How Mitochondria Inform Disease Discoveries with Navdeep Chandel, PhD

[00:00:00] Erin Spain, MS: This is Breakthroughs, a podcast from Northwestern University Feinberg School of Medicine. I'm Erin Spain, host of the show. Today's guest is known for helping the scientific community think of mitochondria as much more than cellular powerhouses, but also major players in lung disease, cancer, brain disease, and immune related diseases. Dr. Navdeep Chandel was recently named a recipient of the 2023 Lurie Prize in Biomedical Sciences by the Foundation for the National Institutes of Health for his breakthrough research. He joins me today to talk about his work and how the field of mitochondrial research is taking on a new focus in the world of biology and medicine, and could lead to the design and implementation of new therapies. Welcome to the show. 

[00:01:03] Navdeep Chandel, PhD: Thank you, Erin, for the kind invitation to talk about our ongoing stuff around mitochondria. 

[00:01:08] Erin Spain, MS: Well, first of all, congratulations on being awarded the 2023 Lurie Prize in Biomedical Sciences. Explain this award to me and what it means to have received it.  

[00:01:18] Navdeep Chandel, PhD: First, I should let the listeners know this was shared with a professor, Vamsi Mootha at Harvard Medical School at MGH, who's also been a pioneer in the field of bringing mitochondria back into the spotlight. I've told people three things about the award. You know, the first one is one of my more famous lines, which is that you're only as good as the people in your lab. So this is really the Lurie Prize awarded to the Chandel Lab. It's really a reflection of the past and present members of the lab. I think the second thing is, you know, I've had a lot of great mentors, in particular University of Chicago during my training, but also here at Northwestern and collaborators as well. I was hired by Iasha Sznajder, who built this amazing pulmonary and critical care division, even though I'm not a physician, nor do I necessarily always work on lung, but he set a culture of scholarship and mentoring. And my current chief is Scott Budinger, who is my longest collaborator going to the mid nineties, when we were together. He was a pulmonary fellow and I was a graduate student and I've had more papers with him than anyone. And he's continued that same excellent scholarship, excellent mentorship, collaborative nurturing, and so, you know, I've had many opportunities to move on from Northwestern, but I've always come back partly because of the environment in my pulmonary critical care niche. And then also beyond that, I'm pretty comfortable in knowing about mitochondria just because I've done it for a long time. You know, you get good at something, but anytime I want to do something new, I have amazing collaborators, especially when you're trying to go into complex diseases. And I would say Northwestern's strength is definitely, we have a lot of expertise in diseases, so someone who knows fundamental mitochondrial biology can go study ALS or Parkinson's or viral pneumonia or the aging process. And then finally, just, you know, beyond the lab, beyond Northwestern, I think anytime any award is given in biomedical sciences or in any field, it's really just saying that the field is doing something interesting that is broadly applicable to many things in biology, right, which can be translated into many, many different areas of physiology, health, and of course, diseases. So it's really, I think, a recognition of how the field has evolved, in part, based on stuff we've done, Dr. Mootha at Harvard, and many, many other people over the last 25 years. 

[00:03:40] Erin Spain, MS: Talk to our listeners about mitochondria and really what was the spark that led you to devoting your career to a field that, to be honest, was pretty quiet. when you started off as a scientist in the late 1980s. 

[00:03:53] Navdeep Chandel, PhD: Yes, if you look at the history of biology, one of the key figures in the late 1800s was Louis Pasteur, you know, baker's yeast making fermentation and alcohol. I think that led initially for the next hundred years, almost a wave of understanding metabolism and almost a disproportionate amount of Nobel prizes went to discovery of metabolism, the cholesterol pathway. But the biggest one is, energy, you know, our energy currency in a cell is ATP, and mitochondria make ATP, and that's what they're called the powerhouse of the cell. This is so fundamental to who we are. You know, we have DNA, but we also have ATP, and you need them both. There was a lot of 1920s, 30s, 40s, 50s, 60s, 70s, a lot of interest in mitochondria, a lot of amazing discoveries. But by 1980, largely the biochemistry of mitochondria, how we make ATP, how we make metabolites for growth, lipids, you know, all of that stuff, that was largely figured out, people thought. And so when I got into it around late sort of 80s as a 19-year-old student at University of Chicago, one of the things that I got interested in is liver transplants. I was actually a math major, so I did this as a hobby. What was fascinating was that, you know, one of the big problems in transplant is you take a donor, you know, somebody perhaps from a car crash. That sits on ice and etc until you find the recipient, but the time lag that it sits outside the body and by the time it gets put in, it can undergo injury, and the injury could be low oxygen, which is called ischemia. I started to think about why that is and how you can keep these livers going longer times and work better when you transplant them. To understand that, you got to think about oxygen. For study oxygen, you got to go to the mitochondria because in any given cell, mitochondria are the largest consumers of oxygen and they use the oxygen to make ATP, and that's called oxidative phosphorylation. Peter Mitchell got a Nobel Prize for it in 1978. And so I started to think, "okay, you know, there must be an energy problem, they're running out of oxygen, right?" I mean, simple ideas. I ended up doing a PhD program with somebody who's a professor of pediatrics now at Northwestern. But this was at the University of Chicago, Paul Schumacher, and he was great. I did a PhD on an enzyme in the mitochondria that uses all the oxygen, right? Makes sense. You want to figure out what oxygen does? Go where the system that uses the most oxygen. Anyway, I started playing around with this complex that uses oxygen and under different oxygen levels, high versus low, whether it's more efficient, less efficient. But again, I'm in the ATP mode here, right? Because this is all linked to ATP. I even was giving cells ATP back, which is very difficult to do, all sorts of crazy stuff. But everything around ATP, energy, energy, energy. As I was finishing in 1996, there was a paper that came out of the blue from somebody who came from the cholesterol world. His name is Xiaodong Wang. At Emory, he had this crazy paper, which suggested that a protein that I worked on every single day-- it's called cytochrome c in the mitochondria-- that if it's in the mitochondria, it gives you energy, ATP. It's part of the ATP production factory. But if it leaves the mitochondria and goes into the rest of the cell, it causes cell death. Just by being in the wrong location. And that was sort of the "aha" moment. I give him a lot of credit. I actually didn't believe it. I'm on record as saying it. I thought it was an artifact. And so, what that suggested was that mitochondria release things to make decisions. So in other words, they release signals. In this case, cytochrome c is the signal, and then and that makes a choice between life and death. So if it's in the mitochondria, you live, if it leaves the mitochondria, you die. So certain death stimuluses use this pathway to kill, right? So I started, thinking like going back to my oxygen responses, could there be signals that control oxygen? And one of the signals we thought about was H2O2, which was really well known by other people. And there was other people thinking that H2O2 could signal, but most people thought that mitochondria, and this goes back 50 years ago, that mitochondria make H2O2 kill. That's oxidative stress. That's why, Erin, you take antioxidants. You take antioxidants because you don't want your mitochondria to release lots of these H2O2 and therefore you'll prevent aging, neurodegeneration, etc. Theory has failed every time in clinical trials. So either the theory is wrong or we don't have the right antioxidants, and I think it's more nuanced than that. I think one of the key insights we had was that H2O2, specifically from the mitochondria, is a normal signal for health. And if you don't make it, bad things happen. If you make too much... Bad things happen. The Goldilocks rule. Remember Goldilocks? Just the right amount. So, cells are constantly making H2O2 in response to the nutrients they're getting and the signals they're getting to differentiate for immune responses. Part of a normal, healthy cell: make H2O2, keep things going. 

[00:08:51] Erin Spain, MS:  So when you came to Northwestern in 2000, you began studying how hydrogen peroxide produced by mitochondria acts as a signaling molecule. Tell me about those early projects and how they now inform so much of what you're doing.  

[00:09:05] Navdeep Chandel, PhD: So when I was with Paul Schumacher, we together started to propose that H2O2 would be important for hypoxic responses, low oxygen responses. So for example, Erin, if you go to high altitude, your body has to respond to that low oxygen. It's a normal stress response, and we started to work on how H2O2 might be key to that stress response. But when I started my lab, I started broadly thinking this is not only for low oxygen or hypoxia or ischemia, but for other things like cellular differentiation, T cells, which are important for immunotherapy, or macrophages, which are important for autoimmunity, for example, both T cells and macrophages. You know, the immune system essentially, as well as, cancer, right? Because there's always a link between H2O2, or let's say oxidative stress, and cancer. In fact, there's been a lot of antioxidant trials that have happened in cancer. They have all failed, and we know now why. One of the things we proposed, it was like a hypothesis paper I published with Dave Tewson in the New England Journal of Medicine. And what we said was, look: what cancer cells do compared to normal cells is they make a lot of hydrogen peroxide, almost 10 times more. They're just pumping out hydrogen peroxide all the time, these cancer cells, and they use those a driving force to proliferate, metastasize, but nobody can live with that amount of H2O2. So what do they do? They jack up their antioxidants internally. Just so the Goldilocks rules, you know, you make a lot, but then you just bring it down to a level that they can survive, but still get all the advantages of H2O2. So would you want to give cancer more antioxidants? Probably not. They'll do better. And in fact, that's what the clinical trials show, the dietary antioxidants, at least, sorry, are all preventing cancer cells from ever dying, and surviving, and it's made in cancer trials, things worse. So, it's a little nuanced, you know, to think that you have a pool of H2O2 from mitochondria that is good for you essentially, and it's good for a normal cell, but from a cancer point of view, it's good for a cancer cell, too. It can grow, but then H2O2 can become other types of what we call oxidants or reactive oxygen species, and the other types of H2O2, its byproducts, let's say, in particular, one called lipid hydroperoxides, they cause death. So, in many ways, you don't want normal cells to accumulate that. But you want cancer cells to accumulate that, right? What's good for a normal cell, may be bad for a cancer cell, vice versa.  

[00:11:34] Erin Spain, MS: So I want to talk about some of your recent publications as well and how a paper you published in Nature investigates the relationship between the mitochondria and epithelial cells and lungs. Tell me about that study and this crucial exchange of oxygen and carbon dioxide to avoid respiratory failure.  

[00:11:53] Navdeep Chandel, PhD: One of our overarching hypothesis is that, and we can go into any tissue and try to test this, is when you inhibit the act of respiration at a cell level, that means that the oxygen that the cells are using for ATP, if you disrupt that, right, the prediction always is you don't make ATP and the cell dies. Okay, so when we genetically, through mouse genetics, if you take any cell type, so we did it in the lung. We knock out the active respiration, so you don't make ATP now. You have to rely on fermentation, glycolysis for your ATP, and so the cells should die, and we don't see cell death. We've rarely seen any tissue cell death. What actually ends up happening is the cell doesn't function properly. So in this case, we did it in the stem cell pool of the lungs. They have to differentiate into proper gas exchanging alveoli unit, and they just didn't do that. And the reason they didn't do that is because the normal signals that come from mitochondria that tell you to make a proper differentiated alveoli got disrupted when we knocked out respiration in those cells. So, it wasn't about ATP, that's the key. Something about a signal, and we figured out what the signal was. When we fixed the signal, even though we didn't fix the mitochondria, but the signaling cascade, when we fixed it, the cells differentiated and the mice now survived, right? It's a nice signaling paradigm.  

[00:13:20] Erin Spain, MS: So what implications could this have for future therapies?  

[00:13:23] Navdeep Chandel, PhD: This was a story in development, and so all developmental programs, once you finish development, they shut down because you're not developing. But most diseases, including cancer and fibrosis, etc. are basically developmental programs that have been reinvigorated, right? So programs that should have been gone, they just come back in the adult, and so, the program that we found in development we think comes back in lung fibrosis, for example. All right, but now we know the signals that control this program. So could we then intervene in lung fibrosis in a similar way? And we're testing that. And with my colleagues, especially I have to give a shout out to  SeungHye Han, who's a new assistant professor that I mentored during her K grant mentoring period, but she's going to do all this stuff. She's going to be the star. And of course, Scott Budinger, the Chief, who is going to help her. So again, the collaborative nurturing environment, we will figure this out, I'm positive. But that leads me to something that is of my other interest. So these experiments we do are chronic inhibition of the respiratory chain. So in other words, the ATP is just being suppressed constantly, but we notice that the cells don't die and they don't function because we think some signals are missing. But what happens if you were to acutely, with a drug, go back and forth, you know, just hit the mitochondria and inhibit it a little bit and then stop, inhibit it a little bit. We think more and more that, anti-diabetic drug metformin, which has been repurposed for many other purposes, including in a recent, phase three clinical trial that looked quite remarkable for COVID, 42 percent percent reduction in hospitalizations, I think was in Lancet. It was a phase three placebo controlled trial. And so, metformin, beyond being a first line anti- diabetic drug has some other interesting anti-inflammatory, maybe it can delay the onset of aging in humans or mice, people are sort of thinking about it. But we think that metformin basically gets into only a few tissues, we know that. The liver, the gut, primarily kidney. And we think what it might be doing is just slightly inhibiting mitochondrial function, and then activates a stress response, and then you pee it out, and it's gone. It's reversible. So you turn it on, some stress response, you turn it off, turn it on, turn it off, turn it on. And that cyclical nature just helps you deal with stress better.  

[00:15:39] Erin Spain, MS: We had Budinger on this podcast talking about metformin and air pollution actually. I'd like to hear a little bit more about that and some of the current research happening in your lab and with collaboration of other Northwestern investigators looking at metformin. You mentioned aging. Could this be a way to prevent some of the natural things that happen to cells during aging?  

[00:16:02] Navdeep Chandel, PhD: So people always ask me, should I take metformin? And I always tell people don't eat too much and exercise. Can't beat those two things. You don't need anything else. But, I think from, Scott Budinger's study that we collaborated on years ago, I think one of the more insightful things in that study was that if you're exposed to sort of Beijing level pollutions, the inflammation can be dampened by giving metformin, at least in mice, and the COVID trial, and there's a COPD trial, which is another inflammation disease, so I think, you know, again, I think people have to test this properly, but for someone who's healthy, you know, if we were to take metformin daily, would that just keep our inflammation down? I think someone has to do a proper clinical trial and tell me that. If that's the case, then there may be some benefits to metformin for health in normal, healthy people. But until someone does that, I'm not ready to jump on it. But if there was, something I want to stress, is that, and is understudied, is that we should think about whether metformin can be given to healthy people and just look at their inflammation markers over a span of a year in a proper clinical trial. And, tell me is it a decent, you know, low grade anti-inflammatory agent? And the idea is that, you know, you and I, if you get exposed to pollution one day, it'll just keep that inflammation down. Then we're okay for a while. Then we go get some other, I don't know, wildfires or something that we're exposed to. We're just generally keeping it a little bit low. We don't get that overshoot of inflammation at any given point And we think that's largely by just reversibly inhibiting mitochondrial function to activate stress responses that can then deal with, you know, when you do get a stress. 

[00:17:40] Erin Spain, MS: With all the challenges we're facing with climate change, and even this year, I mean, kids couldn't go outside because of air pollution…   

[00:17:48] Navdeep Chandel, PhD: Thinking about chronic inhibition of mitochondria versus acute reversible inhibition,we're finding out those are two different states. Now, you know, I think the big challenge for us is in the chronic inhibition space, you know, what diseases might have that. One of the ones I've gotten interested in, I'm very thankful to Jim Surmeier, the chair of neuroscience, is he had a beautiful paper in Nature where he inhibited mitochondrial function chronically. And the cells didn't die again for a long, long time, but they developed Parkinsonian syndrome, right? Parkinsonism, well before cell death in a staged manner. I've been collaborating with Jim on trying to figure out why that is. I don't think it's just ATP. And that's the hypothesis. Yes, the ATP, you know, is low, but they can make up for it by glycolysis. But these signals that I talk about might be disrupted, and so we're working heavily in Parkinson's. I have another nice one with Bob Kalb and Evangelos Kiskinis in ALS, thinking of a similar paradigm because there's always been, you know, if you ask people in those fields, you know, "Do you think mitochondria are involved in your degeneration?" most people say yes, but then you ask them. "Well, what about it?" They say "oh, they you know, ATP." Okay. Well, that's not interesting. Or too much of this ROS or oxidants, H2O2. Maybe that might be it, but it could be other signals. And I think, you know, and having a nice collaboration of real experts, the ones that I just mentioned here and many others at Northwestern, but then bringing my mitochondria very fundamental knowledge and combining the two, I think, I'm hoping, to move the needle in these devastating diseases. 

[00:19:23] Erin Spain, MS: You've mentioned some really heavy hitters here at Northwestern Medicine, folks who are running labs that you're collaborating with, who are doing this incredible breakthrough work. But something that's really important to you as well as bringing along this next generation of scientists and actually in your lab's mission, you talk about this, the next generation of discoverers. You want to create a really supportive environment. How do you accomplish that? Tell me about this goal. 

[00:19:49] Navdeep Chandel, PhD: I think if you ask somebody, you know, what's the point of being in academia, you know, if you're, a leader, of course, sometimes you give the impression, well, you got to get grants and you got to publish. That's the business end of it. Of course, you got to get grants. Without grants, you can't do an experiment. If you don't publish it, no one knows what you discovered. I would say those are important goals, but they're not the goals, right? The goal is first and foremost, is discovering new stuff and equally important is mentoring, right? So I always say, gain new knowledge and pass new knowledge. I'm a soccer player. There's a great quote from a great coach called Pep Guardiola. And he always says, "take the ball, pass the ball, take the ball, pass the ball." It's kind of like that, you know, gain the new knowledge, pass the new knowledge. That's the best way to describe it. And yes, in order to accomplish those goals, you need grants, you need to publish. And I think you need diversity of people, but more importantly, by having diversity in people, they come with a diversity of thought. Not always, yes, but they bring their experiences to the table. So, I've always viewed my mission as to train the next generation. I've been very fortunate. You know, people ask me about the Lurie Prize, obviously, but if I had to pick, an award which even means more to me than the Lurie Prize, is the Versteeg Award, which was given to me in 2014. So it's an award that's given at Northwestern, all of Northwestern. So, both campuses, Humanities, Economics, Physics, you name it, and is given to a mentor for graduate training. And, unbeknownst to me, my own students got together back in 2012 or 13, around that and they wrote lots of letters, and I was fortunate that year I was picked by the committee. To win that accolade was probably one of the most meaningful things, I'm really proud of my training record in that. And to this day, it's one of my highlights. 

[00:21:44] Erin Spain, MS: Well, as you leave us today, what can we expect in the future? We talked about a lot of different collaborations that you're working on and a lot of different diseases that you're focused on. What can we expect next? 

[00:21:57] Navdeep Chandel, PhD: I think the big challenge is that blueprint of mitochondria signaling organelles, so they used to be called mitochondria powerhouses, which is generate ATP, they've evolved, I think, that they generate signals and those signals are normal for biology, normal for health, but if they get too little or too high, then disease starts to occur. Identifying those signals in diseases, or identifying those signals for normal health and how those signals then get perturbed or changed to cause those diseases and identification of those signals and then generating therapies around those, I think could be the next phase of my life. And that's what we're concentrating on, on figuring out which signals are disrupted to cause diseases and figuring out a way to correct those to ameliorate diseases. I've had my lab for 23 years, hopefully for another 20. I will say to people outside Northwestern who may be listening, I think it is very important for the public to be a little patient about basic science. I can't promise you that I have, you know, the cure to anything. I don't. And however, I do have some basic insights into mitochondria, which many people think might be the key to aging, and autoimmunity, and Parkinson's, and ALS, etc., or lung fibrosis. But learning that basic biology is the first key step, because without it, you don't know what drug to make, okay? You're shooting in the dark. And if you look at, I want to just leave with this closing point, if you look at immunotherapy, you look at the mRNA vaccines, you look at CRISPR editing, from the time that people started to muck around in those areas and having a sense of, you know, what to do, to the time you had people injected with some sort of therapy, that's typically a 20 year process, sometimes 25. So the stuff that's happening today, as in 2023, you will not see till 2040. Sometimes it's quicker, but usually it's 20 to 25 years. But I think there's a lot, a lot of talented people in Northwestern and around the world who are thinking about mitochondria signaling organelles, and thinking about mitochondria and how it relates to disease and I think somebody is going to crack that now that we've sort of outlined at least a blueprint. 

[00:24:12] Erin Spain, MS: Well, thank you so much, Dr. Chandel, for coming on the show. It's been great to hear from you and all the work that you're doing with so many people across Northwestern. So thank you so much for your time today. 

[00:24:24] Navdeep Chandel, PhD: Thank you for the kind invite. 

[00:24:25] Erin Spain, MS: Thanks for listening and be sure to subscribe to this show on Apple Podcasts or wherever you listen to podcasts and rate and review us. Also for medical professionals, this episode of Breakthroughs is available for CME credit. Go to our website, feinberg. northwestern. edu and search CME.