Navdeep “Nav” 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 Nav’s lab, and especially his intellectual leadership, has been transformational for the field,” says Gerry Shadel, of the Salk Institute. “Nav 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.
“Nav 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. “Nav 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 Nav 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 Nav for MitoWorld’s “Spotlight” section of the MitoWorld website.
About Navdeep S. Chandel, PhD:
Navdeep S. Chandel, PhD (Nav) 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.
We were honored to hold an interactive session on the work of www.mitoworld.org at the CELL: Multifaceted Mitochondria Symposium in Sitges, Spain, October 27-29.
Three members of the MitoWorld scientific advisory board (Gerry Shadel, Salk Institute for Biological Studies, Mike Murphy, University of Cambridge Mitochondrial Biology Unit, and Heidi McBride, McGill University and I spoke about MitoWorld’s efforts to “mainstream” mitochondria for the public and to the medical sector, pushing also toward a more encompassing mitochondrial science, and beginning a mitochondrial informatics effort.
As a new organization, we were able to hear from the attendees on what they felt was necessary to help the mitochondrial field get more attention and to communicate how essential mitochondria are to health, disease mitigation and solving complex issues from childhood mitochondrial mutation diseases to the issues of aging and age-related diseases, many of which are without therapies.
Symposium attendance was over four hundred mitochondrial researchers from around the world with strong representation from the U.S., UK, Australia, China, Korea, Finland, Germany, Spain and Italy among others. It was also a powerful venue for the interaction between senior researchers and postdocs coming into their positions into the field which is now growing.
Attendees shared with our panel that the public and professional dialog needs to be widened globally. There was an interest in participation with MitoWorld from many of the labs.
The panel invited comments on MitoWorld’s interest in building task forces in various arenas of mitochondrial research mapped to medical practice areas and well-known research subjects. While the task forces idea was well received, the most interest was in finding ways to educate or inform doctors and the medical profession about mitochondria in specific practice areas.
In this case, mitochondria are like the hidden hand in physiology that is not often considered in diagnoses or treatment.
Additionally, there was a sense that the subject of mitochondrial research and eventual practice has to be seen as “across the lifespan,” that mitochondria are ubiquitous and consequential at every stage while, at present, the practice areas are the mutation diseases of early life and the complications of mitochondrial decline in the diseases of aging.
The subject of education, starting in school and college and in medical training, came up several times as a way to anchor mitochondria in culture and eventually in practice. It should be noted that MitoWorld is a project of the R & D nonprofit National Laboratory for Education Transformation, www.NLET.org in California.
We hope the momentum from the Symposium will help build MitoWorld globally.
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
Mitochondria World is the first step in a process to set up a collaborative and informative mitochondria portal that is designed to service three primary communities: a) patients and clinics through listings and referrals, b) researchers, investigators, labs and institutes to manage a flow of up-to-date research, build working groups and communicate about issues in a single place, and c) to inform and build awareness in the public and among professionals about the significance of mitochondrial research for translation into treatments for diseases and conditions across the entire lifespan, including issues of personal and global health.
Together, as MitoWorld expands, we hope to influence the levels of funding and support for research, collaborations and dialogue beyond seeing mitochondria only through the lens of their individual functions, which has not led to success in developing new drugs for mitochondrial diseases.
By widening awareness and collaborations, we hope we can stimulate more investment for broad-based mitochondrial research to support the difficult path to successful therapies for primary mitochondrial diseases as well other secondary mitochondrial dysfunctions observed in the mostly terminal diseases of aging – cancer, diabetes, neurodegenerative diseases, autoimmune problems and many more.
To further our collaborative mitochondria work, we partner with investigators, institutes and labs across the globe: our mission is to expand our reach as far as possible. We support, publicize, and participate in conferences and symposia like the Cell: Multifaceted Mitochondria Symposium in Spain at the end of October. We schedule lab visits to expand our understanding and coverage of labs and institutes, promoting their work as well. Recent visits to Douglas Wallace’s Lab at Children’s Hospital Philadelphia and at Jared Rutter’s Lab at University of Utah were instructive and we plan to meet with several more investigators by the end of the year.
Critically, our work does not stop at creating awareness and sharing information. As part of an active and still-evolving cellular symbiosis, we believe much is to be learned about how mitochondria regulate health and contribute to many yet untreatable diseases and conditions. A key aspect of our mission is to support leaders in the scientific and medical communities to drive technical advances in mitochondrial biology and medicine. The Scientific Advisory Board of MitoWorld and its staff firmly believe that the time has come to define and name a mitochondrial science and informatics effort that elevates mitochondria from single investigations into categories of research that feed into a general understanding of the basic science of mitochondrial dynamics, systems and complex interactions.
We are open to engaging, presenting and collaborating on both the mitochondrial awareness and basic science fronts. We invite your involvement in our efforts to “mainstream” mitochondria with the public, patient groups, medical practice and across the various research communities to support our collective mission to stimulate more investment and involvement into a broader understanding of the trillions of mitochondria in each of us.