:12 and why are you devoting your research to mitochondria. So if we can take a step back, can you give us like the brief 101 about mitochondria? What Are Mitochondria and Where Are They? 3:20 - Sure, yes. And thank you for sharing your story. We have a book at home called "Cell Biology for Babies." 3:26 - Oh, really? - And there's a page there on mitochondria. And I've started this early also with my son. (laughs) 3:33 - Great. - He knows about mitochondria. Yeah, so mitochondria are this beautiful little part 3:40 of our cells, they're called organelles, right? The same way the body is made of different organs 3:46 that do different things, we have a brain, we have a liver, a heart, and each organ has a different role 3:52 in sustaining function and health of the whole body. So mitochondria is one of the organs of the cell. 4:00 And maybe the best analogy there is the brain 4:05 and the way that mitochondria are involved in transforming energy, but also in processing a lot of information. 4:12 So, historically, mitochondria have been known as the powerhouse of the cell. I think that's a misnomer. 4:17 And sure they're central to transforming energy 4:22 from the oxygen that we breathe in, the food that we eat, right, the mitochondria, those two things, 4:31 the oxygen we breathe, the food we consume, they converge in mitochondria. 4:37 And that's where the magic happens where you have incredibly complex processes 4:42 of ripping off electrons and the electron transport chain, for people who've heard about this. 4:47 And then there mitochondria become charged. So there's an electric charge literally inside every one of the hundreds to thousands 4:55 of mitochondria that populate our cells. So the mitochondria become charged like little batteries and they actually behave and exist as a network. 5:04 And something very similar to a social network inside every cell where you have mitochondria 5:09 that can infuse together to form longer filaments or tubules of mitochondria, longer mitochondria 5:15 that can undergo fission or fragment into smaller bits. They have a life cycle. 5:20 Old mitochondria actually die out and then new mitochondria are born. So there's a beautiful cycle there. 5:27 They exchange information the same way that we talk with each other with language and sound. 5:32 Mitochondria have all of these different ways of talking to each other through chemicals and hormones and ions 5:41 and other mechanisms. So there's this social life of these small little being 5:49 to tubule shaped organelles inside the cell. And there's a whole history about how they came to be 5:56 and why they're at the origin of life that we can get into if that's of interest. - Yeah, it's so interesting to think about them 6:02 as having social interactions with other mitochondria and that it's beyond them just sitting there producing energy, but at their core, 6:10 production of energy is sort of one of the main features. And that's why they're known for that. 6:15 And when we talk about disorders in human health, 6:21 whether it's mental illness or whether it's other disorders, we're starting to see it as a disorder of energy production, 6:28 which can then be sort of boiled down to the mitochondria. So you said, mitochondria take in oxygen 6:35 and they take in the food and then they create energy. That's where the magic happens to create energy. 6:41 Now I think what also is a little confusing though, is this happens everywhere, right? It's in your muscles, it's in your liver, 6:48 it's in your heart, it's in your brain. So are mitochondria are really just everywhere in our body. - Yes. They're everywhere. 6:57 The body is made of a few hundred cell types. There's one cell type that does not have mitochondria, 7:03 which is the one cell type that actually carries the oxygen, 7:09 right, towards, the purpose of breathing is to bring in oxygen to your lungs, and then oxygen from your lungs diffuses into your blood, 7:17 and then the blood circulates and touches literally every cell in the body, right? And there's one cell type that is a reason 7:25 why blood is red because of the red blood cells, right? The red blood cells, their life purpose is to carry oxygen 7:33 towards the destination, every other cell in the body, where mitochondria ultimately are the oxygen consumer. 7:42 So red blood cells don't have mitochondria probably because otherwise the mitochondria there 7:48 would consume the oxygen that they're actually meant to transport. But otherwise, every cell in the body, every neuron, 7:55 every glial cell in the brain, every beating heart cell, every liver cell, every skin cell 8:00 have hundreds to thousands of mitochondria per cell. And the beautiful thing 8:07 that we're just starting to uncover now is that mitochondria are not all created the same, and different cell types in the body 8:14 actually have different types of mitochondria. So we think of those as mitotypes, 8:20 the same way that they're different cell types are different mitochondria types. So the brain mitochondria are actually quite different 8:28 than the heart mitochondria, than the liver mitochondria. So there's this beautiful diversity of mitochondria. 8:36 And that makes us think of them as more of a family 8:42 of related organelles and not just kind of a single thing that's passively transforming energy. 8:49 There's a diversity of different types of mitochondria that actually talk to each other. So the mitochondria in your adrenal glands, for example, 8:57 where cortisol is made, talk to mitochondria in the brain. The organism, you can see if you think about the organism Ecosystem of Mitochondria 9:08 as an ecosystem where you have cells and energetic system that talk to each other, mitochondria is a key part of this. 9:15 And if you look at this from a mitocentric perspective, 9:22 you can think of the whole ecosystem of mitochondria as an energy transformation system. 9:29 And mitochondria transform energy, they don't create energy per se. 9:35 They take the energy from the food and the oxygen and then as they combine, they can extract energy from this. 9:41 So they can transform chemical energy from the food and oxygen into electrical energy 9:47 inside the membrane potential that's called. And then take the membrane potential, this other form of energy, 9:53 and then turn this into a different kind of energy like ATP, maybe some people have heard about. 9:59 And then that is what powers the beautiful diversity of human function and human experiences 10:05 and eventually consciousness. And it all comes down to this transformation of energy inside mitochondria. - Yeah, I like how you said, 10:12 if you look at it from a mitocentric standpoint, coming from the mitochondria as the center. 10:19 But I think that's a hard thing for a lot of people to do because you can't see mitochondria, Mitochondria and Disease 10:25 you don't get a blood test for mitochondria, right? You get a blood test for your hemoglobin levels and your kidney function and your liver function, 10:31 but you don't measure mitochondria. So it's sort of like a leap for people to say 10:38 or for some people to understand how widespread mitochondrial function and dysfunction 10:44 impact our health. But is it safe to say that they're involved with, I mean just about any health or disease process at its core 10:55 could be related to mitochondrial function? - Yes, certainly. We try to review this. 11:02 I should take a step back and say, we think of mitochondria and that organelle as a potential cause, 11:11 first, a source of health and life, but then a cause of potential diseases, 11:19 that's a scientific model, right? That's a hypothesis that we're invested in rigorously testing. 11:26 And so we need to do this carefully, but what the evidence that's there, 11:32 if you go into PubMed or onto Google and you look for studies that have looked at some mitochondrial impairment, 11:40 mitochondrial have many functions, right, so alterations and some mitochondrial function 11:45 including energy transformation, but also mitochondrial signaling. And any disease you can think of, 11:50 there is likely a scientific study that has investigated and identified a connection. 11:55 And then the question is, are impairments in mitochondrial biology driving those diseases? 12:02 And I think the answer is likely yes. And why is that? I think it's likely because energy is such a central part 12:11 of what we are and of who we are to some extent. 12:17 So I think that's why mitochondria have been implicated, there's growing interest in understanding the connection 12:24 between mitochondrial biology and health and different disorders is because energy is central 12:30 to what we are and how we function. And if we think about the brain, if you want to convince yourself and make this real, 12:37 'cause you're right, we can't see mitochondria and we have the chance here to have cool microscopes and you can put living cells 12:44 and make the mitochondria fluorescent. And then you look down the eyepiece and you see them move and fuse. 12:50 And so you can see them if you have the right equipment, but our day-to-day experience or subjective experience 13:00 and kind of the reality of the body and how we feed it and so on. We're not aware of our mitochondria, 13:06 which is probably for the better. (laughs) But if you want to convince yourself how central energy is, 13:13 if you just block blood flow to the brain, right? If you occlude the blood going to perfusing your brain 13:20 for just a few seconds, you're out, (laughs) consciousness is gone, right? And the reason consciousness disappears 13:28 if you don't have blood flow to your brain or if your heart stops is because you're not feeding your mitochondria anymore, 13:34 right, you're not bringing them oxygen, you're not bringing them food substrates and that shuts down everything. 13:40 So that's I think a very real example of how energy just sustains human life 13:49 and human consciousness. So anything we do as you've discussed 13:57 with many scientists and clinicians, the way we feed our body, the kind of energy we put 14:04 into the system can actually influence how the system works, the brain, and the whole organism. 14:09 - Yeah. So let's talk about that for a second because one of the things we focus on at Metabolic Mind is the connection between metabolic and mental health. 14:17 So when there's metabolic dysfunction that can impact mental health 14:24 and contribute to mental illness, and at its core, presumably mitochondria are involved in that. 14:31 So how does metabolic dysfunction and insulin resistance and some things that are so prevalent in today's society, 14:39 how does that impact mitochondria? - So, yeah, metabolic dysfunction is an umbrella term, 14:47 that in my view reflects impaired energy flow, right? 14:53 So what sustains life is the blood flow that the, 15:00 beating heart is a clear sign of light because by moving blood, you move energy, you move oxygen, you move ketones bodies, 15:08 and fatty acids and glucose and proteins and so on. So these are energy forms. 15:13 So the disorders of energy or metabolic dysfunction can be reflected in insulin resistance 15:21 which is reflected or which represents the inability of cells to take in food substrates when that's needed. 15:30 So there can be metabolic dysfunction at the whole organism level, right? 15:36 Which can cause or materialize and obesity, for example, 15:42 then there's kind of systems level metabolic dysfunction, 15:48 insulin resistance would be a feature of this, at the cellular level, there can be metabolic dysfunction there. 15:54 And then if we go inside the cell, there can be mitochondrial energy transformation defect 16:00 or impairments, which of course ripples out if the mitochondria are not functioning properly, 16:06 that can impair how cells function, how the tissue function, and how the whole organism functions. So mitochondria are such a metabolic hub 16:14 that their inability to transform energy properly 16:20 or misregulation of mitochondria getting turned on and making a lot of ATP 16:26 or being dialed down and making less ATP can really affect other levels of biological 16:33 and physiological complexity. - Yeah. Yeah. And I think it's clear there are a lot of things Genetics and Mitochondria 16:38 that can impact mitochondria function, but when it comes to mental illness 16:44 and psychiatric conditions in general, there's been a lot of talk about genetic predispositions. So are there genetic predispositions 16:52 to mitochondrial dysfunction as well as environmental factors of just how we live our life that impact it? 16:57 But what do the genetics say about it? - Yes, that's a great question. So, yes. 17:03 And I'm not a clinician, but I spend half a day a week in the clinic with my close colleague neurologist Michio Hirano, 17:10 where I see patients who have rare genetic mitochondrial disorders. 17:15 So some people may know mitochondria, those small living life forms inside every cell, 17:23 they have their own DNA and that's related to their past life as bacteria 17:30 and when they were incorporated. So they have a circular little piece of DNA like bacteria, 17:36 which have a few genes that are involved in energy transformation. And some people are born with a defect, a mutation, 17:43 or they lose a chunk of mitochondrial DNA, a portion of the mitochondrial DNA sequence. 17:50 So those are called mitochondrial DNA deletions. And that causes primary genetic mitochondrial diseases. 17:59 So these are rare genetic conditions 18:05 but I think they're incredibly illustrative of what impaired mitochondrial biology can do 18:13 to the whole body and to the whole mind. And these people suffer from multi-system disease, right, 18:20 so often they have cardiac involvement, digestive issues, renal issues, and endocrine issues, 18:28 immune alterations in some ways, and many of them have cognitive 18:34 and psychiatric manifestations. So there's a lot of comorbidity 18:40 between primary mitochondrial diseases that have historically been the domain of neurology 18:47 and psychiatric conditions. And this is an area that we're interested to understand more, 18:53 but that has been understudied. So I think that's one of the good evidence that if something's wrong with the mitochondria, 19:00 and here we have a primary genetic defect in mitochondria, this leads to impaired brain function 19:07 and psychiatric conditions. - Yeah, that is very clear evidence about that connection. 19:14 But then as I alluded to, it certainly doesn't have to be a genetic reason, there are unfortunately plenty of lifestyle things Lifestyle Choices for Poor Mitochondrial Health 19:21 we can do to ourselves to decrease our mitochondrial function and decrease our mitochondrial health. 19:28 And the big ones that seem to get a lot of attention are, of course, nutrition and then sort of poor sleep and toxins. 19:35 And so I mean, how do you see the main detractors 19:41 from mitochondrial health that unfortunately we do in our society? - Yes. So you're pointing to, what I just described 19:50 were inherited mitochondrial disorders and then they're acquired mitochondrial disorders. 19:56 So all of the acquired result from our exposures and kind of internal exposures 20:02 who were studying how psychological states and exposure to chronic stress or early life adversity 20:08 or the kind of the disorders that we can create ourselves 20:14 either psychologically or through nutrition and other things and how they can influence mitochondria. 20:20 So this is all part of the acquired mitochondrial impairments or dysfunctions. 20:29 So there's a number of things there that converge on mitochondria, including diet, 20:34 which is a very big one. Everything we put in her mouth ultimately converges either directly on mitochondria 20:40 or around the metabolic pathways that mitochondria are involved in regulating. 20:46 So that's a very big one. There's a lot of good research on insecticides and pesticides 20:53 and some of those that were used back in the days where we used at the laboratory as poisons for mitochondria, 21:00 if you want to know how a mitochondrial impairment will change gene expression, right, 21:06 some genes that are turned on or turned off in a cell, you can do experiments in this where you have living human cells with their mitochondria, 21:12 which you can image, and then you can perter mitochondria, right, experimentally, and then you ask, ooh, what does that do to the signals 21:20 that the cell will secrete or to the process of cell division or the effect on a stem cell or things like that. 21:27 And some of the tools we use there or formerly used poisons or insecticides 21:34 that are direct poisons to mitochondria. So there are many things that we've used 21:44 or that are around our ecosystems that can adversely affect mitochondrial biology. 21:52 - Yeah, that's really disturbing that you don't have to come up with some specialized mitochondrial poison. 21:57 It can just be something that's a run-of-the-mill pesticides that's been used before. And that's a potent mitochondrial toxin. 22:05 It's a little disturbing. I like how you also mentioned about psychological states Impact of Psychological States on Mitochondria 22:12 and how that can affect your mitochondria and so how does our psychological state influence our bodies? 22:18 That's like a big question that you are researching and the whole brain-body connection 22:24 kind of goes both ways, right? The dysfunction in the body can affect the brain, 22:31 and I don't know if you want to call it dysfunction in the brain, but brain experiences psychological experiences can affect the body. 22:38 And it seems like mitochondria are the connector there. I mean, that's the common variable, is that right? 22:44 - Yes. So the brain is part of the body and lets a remind ourselves, right? (laughs) 22:51 But there's many reasons why we think of brain and body. And I think it's useful to think of brain-body 22:58 or mind-body processes, right, that drive the human experience. And as you know there is good evidence, for example, 23:06 that the gut microbiome sends signals to the brain and then that actually influence mood 23:11 and affect and might contribute to mental health. 23:18 So there's clear kind of body to brain signals, right, 23:23 and the brain can experience and respond to the metabolic state of the body. 23:29 And then there of course a very important drivers, top-down brain body signals 23:36 where the brain actually regulates blood glucose, for example. And psychological stress can trigger hyperglycemia, 23:45 especially in susceptible individuals, right? So you see a stressful email or you have a stressful interaction, 23:53 and then you secrete cortisol that come from the adrenal glands and then cortisol goes to the liver 23:59 and release glucose into the blood and then will go to the muscle, the cortisol go to the muscle and causes insulin resistance. 24:08 So then that drives hyperglycemia. So a simple psychological state can drive a change 24:15 in peripheral glucose levels. So there's metabolic influence on the brain 24:23 and the brain can influence systemic energy metabolism. But every little process 24:28 when we think of like brain-body interactions, a stressful thought will accelerate a heart rate 24:34 within seconds, right, while the heart beating faster cost energy, right, every time the heart beats, 24:40 there's energy consumed that need to come from mitochondria. And if you're having an experience, 24:45 this changes gene expression inside of cell, you produce or release a hormone 24:51 while turning on a gene, right? Turning DNA into RNA cost energy, then taking the RNA making a protein cost energy, 24:58 and then taking that protein, that hormone, let's say, and then folding it and then packaging it and then releasing it, all of this cost energy. 25:05 So every little bit of communication between brain and the body is energetically demanding 25:12 and is an energetic process by nature. So we think that's why energetic processes 25:21 and then mitochondrial biology being a central part of this is an important driver or if you want the fabric, right, 25:34 the brain-body connection is an energetic connection and therefore energetic perturbations 25:39 in the mitochondria can likely perturb that system. 25:45 - Yeah. It is fascinating how the two-way street between the brain and the body is constant and there's such an impact both ways 25:52 that we need to be aware of in so many variables. But now to bring it back to psychiatry Medications and Mitochondrial Dysfunction 25:59 and to symptoms of whether it's bipolar disorder or schizophrenia, a major depression. What about medications? 26:04 Because if those diseases have a mitochondrial basis 26:10 and then medications are used to treat them, can medications also further mitochondrial dysfunction 26:17 or are there some that can improve mitochondrial function? What have you learned from a medication standpoint? - Yeah, there's recent interest in this. 26:25 And so people have studied this in fairly rigorous studies in vitro with cultured human cells or in vivo in animals. 26:34 And so you can give cells or animals different classes 26:40 of psychotropic medication and ask, does this change the ability of mitochondria to transport the electrons to charge the membrane 26:48 to make ATP, so different domains of mitochondrial biology. And the answer yet is yes, certainly. 26:54 There's specific classes of medication that impair mitochondrial energy transformation 27:02 pretty signif