Biomedical evidence systematically collected from astronauts, mice and rats during and after extended time on the International Space, shorter trips (weeks), and even on much shorter trips such as SpaceX’s Inspiration 4 flights show mitochondrial stress.
If Elon Musk intends to plan for life on Mars or NASA plans for settlement on the Moon, they might want to consider one of the most interesting and mysterious parts of every cell in every complex organism (e.g. animals and plants), including us, mitochondria. This biological-physiological issue cannot be solved by successful SpaceX rocket launches or settlement selection. It’s not an engineering or planetary issue, but a deeply scientific and medical one.
Many scientists, philosophers, and writers have dreamed of a destiny for humanity that may exist beyond our home planet. All the global superpowers have their sites on the Moon, Mars and asteroids. Yet, the engineering, physics, material science, propulsion, planetary science and trajectories are still being mastered. In all these calculations, eventually requiring trillions in investment in engineering, there is something profoundly left out of the equation: humans and our bodies.
A MitoCast Interview with Chris Mason (WorldQuant Professor at Weill Cornell Medicine) and Afshin Beheshti (Director of Center for Space Biomedicine, Associate Director of McGowan Institute for Regenerative Medicine, and Professor of Surgery and Computational and Systems Biology at University of Pittsburgh) , top space biomedicine researchers who continue to form teams and pour over the astronaut (and mice and rat) data of those who have been in the International Space Station and on the shorter flights, tells a cautionary story, but also a focal point for countermeasures.
Listening to Mason and Beheshti, it is clear that the planned long space transits or moving off Earth will need to consider the health, function, and stress on the tiny mitochondria in each of our cells, and those of animal-nauts, which may need treatments or modifications to support life away from Earth.
Mitochondria are starting to make it into the news because of their role across the medical and health spectrum. Most people remember the biology class refrain, Powerhouse of the Cell, describing the mitochondrial role in energy production (Krebbs Cycle, ATP production). However, mitochondria, which number from 150 to 7000 per cell, depending on the tissue or organ, have deep regulatory roles in cell life and death, the immune system, and signaling in multiple ways.
Mitochondria are coming of age.
For the last twenty-years, the primary research domain has been the rare mitochondria DNA mutational diseases, primarily of childhood. However, that balance is shifting as mitochondria are now implicated in cardiac disease, diabetes, neurodegenerative diseases and in aging itself. While mitochondrial research rapidly gains ground in the search for cures for chronic diseases, health and diet, a current focus in U.S. policy, a rapidly growing parallel track runs in health and fitness circles and high-performance athletics.
Will Mitochondria Keep Us on Earth?
However, there is a certain amount of hubris to suggest that creatures specifically evolved on Earth within its gravitation, magnetic, atmospheric, biodiverse and radiation envelope would be suitable, or adaptable, to other environments, including life on the Moon or transit time to Mars. While both of those planetary objects have substantially lower gravity (Moon 1/6th, Mars 3/8th), they also either have no shielding from an atmosphere (the Moon) or very little (Mars) and have very different radiation and magnetic signatures and, of course, no known life forms.
As daunting as it was for the earliest human to migrate around the planet, chasing megafauna driven by some innate drive, leaving Earth is a very different biological, physiological and cultural challenge.
We asked Mason and Beheshti a few questions to go along with their longer MitoWorld Spotlight video.
MitoWorld: How did you end up focusing on life in Space and becoming experts in this emerging field?
Beheshti: Chris and I have been working together for almost a decade on various projects from Space biomedicine to COVID-19/Long COVID to cancer… We have had many papers in high impact journals and have put together two high profile paper packages one in Cell Press and the other in Nature Portfolio.
MitoWorld: How did you two end up working on NASA and other bio-data?
Mason: We met originally though some of the GeneLab working groups (now OSDR), working on a variety of projects for human and mouse genomics and other omics data analysis and then really to follow up on the Twins Study. This led to several sets of large-scale collaborations for the Biology of Spaceflight Cell Package in 2020, a range of papers and grants from 2019-current, and also the Nature Space Omics and Medical Atlas Resource in 2024.
Beheshti: Chris and I have been working together for almost a decade on various projects from Space biomedicine to COVID-19/Long COVID to cancer. We have had many papers in high impact journals and have put together two high profile paper packages one in Cell Press and the other in Nature Portfolio.
MitoWorld: How did you two become a team?
Mason: We kept dreaming of ways to integrate more data, leverage human and animal models for analysis, and how to engage the broader community more. We also kept making jokes during calls and enjoying each other’s company.
MitoWorld: Did NASA contract directly with you or through other entities for the work that ended up in the Omics Atlas?
Mason: We have about 12 NASA grants that have supported our work since 2014, but it was not a “contract,” but a grant, as well as NIH and NSF funding. We also had significant support from philanthropy (WorldQuant, Sloan, and Pershing Foundation)
MitoWorld: How were the writers and teams chosen to work on the key papers?
Mason: We offer a spot to everyone and anyone, but ideally get younger scientists to lead these papers and projects to help them propel their career.
MitoWorld: When did each of you become interested in life in space?
Mason: Ever since I was a kid! I went to Space Camp twice in elementary school, and loved genetics since middle school. I am grateful and honored I get to worked on the two things I love most, with people that are very enjoyable like Afshin!
Beheshti: I was always a Sci Fi fan so naturally when I started my journey with Space Biomedicine research in my second postdoc it was a great fit with my large interest in Science Fiction.
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Mason Lab Background: The Mason Lab performs research in three principal areas: (1) clinical genetics, (2) computational algorithms and data structures, and (3) synthetic biology. Clinical genetics work spans Mendelian diseases, aggressive cancers, novel viruses, and astronauts in the Space Omics and Medical Atlas (SOMA). Computational methods include new techniques in DNA/RNA sequencing, spatial imaging, planetary-scale metagenomics, and DNA/RNA base modifications. Synthetic biology research deploys new models for genome, cellular, and microbial ecosystem engineering, including synthetic T-cell systems, built environment modifications, and microbially optimized regolith. [Link]
Beheshti Background: Afshin Beheshti recently joined the University of Pittsburgh as a Professor of Surgery and Computational and Systems Biology, Director of the Space Biomedicine Program, and Associate Director at the McGowan Institute of Regenerative Medicine. In these roles, he will continue his ongoing projects and launch a new space biomedicine program at the University. With this new initiative he will create research opportunities to explore space health issues, research countermeasures to mitigate the damage caused by the space environment and develop outreach/education programs for space biology research. [link]
MitoWorld: The text notes that you enjoy thinking about “crazy” ideas. What is the “craziest” idea that intrigues you now?
One idea I’ve had for years is to replace the electron transport chain, complex I, III, and IV, for only two proteins. One would be an NADH dehydrogenase from yeast (for example NDi1), and the other would be an alternative oxidase (AOX). These can move electrons from NADH to oxygen, bypassing the traditional complex I/III/IV pathway. But here’s the crazy part: they don’t pump protons. That’s where proteorhodopsin comes in. It’s a light-driven proton pump. So, the idea is to express NDi1 and AOX in mitochondria to maintain redox balance and electron flux, and then express proteorhodopsin to regenerate the proton gradient using light. That proton gradient could then be used by ATP synthase to produce ATP.
But it gets even crazier. What if the AOX or NDi1 steps themselves could be engineered to emit light as a byproduct of electron transport? Then proteorhodopsin could be activated by that endogenous light, creating a feedback loop: electrons generate light, light drives proton pumping, protons drive ATP synthesis. In theory, with only three proteins—NDi1, AOX, and proteorhodopsin—we could reconstruct a functional, energy-producing electron transport system in mammalian mitochondria.
It’s very ambitious—perhaps impossible—but it has fascinated me since I was a student. The goal isn’t just synthetic biology, but to explore whether we can dissect the respiratory chain’s functions: electron flux, proton pumping, and ATP synthesis. These functions are often tightly coupled, but in biology, it’s not always beneficial for them to be. If we could separate them, we might gain insight into how they contribute independently to mitochondrial and cellular physiology. Whether I’ll ever be able to do it before the end of my career, who knows?
MitoWorld: A controversial hypothesis is that mitochondria move from cell to cell and that these transfers might serve as the basis for therapies. Do you have any thoughts about that possibility?
We not only have thoughts, but we also have experiments. In cardiac tissue, for example, mitochondria are packaged into membrane-bound structures we call “exopheres” and released. These are then taken up by neighbouring macrophages, which degrade them in a tightly regulated process. It’s a form of quality control but not necessarily a functional mitochondrial donation.
We’ve also shown, with Francisco Sánchez-Madrid, that mitochondrial components, especially mtDNA, can be transferred via immune synapses. The recipient cell sees that mtDNA as a danger signal, triggering antiviral responses.
Now, some studies—particularly in cancer—suggest that mitochondria can be taken up by recipient cells and remain functional, contributing to cell survival. However, while labeled mitochondria seem to transfer between cells, there’s little definitive evidence that they remain functional in the recipient cells or integrate into their networks.
The effects observed may often be immune related rather than metabolic. For instance, injecting mitochondria into blood has been proposed as a therapy, but the doses used are minuscule compared to endogenous mitochondrial populations in cells. Any physiological effects are more likely immune-mediated than due to actual mitochondrial “colonization.”
So, I think mitochondrial transfer happens, yes, but mainly as a signaling or quality control process. The notion of mitochondria behaving like autonomous, transferrable symbionts is still speculative.
MitoWorld: Can you speculate on how cells might regulate the specialization of mitochondria?
Between cell types, it’s mostly transcriptional regulation: different cells express different mitochondrial proteins or isoforms. But even within a single cell, mitochondria can be very different. One possible explanation is temporal regulation. A cell might express different sets of mitochondrial proteins at different times (e.g., day vs. night), and since mitochondria are relatively long-lived, this might create functionally distinct subpopulations. Another possibility is spatial regulation. Mitochondria traveling to different parts of the cell might encounter localized signals (e.g., specific mRNAs, post-translational modifiers, or regulators of protein import) that tune their function to local demands. In principle, if mitochondrial transfer between cells were robust, one could imagine specialized mitochondria being produced in one cell type and shared with another. But again, that’s still speculative.
MitoWorld: The role of mitochondria in energy production ensures that they are critical to cell and organismal health. Do you have any thoughts on how this might translate directly to health and aging?
Here I take a somewhat contrarian view. I don’t believe mitochondria drive aging. Aging is ultimately a consequence of entropy, a physical rather than strictly biological phenomenon. Biological systems resist entropy via repair and homeostasis, but over time, these processes lose efficiency.
That said, mitochondrial dysfunction is certainly part of the picture. As the cell accumulates damage (e.g., lysosomal inefficiency, metabolic imbalance, chronic inflammation), mitochondrial quality suffers. But so does everything else. For example, if oxygenation drops in the blood, the heart compensates by beating harder. Chronic compensation leads to hypertrophy and, eventually, pathology. The failure isn’t just in one organ or cell type; it’s in the integrated function of the whole.
So, while supporting mitochondrial function can help maintain cellular health, it won’t “cure” aging. In other words, mitochondria reflect the overall fitness of the cell. They are important, yes, but not supreme. Many age-related interventions that “target mitochondria” probably act through broader systemic effects: diet, exercise, metabolic control.
MitoWorld: Reversal of ATP synthase is counterintuitive. As you note, it might suggest a role in mitochondrial quality control. Can you elaborate on this hypothesis?
This might seem controversial at first: consuming ATP to pump protons. But it makes sense when you consider that the mitochondrial membrane potential must be tightly regulated. If it drops too low, apoptosis can be triggered. If it gets too high, ROS levels rise. So, reverse ATP synthase activity is a safety valve. It helps maintain an optimal membrane potential, even if doing so costs energy. In this light, ATP synthase becomes not just a producer of energy but a key regulator of mitochondrial homeostasis.
MitoWorld: FGR and OM1A are encoded by the nuclear DNA and imported into the mitochondria. That suggests a complex process with multiple potential therapeutic targets. Do you have thoughts about the most effective mechanism to inhibit it if it is not simply the enzymatic activity?
The challenge is that these enzymes have multiple substrates. Inhibiting their entire activity entirely can have off-target effects. A better strategy is to selectively block their interaction with specific targets, while leaving other interactions intact. Now that we know their structures, we can start designing molecules that interfere with specific protein-protein interactions to disrupt pathological effects while preserving beneficial ones. This is a more nuanced and promising strategy for targeting multifunctional mitochondrial regulators.
MitoWorld: One of the key questions in mitochondrial biology is how the mitochondria and the nucleus work together to keep things running smoothly—or not—when something goes wrong. Do you think your population studies might help us understand that relationship better?
This is a very important question. One of the biggest challenges in mitochondrial biology is that most mitochondrial protein complexes are assembled from proteins encoded by two different genomes: the mitochondrial genome and the nuclear genome. This creates a need for very tight coordination between the two, despite the fact that they evolve at different rates and under different selective pressures.
From a population genetics perspective, we can use large datasets to ask: (I) Which positions in these proteins are highly conserved (i.e., intolerant to change)? (II) Which positions vary more across individuals or species (i.e., more permissive to variation)? Some variants in mtDNA are never observed in the population, suggesting they are incompatible with nuclear-encoded partners.
We recently created a database scoring every amino acid in mitochondrial and nuclear-encoded ETC proteins for its permissivity—how often it varies across species and individuals. This helps us identify evolutionarily constrained sites where mitonuclear compatibility is critical.
We also see that mitochondrial and nuclear subunits in physical contact tend to co-evolve, whereas regions not in contact evolve more independently. This helps us map critical interaction interfaces and might uncover regulatory hotspots we don’t yet understand.
So yes—population studies can teach us a lot about mitonuclear compatibility, evolutionary constraints, and potentially, disease susceptibility.
We are happy to announce that Dr. Dane M. Wolf, recently an EMBO Long-Term Fellow at the University of Cambridge, is starting his own mitochondrial microscopy consultancy and will serve as MitoWorld’s Director of Microscopy.
Wolf is a mitochondrial biologist specializing in advanced imaging technologies. He completed his PhD at Boston University and University of California, Los Angeles, where he used live-cell super-resolution microscopy to study the structure-function relationship of mitochondrial cristae. As an EMBO Long-Term Fellow at the University of Cambridge, he investigated mitochondrial (mt)DNA dynamics using cutting-edge imaging approaches.
Wolf founded MitoGraphica, a scientific consultancy focused on mitochondrial image analysis and research, to support both academia and industry. He is deeply passionate about mitochondria and is committed to advancing and communicating our understanding of their vital roles in human health and longevity.
“In my lab, Dane became an imaging virtuoso,” said Dr. Orian Shirihai, Wolf’s PhD mentor, “not just because of his technical skill, but because of his creativity and attention to detail. What he’s built with MitoGraphica is a natural extension of his scientific work: a consultancy grounded in rigor, reliability, and precision. He brings not only innovation and vision, but also the discipline to deliver timely, well-documented, statistically sound solutions to complex image analysis challenges—something the field truly needs.”
MitoWorld: You assembled a nice slide deck (download PPTX) tour of some of the imagery you produced while at UCLA. Can you say a little bit about what we see in that deck?
Wolf: It’s an overview of the imaging that I performed at UCLA. The lab focused not only on the role of mitochondria in single cells, but also on how they regulate metabolism across the body. I spent a lot of time imaging a pancreatic β cell line (INS-1) and primary hepatocytes—which carry out the bulk of the liver’s metabolic activity. The deck also includes images of antibody-producing B cells undergoing mitosis in response to a stimulatory signal, along with super-resolution imaging of cristae, lipid droplets, lysosomes, and mtDNA in a variety of cell types.
The main takeaway from this set of images is that virtually all eukaryotic cells are densely populated with mitochondria. They inhabit the cell almost like individuals in a village—exhibiting complex behaviors, being born and dying, in a manner of speaking—and recent work suggests they take on specialized roles within the broader cellular environment. Remarkably, mitochondria can even travel between cells via membranous bridges or vesicles, coming to the aid of stressed neighbors.
MitoWorld: Which came first, your interest in mitochondria or imaging? How did the two evolve together for your work at UCLA and then Cambridge?
Wolf: I’ve been interested in the biology of aging for as long as I can remember. Since mitochondria are central to cellular homeostasis—and their dysfunction is closely linked to the systemic decline associated with aging—my interest in mitochondria came first. That said, it wasn’t until I began my PhD and saw live mitochondria under a confocal microscope that this interest grew from an abstract, academic curiosity into something visceral and compelling. There’s something truly captivating about looking through a microscope and watching thousands of mitochondria wiggle and dart around a field of cells, sometimes undergoing fusion and fission. In those moments, mitochondria seem to exhibit their own kind of behavior. That sense of wonder made me want to follow them more closely, and I became increasingly focused on developing approaches that would allow me to visualize them in greater spatiotemporal detail. The more clearly you can see them— really scrutinize their movements—the more their inner life begins to emerge, in surprising and often beautiful ways.
MitoWorld: During your PhD at UCLA in the Shirihai Lab, what were you trying to accomplish with imaging that you or the lab thought was beneficial, and how did this work add to the field of mitochondrial microscopy?
Wolf: In Orian’s lab, there has always been a strong emphasis on mitochondrial dynamics—how mitochondria move, divide, and fuse. As a PhD student, I was fortunate to have a great deal of freedom to explore, and at UCLA, we had access to cutting-edge super-resolution imaging technologies. One of these systems, Airyscan, allowed us to visualize mitochondria beyond the optical diffraction limit, opening up new possibilities for studying their complex internal structures in live cells.
By optimizing this technology, we developed methods to resolve the inner mitochondrial membrane in living cells. Using membrane-potential-sensitive dyes, we discovered that cristae—the characteristic folds of the inner membrane—were more polarized than other regions, and that individual cristae within the same mitochondrion could display distinct membrane-potential signatures. This supported a new model of the proton motive force, in which the electrical potential that drives ATP synthesis is compartmentalized at individual cristae. In this model, each crista functions like a miniature battery within the larger mitochondrion—much like how a Tesla battery pack is made up of many smaller battery cells (see Wolf et al., 2019).
This level of compartmentalization is thought to enhance energy efficiency. Just as importantly, it provides a form of bioenergetic buffering—if one crista becomes damaged or dysfunctional, it doesn’t compromise the entire organelle. Crista-level autonomy hadn’t been fully appreciated before, and this work added a new layer of understanding to mitochondrial resilience and function.
MitoWorld: Can you briefly describe the range of imaging techniques that you used to investigate mitochondria and how they aid in fundamental research?
Wolf: The imaging techniques that we used are primarily Airyscan and structured illumination microscopy (SIM), two different types of extended or super-resolution microscope. Airyscan employs a 32-channel GaAsP detector array in place of a traditional single-point detector, allowing it to capture more spatial information from the Airy disk of emitted light. Each detector element collects light from a slightly different position, and the combined data are computationally reconstructed to enhance both resolution and signal-to-noise ratio. This approach enables imaging beyond the diffraction limit, down to approximately 120 nm in the x-y plane. Airyscan is also highly sensitive, allowing us to image mitochondria using relatively low laser power. This reduced phototoxicity was critical for measuring membrane potential, as mitochondria are prone to depolarization when exposed to laser-induced stress.
SIM, by contrast, works by projecting striped patterns of light onto a sample from multiple angles and phases. These patterns create moiré interference with fine cellular structures, effectively shifting high-resolution information into a detectable range. By capturing a series of these patterned images and applying computational reconstruction, SIM achieves resolution beyond the optical diffraction limit—down to approximately 120 nm or roughly twice the resolution of conventional confocal microscopy.
Without super-resolution techniques, we wouldn’t be able to resolve the fine details of mitochondrial architecture without resorting to electron microscopy, which requires fixation or freezing, ruling out real-time measurements of structure and function. To truly understand something, you have to see how it moves. Super-resolution microscopy allows us to visualize the dynamics of mitochondria’s innermost structures, shedding light on core aspects of their function.
MitoWorld: What other works of yours might be forthcoming?
Wolf: In many ways, my work in Cambridge built upon the skill set I developed at UCLA. I applied a combination of super-resolution and 4D imaging to investigate the dynamics of the mitochondrial genome. This work is still unpublished, so I can’t go into detail just yet, but I’m looking forward to sharing it with the community, as I believe it offers new insights into fundamental aspects of mitochondrial function.
MitoWorld: Where do you think the field will go over the next 5 years? What do you hope to perfect and investigate over this time?
Wolf: Naturally, it is difficult to predict where the field will go. But if I had to guess, I’d say mitochondrial biology will become increasingly integrated with other disciplines. There’s a growing recognition that mitochondria are fundamental to a wide range of cellular functions, and mitochondrial dysfunction has emerged as a hallmark of an expanding list of diseases.
We’ve known since the mid-20th century that mitochondria are the cell’s powerhouses. A conceptual leap at the end of that century was the realization that they also play a central role in determining whether a cell lives or dies. The 21st century has brought about a renaissance in mitochondrial biology, with new discoveries revealing their involvement in diverse physiological contexts—from maintaining stem cell identity to driving specific cancer behaviors through shifts in metabolic activity.
I’m particularly interested in the role of mitochondria in the aging process. Finding new ways to preserve or rescue mitochondrial function, especially under stress, will likely be essential in efforts to combat age-related diseases such as neurodegeneration. And of course, I am always working to stay at the forefront of imaging technology, as visualizing mitochondrial behavior in ever-increasing detail continues to unlock new insights.
MitoWorld: How do you hope to shape your business, and what services can you bring to labs to improve or design their microscopy for cutting-edge research?
Wolf: After studying mitochondria for over a decade, I’ve come to appreciate that mitochondrial shape is a powerful indicator of function. This isn’t surprising—structure and function are fundamentally intertwined. Understanding how and why mitochondria change shape can reveal important clues about their physiological state, which in turn affects cellular and even organismal homeostasis.
That said, accurately measuring mitochondrial morphology is far from trivial. It requires not only high-quality imaging, but also the expertise to use specialized analysis platforms capable of segmenting and quantifying complex mitochondrial networks. Interpreting these changes—and uncovering the mechanisms behind them—can be especially challenging for researchers who aren’t specialists in mitochondrial dynamics or function.
Given the growing interest in mitochondria across both industry and academia, I founded www.MitoGraphica.com to make this expertise more accessible. The goal is to support researchers who want to image mitochondria but need guidance, as well as those who already have images but require expert help with analysis and interpretation. Ultimately, progress in both basic biology and therapeutic development depends on rigorous experimental design and accurate data. I want MitoGraphica to be a reliable resource—ensuring that anyone studying mitochondrial function has access to the tools, insights, and support needed to do it well.
MitoWorld’s life sciences reporter, Danny Levine of the Levine Media Group, conducted an in-depth video interview or MitoCast with Dr. Thompson as part of MitoWorld’s Spotlight series.
Watch the video on YouTube here.
In March, Gary Howard, MitoWorld’s editorial lead, wrote a MitoWorld post about Craig Thompson’s Lab at Memorial Sloan Kettering (MSKCC) and their detailed analysis of a new type of mitochondria devoted to building cell structures, not just producing ATP. Howard summarized Thompson’s and his collaborators work in Nature, Cellular ATP demand creates metabolically distinct subpopulations of mitochondria.
Howard wrote, “The laboratory of Craig Thompson reports that, under stress conditions, mitochondria assume different roles. Dr. Thompson is the former president and CEO of Memorial Sloan Kettering Cancer Center (2010-2022) and currently holds the Douglas A. Warner III Chair in the Cancer Biology and Genetics Program.
“Dr. Thompson’s research team began their search with a careful rethinking of mitochondrial functions. While mitochondria have many key functions, they are best known for producing the energy that we all need from the food that we eat.” [Sloan Kettering Press Release]
Navdeep “Nav” S. Chandel is both a leader and steward of the evolving field of mitochondrial biology.
As a newcomer to this area of science I was taken by Chandel’s energy, rigor, and enthusiasm for mitochondria, as well as his impatience on the pace of funding for the rapidly evolving field. Chandel provides leadership that is both expansive and contagious. It is a commitment that is necessary raise the visibility of the field across medicine, health, and research to stimulate more funding and to establish mitochondria as a unique field of science.
A Scientific American article in 1957 entitled “The Powerhouse of the Cell,” followed by three profound discoveries elucidating how mitochondria make energy – John Mitchell (Chemiosmotic hypothesis, Nobel 1978 ), Paul Boyer (ATP synthase, Nobel 1997 ) and John Walker (mechanisms of ATP synthase, Nobel 1997, shared with Boyer) sealed mitochondria’s identify as the converter of what we consume into the energy we use to power our cells, organs, and lives.
As a result, many biologists, researchers, textbook authors, and students failed to develop an understanding of mitochondria that went deeper than that. In many ways the science of mitochondria became limited to its role in energy production. For some time, this narrow view shut off further investigations. As a Ph.D. student in the 1990s at University of Chicago, Chandel began to suspect that mitochondria played many other significant roles. This became his passion when started his in his lab at Northwestern University in January 2000.
To understand Chandel’s contribution to the field, just ask his colleagues.
“The work of Navdeep’s lab, and especially his intellectual leadership, has been transformational for the field,” says Gerry Shadel, of the Salk Institute. “Navdeep has been at the forefront for decades of trying to convince the world to think about mitochondria beyond just making ATP. This position has turned out to be prescient as we have learned of the many, many ways that mitochondria impact health and disease, many of which have little to do with producing ATP.”
Chandel’s work in recognizing mitochondrial functions beyond ATP production has been part of the process to reinterpret mitochondria much more broadly.
“For decades, the mitochondria have been primarily viewed as biosynthetic and bioenergetic organelles generating metabolites for the production of macromolecules and ATP, respectively. We began to provide initial evidence that mitochondria have a third distinct role whereby they participate in cellular signaling processes to control physiology through the release of reactive oxygen species (ROS), “Chandel wrote on his website. “In the past two decades, many scientists have contributed to elucidating multiple modalities of how mitochondria communicate with the rest of the cell to dictate their function in physiological contexts. A key aspect of mitochondrial signaling paradigm is that various pathologies linked to mitochondria dysfunction might occur not simply due to lack of ATP generation or metabolites but disruption of these normal signaling functions of mitochondria”.
This expanded view reflects what Chandel has been able to accomplish by showing that mitochondria are not a biological sideshow, but a star that belongs on the main stage.
“Navdeep has made numerous profound contributions to the understanding of how mitochondrial function and disruption contributes to human pathology, particularly in cancer and immunology,” said Mike Murphy, program leader at the University of Cambridge’s MRC Mitochondrial Biology Unit. “Navdeep has pioneered the use of innovative transgenic animal models in which subtle modulation of respiratory function leads to important new insights into disease processes and opens the way to the development of novel therapies.”
Allyson Evans, editor in chief of the journal Cell Metabolism, in 2013 established a new symposium, the “Multifaceted Mitochondria Symposium.” The conference is held every two years. I just attended the 2024 Symposium in Sitges, Spain, where MitoWorld was a sponsor. Before I did, I had an opportunity to ask Evans how she and Cell decided to launch a symposium dedicated to mitochondria a decade ago, and how they gave it the name, “Multi-Faceted Mitochondria.” Her answer was simple. It was Navdeep Chandel who stimulated the interest and advocated for it.
This was same for our launching the global web portal MitoWorld, www.MitoWorld.org, in 2023. Chandel provided the confidence and connections for MitoWorld to begin its mission to mainstream mitochondria issues, provide a community hub for the public, patient, and professional mitochondria communities; and to advocate for the development of a mitochondrial science and informatics.
For others to get to know Chandel better, we asked life sciences journalist Daniel Levine to interview Navdeep for MitoWorld’s “Spotlight” section of the MitoWorld website.
About Navdeep S. Chandel, PhD:
Navdeep S. Chandel, PhD is the David W. Cugell Professor of Medicine, Biochemistry, and Molecular Genetics at Northwestern University. He received his BA in Mathematics (1991) and Ph.D. in Cell Physiology at the University of Chicago (1993-1997, Paul Schumacker) as well as a post-doctoral fellowship at the University of Chicago (1997-1999, jointly with Paul Schumacker and Craig Thompson). In 2000, he started his laboratory at Northwestern University on the concept of “Mitochondria as signaling organelles”. He has written a widely utilized introductory book entitled “Navigating Metabolism” (Cold Spring Harbor Press, 2014). He received the Clarence Ver Steeg Faculty Mentor Award in 2013, which recognizes faculty members from any department throughout Northwestern University for their outstanding mentorship of graduate students. In 2023, he was co-recipient of the FNIH Lurie Prize in Biomedical Science with Dr. Vamsi Mootha.
Professor at University College London was recognized for his work connecting mitochondria to human diseases and for finding potential therapeutic targets.
MitoWorld congratulates Professor Michael Duchen on being awarded the prestigious 2024 Keilin Memorial Lecture by the Biochemical Society. Each year, the Society recognizes outstanding scientists for achievements in the study of molecular biosciences. Professor Duchen was honored for his seminal contributions to the research into mitochondria in disease.
“This award is a great honor, and I thank the Biochemical Society for it,” said Professor Duchen. “I accepted the Keilin award on behalf of the lab. I have been very lucky to work with outstanding people over the years who shaped the work that we have generated. I am not the one who is coming to work at weekends to feed the iPS cells or working late at night because that’s the only time the confocal microscope is free! Many of those people are now professors and some of the greatest pleasure comes from seeing people grow and flower and find their own scientific voice.”
Working at University College London since 1981, Duchen began his research into neurotransmitter receptors and then calcium signaling and metabolism and finally mitochondria. He has been a leader in connecting mitochondrial dysfunction to diseases and in establishing mitochondria as therapeutic targets for a variety of diseases.
MitoWorld reached out to Professor Duchen to learn more about his research. His responses to our questions are reproduced here.
How did your research evolve from signaling and metabolism to mitochondria?
The story is a bit long? My PhD supervisor, Tim Biscoe, had previously done some work on the carotid body, the structure that sits on the carotid artery and senses and reports oxygen tension in the arterial blood en route to the brain. We were using patch clamp techniques to study neurotransmitter receptors in freshly dissociated neurons and one day had a visit from an old friend of Tim’s, Jose Ponte, who suggested we try to patch cells isolated from the carotid body. We tried as a ‘Friday afternoon experiment’. No one knew anything at all about the physiology of these cells, and we discovered that they were excitable. The question then was how do they respond to low oxygen? There was some evidence from Elliott Mills that mitochondria might be involved as mitochondria are the main oxygen consumers. That made sense. I was then faced with the challenge of how to study changes in mitochondrial function in these cells in response to changing pO2, especially difficult as the structure is very tiny with a very small population of cells. That eventually led to measurements of changing mitochondrial membrane potential in response to graded changes in oxygen which were amongst the first measurements of changing mitochondrial membrane potential in living cells. That opened up a huge swathe of questions about how mitochondria behave in different cell types and in response to different physiological conditions or in disease, about which we then knew nothing at all, and those questions have kept me busy for ~30 years!
What are the main connections between mitochondria and diseases, such as PD?
We can broadly divide roles of mitochondrial dysfunction in disease into ‘primary’ where the primary defect is in the mitochondria, such as a mutation of mitochondrial DNA (mtDNA) and ‘secondary’, where mitochondria are damaged as part of a cascade of cell injury and the defect is extramitochondrial. The latter group probably includes diseases, such as Parkinson’s disease (PD), amyotrophic lateral sclerosis, frontotemporal dementia, Alzheimer’s disease and many others. It seems clear at least in familial forms of PD, that the primary genetic defects lie on pathways that have an impact on mitochondrial function. As the resulting mitochondrial dysfunction may play a critical role in defining the disease progression, this is still an interesting potential therapeutic target.
What potential therapeutic targets interest you most?
Recent work has highlighted multiple pathways that affect and are affected by mitochondrial function in a host of different ways. These include cell death pathways governed by mitochondria, mitochondrial quality control pathways that include biogenesis, mitophagy, fission, fusion and trafficking, and most recently the activation of innate immune pathways by mtDNA that is released from damaged mitochondria. All of these pathways represent potential therapeutic targets.
Is any disease “low hanging fruit” for mitochondrial treatments?
There may be low hanging fruit in relation to process rather than to one specific disease. There is quite a lot of evidence for a mitochondrial catastrophe. The opening of the mitochondrial permeability transition pore may be the cause of sudden cell death of cell dysfunction in multiple diseases. This is most interesting as the pore is an established therapeutic target, but so far, preclinical findings haven’t translated well into the clinic. I like to think that, if we could find a compound without unwanted off target effects and with good pharmacokinetic properties, this might prove valuable in multiple diseases. Mitophagy and biogenesis also appear to be a potentially powerful processes that can be modulated pharmacologically, and I suspect those will prove to be major drug targets in multiple human diseases.
For more information on Professor Duchen, please visit his UCL website at https://profiles.ucl.ac.uk/3559. More information on the Biochemical Society awards can be found at www.biochemistry.org/about-us/news-media/biochemical-society-announces-2024-award-recipients/.
Mitochondrial medicine pioneer Douglas Wallace is the subject of MitoWorld’s first “Spotlight” feature, in this case a 40 minute interview, conducted by life sciences journalist Daniel Levine, with a page of citations and links.
Wallace’s career, discoveries and insights cover the fields of mitochondrial genetic medicine from its beginning to trying to unraveling the issues of Long-Covid and novel approaches to cancer treatment.
Last May, I was lucky enough to visit the Wallace Laboratory at Children’s Hospital Philadelphia (CHOP), one of the most extensive and exciting mitochondrial research centers in the world. For those who don’t know Douglas Wallace, if there was a mitochondrial medicine hall of fame, Wallace would be its first member.
The Wallace Lab is a very impressive entire floor of researchers and the most advanced storage specimens, latest imaging and analysis equipment. The lab environment is congenial and professional. But most impressive is Wallace – soft-spoken, witty, insightful and encyclopedic. A biology convert from physics, Wallace’s work fifty years ago studying the genetics of the mitochondrion which provides the powers for every aspect of human and all animal biology. However, for Wallace, the frustration has been immense, because the traditional worlds of medicine and biological have not shifted their focus to include the central role of energy and thus mitochondria and in health and medicine.
In his Spotlight interview, Wallace points out, “What’s happened is that we have NIH institutes that are all organized around anatomy. And we have clinical departments all organized around anatomy. So as a result, we don’t have a unifying view of how bioenergetics affects all the different health problems we have. [1] So what we really need is to find ways to bring this community together. Now, one area that’s been done in the primary mitochondrial disease area is an organization like the United Mitochondrial Disease Foundation (UMDF), which has worked hard to bring families together with clinicians to help children. But we don’t have that kind of structure for the common diseases.”
According to Carlos Moraes, PhD, Esther Lichtenstein Professor in Neurology at the University of Miami, who has been studying the pathobiology of mitochondrial diseases and related disorders for more than 30 years, “In the 1970s, Doug Wallace started a revolution in genetics by showing that the mitochondrial genome is inherited exclusively from the mothers and can confer distinct phenotypes to the cell. His work set the stage to trace the origins and migrations of humans and to the understanding of a large group of mitochondrial diseases.” [2] Moraes’ current focus is on mtDNA gene editing with nucleases and base editors.
Wallace’s SARS-CoV-2 collaborator Afshin Beheshti, PhD, University of Pittsburgh Professor of Surgery and Computational and Systems Biology, speaks to their on-going work.
“In the context of COVID-19, our research has revealed that SARS-CoV-2 directly targets mitochondria, leading to systemic mitochondrial dysfunction that persists in long COVID patients. This groundbreaking work has the potential to uncover mitochondrial biomarkers and therapeutics, offering new avenues to address long COVID, which continues to affect millions globally.”
On both the lighter side and the deeper side, Wallace’s mind and writing has made direct parallels between bioenergetics and the Chinese medicine concept of “Chi,” or energy flow. [3] Martin Picard, Associate Professor of Behavioral Medicine in the Departments of Psychiatry and Neurology at Columbia University Irving Medical Center, supports Wallace’s wider view. “Doug has been a ray of light for the field, illuminating possibilities for mitochondrial science and medicine. Mitochondria are indeed the vehicle for Chi – supporting the life-giving energy transformation that power the mind and the flow of human consciousness.”
On the deeper side, Wallace’s physics roots and knowledge of the evolutionary role of ATP producing ancient bacteria led to the modern eukaryotic life-building cells led to a fascinating paper on the connection between “energy flux” and “biological information stored in nucleic acids.”
Complex structures are generated and maintained through energy flux. Structures embody information, and biological information is stored in nucleic acids. The progressive increase in biological complexity over geologic time is thus the consequence of the information-generating power of energy flow plus the information-accumulating capacity of DNA, winnowed by natural selection. Consequently, the most important component of the biological environment is energy flow: the availability of calories and their use for growth, survival, and reproduction. [4]
[1] A mitochondrial bioenergetic etiology of disease, 2013, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3614529/
[2] A Mitochondrial Paradigm of Metabolic and Degenerative Diseases, Aging, and Cancer: A Dawn for Evolutionary Medicine, 2005: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2821041/
[3] Mitochondria as Chi, 2008, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2429869/
[4] Bioenergetics, the origins of complexity, and the ascent of man, 2013, https://www.pnas.org/doi/full/10.1073/pnas.0914635107