If our website is MitoWorld, the Mechanisms of Mitochondrial DNA Mutation and Repair conference was the introductory gathering of what could be called “mtDNA World.”
The organizers, Patrick Chinnery (Cambridge), Agnel Sfeir (Sloan Kettering) and Michal Minczuk (Cambridge), emphasized that this conference focused solely on mtDNA is a first of its kind.
“This brand-new conference will focus on understanding how mitochondrial DNA mutations occur in the germ line and somatic tissues with age and how they contribute to common diseases, including neurodegeneration and cancer. The conference will also cover mitochondrial DNA’s molecular and cellular consequences and new approaches to repair and remove mutations.” [conference website]
The global mitochondria conference circuit generally is focused on mitochondria themselves (often in primary mitochondrial disease) in all their complexity with a smaller percentage of presentations on mtDNA itself. In Nashville, June 1–5, about 75 individuals representing labs globally, went deep into a range of heteroplasmy dynamics over lifetimes and in various disease and dysfunction cases. There was a sense of the importance of mtDNA and its relationship with the nuclear DNA as a primary and secondary driver of disease and dysfunction and also as part of the fundamental aging process.
“The result was an interactive meeting that highlighted the current multi-functional nature of mtDNA (beyond its known role in ATP production) and the cutting-edge new techniques and approaches now available to understand how mtDNA genes are expressed, how mtDNA mutations contribute to human physiology and pathology, and how we can now edit mtDNA or otherwise modulate this maternally inherited genome to improve human health,” said Gerry Shadel (Salk Institute).
The conference was very participatory and, since it was held in Nashville, ended with an evening of line dancing.
In the words of some of the organizers and attendees:
Agnel Sfeir, Organizer, Sloan Kettering
The meeting exceeded our expectations in every way. The quality of the science, the level of engagement, and the sense of community were truly exceptional. One of our goals was to create a space that fostered open discussion across disciplines and career stages, and I think we succeeded, which was evident by the engagement of trainees, the quality of their presentations, and the insightful questions they asked.
Dmitry Temiakov, Thomas Jefferson University
The conference’s exclusive focus on mitochondrial DNA was both timely and highly valuable for the scientific community. By concentrating on mtDNA, the meeting brought together researchers across diverse disciplines—from genetics and structural biology to clinical medicine—who might otherwise not engage in direct dialogue. This focused format fostered in-depth discussions on unresolved questions, including the mechanisms underlying mitochondrial diseases, maternal inheritance, and the role of mtDNA in inflammation and aging.
Maria Falkenberg, The Falkenberg Lab, University of Gothenburg
The meeting was a unique and refreshing experience, being the first to focus only on mtDNA. It gave space for interesting discussions that went all the way from basic science to possible new treatments. The talks covered many parts of mtDNA biology, from how it is maintained to how it can be targeted in disease. It was great to see the community come together around a topic that is often included in bigger meetings, but not usually the main focus.
Gerald Shadel, Salk Institute
Our genome comprises nuclear and mitochondrial DNA, both of which are essential for life and contribute to human diseases and aging. The biology and genetics of mtDNA is complex due to it being present in multiple (often thousands) copies/cell and its sequence dynamically changing in our bodies as we age. While there are many meetings on nucleic acids (DNA and RNA), genetics and even mitochondria, rarely is mtDNA a central theme. This FASEB meeting was therefore unique by focusing a lens on mtDNA and effectively bringing together many of the senior researchers who have long influenced our understanding of mtDNA with exciting new investigators in the field.
Carlos T. Moraes, University of Miami
It was right time for a meeting focused on my favorite genome (mtDNA). There have been so many advances in our understanding and manipulation of mtDNA in the last few years, and it was exhilarating to hear and discuss them with experts and colleagues. My recent area of work is mtDNA editing, and new techniques have opened a whole area of investigations and therapeutic development. As always, new knowledge raises many questions, so this meeting was a great forum to generate new ideas and how to overcome barriers, such as the off-target edits of mtDNA base editing.
Amutha Boominathan, MitoSENS
The conference provided a comprehensive overview of recent advances in mitochondrial DNA research, with a strong focus on its role in cellular function and pathology. A key highlight was the application of advanced sequencing technologies to resolve mitochondrial heteroplasmy at the single-cell level and to establish genotype-phenotype correlations. It brought together students and junior and established researchers, with particular emphasis on emerging topics, such as mitochondrial regulation of immune responses, novel metabolic functions, and targeted approaches to silence/modulate the mitochondrial genome. The meeting was highly interactive and engaging. Looking forward to the follow-up!
Olvia Conway, Duke University
This meeting was extremely valuable to me as a trainee because of the networking and learning opportunities available. My mtDNA project is a new area for the lab, so this meeting was a way to meet others focused on this topic, receive feedback on some of my early work, and determine in which direction the field is heading. I am grateful for the opportunity to talk to other scientists during the conference sessions, and I am planning on implementing many of the suggestions I received. This was my first meeting as a graduate student, and I had a great experience.
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]
Ana Andreazza, PhD, professor of pharmacology and toxicology at the University of Toronto’s Temerty Faculty of Medicine, leads the Mitochondrial Innovation Initiative, Mito2i, a research hub at University and affiliated institutions and hospitals.
The new project, MitoRevolution: Mitochondrial Transplantation Transforming Regenerative Medicine — from research to patient care to global impact, is part of the university’s
Institutional Strategic Initiative portfolio, is supported by a $23.8-million grant from the Canadian federal government’s New Frontiers in Research Fund Transformation Stream and brings together an interdisciplinary team that is committed to transforming regenerative medicine through mitochondrial transplantation.
Mitochondrial transplantation is defined as the process of introducing new mitochondria into cells, tissues or organs, and mitochondrial transfer is the natural movement of mitochondria between cells or into bodily fluids.
These processes are both controversial, and mitochondrial transplantation as a therapy is viewed with a considerable skepticism. Nevertheless, there is a growing interest in research into transplantation for emergency, resuscitation and regenerative purposes. Some cases have yielded positive results. However, those results cannot be attributed to an increase in mitochondrial capacity and function or to actions by the immune system or other reactions.
The infusion of federal funding in Canada to explore the wide-ranging question posed by mitochondrial transplantation marks the first nationally funded initiative of its kind.
Discussion with Dr. Andreazza
MitoWorld: There seems to be a real divergence in the thinking in the scientific community of whether transplantation is real in terms of transplanted mitochondria taking up their full functions once transplanted. How do you and the team answer those questions?
Andreazza: Indeed, this divergence is a major reason our team has come together under the NFRF-Transformation grant. Rather than assuming one mechanism over another, our approach is to systematically evaluate how transplanted mitochondria interact with host cells, whether by integrating functionally, or by initiating signaling pathways that support recovery or regeneration. Using innovative tools such as live imaging, mitochondrial tagging, and 3D tissue models, we aim to directly observe and measure mitochondrial behavior post-transplantation.
MitoWorld: On the other hand, there is the fear that the patient communities, especially those who have mitochondrial genetic diseases or are parents of children who do, will have their hopes falsely raised in the short term. How do you and your team counsel the mitochondrial patient community at this point?
Andreazza: We are deeply aware of the responsibility we have to the patient community. Transparency is central to our approach. While mitochondrial transplantation holds promise, we are careful not to frame it as a near-term therapeutic option for genetic mitochondrial diseases. Instead, we emphasize that this is an early-stage scientific endeavor with an initial potential for ex-vivo organ regeneration. We engage with patient groups regularly. In fact, the MitoCanada Foundation was part of the design of the project from the beginning, and it is now forming patient and communities committee that will oversee the project development. Most importantly, listening to concerns and co-developing knowledge translation strategies are central to ensure expectations remain grounded in the realities of where the science currently stands.
MitoWorld: Where do you and the cross-disciplinary and cross-institutional team hope to focus first, and what solutions or findings do you anticipate?
Andreazza: Our first focus is to establish the mechanism that underlies mitochondrial transplantation. Using 3D tissue and animal models, we hope to determine how mitochondria survive transfer, how long they persist in recipient cells, what cells uptake mitochondria, and what outcomes they influence. We’re particularly interested in ex-vivo organ regeneration for improvement of organ transplant. From this foundational science, we hope to develop tools that can guide future clinical applications, including standardized protocols and safety metrics.
MitoWorld: It would seem that Canada is the first national government to make an investment in mitochondria transplantation. What do you think motivated decision from a policy, scientific, and treatment perspective?
Andreazza: Canada’s investment reflects the country’s forward-looking research framework that embraces high-risk, high-reward strategies. It aims to elucidate the roles of mitochondria in health and in nearly every major disease with an opportunity to transform our understanding, and hopefully treatment strategies. In my view, these opportunities made this a compelling story for support under the NFRF’s Transformation Stream. Additionally, the interdisciplinary and community-driven nature of the project aligns well with Canada’s emphasis on collaboration and innovation.
In a recent paper published in Nature Communications, a research team led by Nick Jones at Imperial College London explored the relationship between mutations in mitochondrial DNA and aging. More specifically, they examined “cryptic mutations” that are somatic mtDNA mutations unique to single cells in the sample.
The team accessed publicly available sequencing of the nuclear and mtDNAs of 140,000 individual cells from four mammalian species and seven tissues. Both DNA types show increased numbers of mutations with aging. As assumed, the increase in nuclear DNA mutations was linear. However the mtDNA showed a nonlinearity. In fact, the number of mutant genomes in a cell reached high levels around the time when the effects of aging are seen in humans. Although these results are surprising, they are also consistent with previous studies that show that mice with more rapid rates of mtDNA mutation age more rapidly.
They also noted that the rise of mtDNA mutations correlates with key aging manifestations, such as protein misfolding, endoplasmic reticulum stress, and markers of neurodegeneration.
Conversation with Dr. Alistair Green and Prof. Nick Jones
MitoWorld: These are intriguing results. Others have suggested that infusions of healthy mitochondria into cells would have therapeutic benefits. Might they also slow the aging process?
Jones: This could be a fertile direction to pursue, though there is not much evidence that large amounts of mtDNA are transferred into cells.
MitoWorld: Mitochondria are associated with many key cellular functions, but they have genes for little more than energy production. Can you speculate on the mechanism that links these mutations to aging? Could it be as simple as the loss of ability to produce energy, or is there more?
Green: Loss of energy production is definitely the leading order concern, but there are other mechanisms that could be at work. Mito-nuclear mismatch has been known to impair function, and we see a stress response in cells carrying cryptic mutations. If mutant mtDNA is released into the cytoplasm this could also be causing this stress response.
MitoWorld: Your results seem to correlate with caloric restriction as a mechanism to slow aging. Interestingly, that would seem to lower available energy levels. Can you comment on that seeming contradiction?
Green – While severe caloric restriction can lower energy levels, the opposite is true for mild restriction. Mitochondria can become more efficient and crucially for our model, cells can switch on mitochondrial biogenesis, increasing the number of mitochondria in cells. This increase in copy number is what our model predicts would slow the ageing we observe.
MitoWorld: Could there be some “cryptic” signaling between the mtDNA and nuclear DNA to account for this correlation?
Jones: Trying to establish just what is causing the correlation is definitely the focus of future work. Some signaling between nuclear DNA and mitochondrial DNA is definitely one avenue of investigation.
MitoWorld: Did you find any particular mtDNA mutation that seemed to stand out or were they more or less equally distributed?
Green: They are fairly evenly distributed across the genome, excepting the known mutational hotspot by the origin of replication. The lack of selection we see would support that cells have a hard time identifying mutations in any particular region that they might be less tolerant to.
MitoWorld: What do you see as the next steps in this research?
Jones: We would like to corroborate these effects in more proliferative cell types.
MitoWorld: How did a mathematician become interested in mitochondria?
Jones: There are multiple copies of mtDNA in a cell and the fluctuations in that number, and the number of mutations they contain, is quantifiable and presents tricky mathematical challenges. Simultaneously the products of this single quantifiable entity have wide-reaching cell physiological effects: this is thus a setting where bringing together stochastic modelling, inference, informatics and experimental design can yield transformative insights.
MitoWorld: Another recent paper reports on mtDNA mutations and aging (Wang, Z., Li, Z., Liu, H. et al. Mitochondrial clonal mosaicism encodes a biphasic molecular clock of aging. Nat Aging (2025). https://doi.org/10.1038/s43587-025-00890-6). Do you have any thoughts on that paper?
Jones: This recent interesting paper is based on using bulk-RNA seq — our paper first appeared on bioRxiv two years ago and is focused on single cells and thus gives a direct insight on the process at hand.
Reference
Green AP, Klimm F, Marshall AS, Leetmaa R, Aryaman J, Gomez-Duran A, Chinnery PF, Jones NS (2025) Cryptic mitochondrial DNA mutations coincide with mid-late life and are pathophysiologically informative in single cells across tissues and species. Nat Commun 16: 2250. https://doi.org/10.1038/s41467-025-57286-8
In a paper in Nature Communications, a multi-institution research team, led by Phillip West at The Jackson Laboratory, describes hyperactivity of the innate immune system in models of polymerase gamma (PolG)-related mitochondrial disease (VanPortfliet et al., 2025). This work advances understanding of how mitochondrial diseases impact the immune system and identifies potential therapeutic targets to limit immunopathology and other infection-associated complications.
Mitochondrial diseases (MtDs) are the most common inborn errors of metabolism. Although patients with MtD do not appear to have more viral and bacterial infections than others, emerging research suggests infections can result in more severe outcomes, including sepsis and death. The relationship of MtDs and inflammation has therefore become a topic of considerable interest in the research community. Mitochondrial dysfunction can activate the innate immune system, which responds with inflammation that, when unregulated, further damages mitochondrial activity.
In their paper, West’s team delved further into this problem. More specifically, they examined two mouse models that carry deleterious mutations in the PolG gene (PolgD257A and PolgR292C). They found that these mutations, which impact mitochondrial DNA (mtDNA) stability, result in chronic activation of the type I interferon (IFN-I) pathway in immune cells and tissues. Furthermore, they uncovered that IFN-I hyperactivates another immune sensor called caspase-11, which senses bacterial cell wall components and promotes inflammatory cell death in macrophages. This form of cell death, called pyroptosis, is critical for control of bacterial infections, but must be tightly regulated because it promotes the release of cytokines and other factors that lead to a strong inflammatory response. When innate immune cells from the PolG mutant mice were infected with bacteria, they underwent pyroptosis much more readily and caused a dramatic increase in inflammatory responses. This overactive innate immune response was also seen when PolG mutant mice were infected with bacteria.
Although these PolG mutant mice do not recapitulate all aspects of PolG-related MtDs, chronic activation of the innate immune system, increased inflammatory responses, and other symptoms are seen in MtDs in humans. Thus, this experimental system is an excellent model for studying innate immunity in MtDs.
A Conversation with Dr. West
MitoWorld: What caused you to become interested in mitochondria and MtDs?
West: I have been studying the interplay between mitochondria and the innate immune system since my PhD training at Yale. I somewhat stumbled into mitochondrial biology during my thesis research, but have been fascinated by these organelles ever since. As a postdoctoral fellow with Gerry Shadel, I found that mtDNA release is a potent trigger of interferon and inflammatory responses. As all of our early work was in cells, I wanted to translate our findings into animal models when I opened my own lab. We hypothesized that because MtDs have dysfunctional mitochondria and often exhibit mtDNA instability, there may be an unappreciated role for immune dysfunction in these diseases. We are addressing this hypothesis in mouse models of MtD, including the PolG mutants used in this paper, but are also striving to translate our results into understanding immune dysfunction in human MtDs.
MitoWorld: Under normal circumstances, the immune system is carefully regulated. Too little control is thought to allow cancers to grow. Too much results in autoimmune diseases. MtDs are yet another source of immune dysregulation. Do you have ideas about how to follow up your work in humans?
West: We are working collaboratively with Dr. Peter McGuire’s group at the NIH/NHGRI, who are also studying in immune dysregulation in MtDs. We were fortunate to be included on Peter’s recent study (Warren et al., 2023) that revealed interferon and inflammatory gene signatures in the white blood cells of patients with diverse MtDs. There was significant overlap in the immune signatures seen in patient cells and two of our mitochondria mutant mice, so we do feel our animal studies correlate with human data. Our goal now is to identify immunotherapeutics that may be used to restore proper immune function and limit infection-related complications in individuals with MtDs.
MitoWorld: It’s interesting that MtD patients are more susceptible to infections and have an enhanced innate immune response. During the Covid pandemic, any vaccination was thought to activate the innate immune system and protect (to a degree) against coronavirus infection. Is the MtD case, just another example of the immune system gone awry?
West: This is an interesting question. I think it is important to highlight that the immune phenotypes in MtDs will probably be diverse and not manifest in exactly the same ways. For example, those with Barth syndrome often have neutropenia, or to few neutrophils, and are susceptible to bacterial infections. In addition, Dr. Anu Suomalainen-Wartiovaara’s group recently reported reduced antiviral responses in patient samples and mice carrying the PolG MIRAS allele, suggesting that there may be dramatic differences in immune phenotypes even within PolG-related MtDs (Kang et al., 2024). Other MtDs may cause hyperactive innate immunity, whereas some may lead to problems with adaptive immunity (i.e., antibodies and T cells). We are early in these studies, and MtDs are rare diseases, making it often difficult to obtain large patient cohorts for study. However, we can rapidly advance the field by generating new, more relevant animal models of MtD and coupling these findings with data from human studies.
MitoWorld: MtDs manifest at different ages. Do you have any ideas about what might activate the immune system in an MtD?
West: We hypothesize that mitochondrial dysfunction in MtDs basally alters the tone of immune cells. This is likely due to small amounts of cytokines and other stimulatory factors being released constitutively. For example, we showed that the aberrant release of mtDNA and other nucleic acids triggers the innate immune system in the absence of infection. Metabolic alterations in MtDs can also profoundly impact immune cell development and function. In the context of infection, innate immune cells, such as macrophages, may mount an overactive response, and this can feed forward to damage mitochondria and trigger subsequent rounds of mtDNA release or elevate metabolic crisis.
MitoWorld: So many of the former mitochondrial genes are now part of the host genome. Could mutations in those genes cause similar problems in mitochondria?
West: Most of my lab’s work has focused on examining innate immune responses in mouse models where nuclear-encoded mitochondrial genes are missing or mutated. However, others are examining immune responses in patients and animal models with particular disease-relevant mtDNA mutations. For example, Dr. Martin Picard has shown that cells from patients carrying a single, large-scale mtDNA deletion have blunted inflammatory cytokine responses (Karen et al., 2022). In contrast, a mouse model carrying a heteroplasmic mtDNA mutation (m.5019A>G) mirroring that seen in humans exhibit a hyperinflammatory immune status characterized by elevated interferon (Marques et al., 2025). Therefore, mutations in nuclear and mtDNA encoded mitochondrial genes can impact the immune system.
MitoWorld: How do you plan to extend this research?
West: My lab and colleagues at JAX are working to expand the toolkit of mouse models for MtDs, and we are excited to send our new models into labs around the globe. I am quite hopeful that MitoWorld, the UMDF, the PolG Foundation, and other advocacy groups will better unite researchers examining immunological issues in animal models and patients with MtDs.
* Two hours after infection, macrophages were stained with antibodies and dyes to mark the cell membrane (white), mitochondria (green), the nucleus (blue), and Pseudomonas bacteria (magenta). Cells were then imaged on a confocal microscope. The macrophage at the bottom right is undergoing pyroptosis, an inflammatory cell death pathway resulting in nuclear condensation, membrane permeabilization, loss of mitochondria, and release of cytokines.
References
Kang Y, Hepojoki J, Sartori Maldonado R et al. (2024) Ancestral allele of DNA polymerase gamma modifies antiviral tolerance. Nature 628: 844–853.
Karan KR, Trumpff C, Cross M, Engelstad KM, Marsland AL, McGuire PJ, Hirano M, Picard M (2022) Leukocyte cytokine responses in adult patients with mitochondrial DNA defects. J Mol Med (Berl) 100: 963–971.
https://pmc.ncbi.nlm.nih.gov/articles/PMC9885136/ (PubMed Central)
https://link.springer.com/article/10.1007/s00109-022-02206-2 (behind paywall)
Marques E, Burr SP, Casey AM, Stopforth RJ, Yu CS, Turner K, Wolf DM, Dilucca M, Tyrrell VJ, Kramer R, Kanse YM. An inherited mtDNA mutation remodels inflammatory cytokine responses in macrophages and in vivo. bioRxiv 2025 Jan 5:2025-01.
https://www.biorxiv.org/content/10.1101/2025.01.05.631298v1
VanPortfliet JJ, Lei Y, Ramanathan M, Guerra Martinez C, Wong J, Stodola TJ, Hoffmann BR, Pflug K, Sitcheran R, Kneeland SC, Murray SA, McGuire PJ, Cannon CL, West AP (2025) Caspase-11 drives macrophage hyperinflammation in models of Polg-related mitochondrial disease. Nat Commun 16: 4640.
https://doi.org/10.1038/s41467-025-59907-8
Warren EB, Gordon-Lipkin EM, Cheung F et al. (2023) Inflammatory and interferon gene expression signatures in patients with mitochondrial disease. J Transl Med 21: 331. https://doi.org/10.1186/s12967-023-04180-w
The UMDF Mitochondrial Medicine for Scientists and Clinicians Mitochondrial Medicine 2025 conference provides an international stage for leaders in mitochondrial medicine and offers programs to inspire the next generation of researchers. Attendees will learn about the latest developments in the field of mitochondrial medicine, including industry advancements, potential treatments, therapies and cutting-edge research. The event also gives the scientific communities the unique experience of engaging with affected patients to better understand symptoms and work faster towards a cure. This year’s conference is being held in St. Louis, Missouri on June 18-21, 2025. https://www.umdfconference.org/
Jonathan Brestoff, MD, PhD, MPH, leads the Brestoff Lab and is Associate Professor of Pathology & Immunology, Director of the Initiative for Immunometabolism, and Medical Director in the BJH Clinical Flow Cytometry Lab at WashU Medicine in St. Louis.
We asked Jon to explain a bit about this his work and what is being organized from the scientific and medical community at UMDF 2025.
MitoWorld: Jon, how did you become involved with the UMDF Clinical & Scientific Program?
Brestoff: My lab has been working on trying to develop mitochondria transplantation as a new therapy for primary mitochondrial diseases, and this work has gotten me engaged with the UMDF. With the meeting being in St. Louis, they sought a local presence on the organizing committee. I’m very honored to help with this meeting and think it will be very exciting!
MitoWorld: What can researchers and clinicians expect from this year’s program?
Brestoff: This conference includes an amazing lineup of speakers on diverse scientific topics on mitochondrial biology and clinical issues in mitochondrial medicine. Main scientific sessions include Inflammation and Metabolic Diseases, Mitochondria on the Move, Mechanisms of Clearing Damaged Mitochondria, and Multi-omics. Clinical sessions include the NAMDAC Registry Session, Mitochondrial Medicine Society Platform, and Clinical Trial Updates. On Saturday, there are 2 parallel Master Classes, one on emerging clinical topics chaired by Dr. Michio Hirano and one on scientific career development chaired by me.
MitoWorld: Is there any particular theme or emphasis this year?
Brestoff: The main themes are around emerging scientific discoveries about mitochondria and clinical updates. One of the most exciting aspects of this meeting is that patients, families, clinicians, and scientists all come together for one conference. This creates a unique experience that, in my experience, has been incredibly motivating and inspiring.
MitoWorld: With your lab at Washington University in St. Louis, will you be discussing or your lab members presenting on your lab’s work?
Brestoff: Yes! While I am not speaking to yield time to other investigators, a couple exceptionally talented scientists from my group are presenting their work on mitochondria transfer and transplantation.
MitoWorld: What are your hopes in your work for the next year and what issues are on the forefront that may materialize over the next year?
Brestoff: There are so many new and exciting discoveries about mitochondria — how they work, what they do, and how we can leverage their biology to develop new therapeutics. There is tremendous untapped potential in this field for many diseases, not just primary mitochondrial diseases but also others like obesity, heart disease, and even aging. I hope we can find ways to team up with each other, industry partners, and investors to make some of these new therapeutics a reality for patients who need them. For my own lab, we’re currently working to make mitochondria transplantation a future possibility for patients with primary mitochondrial diseases. I hope we can get there.
In a review paper in Endocrine Reviews, Rachel Varughese and Shamima Rahman of University College London describe the effects of primary mitochondrial disease on the endocrine system and how these diseases can be diagnosed and treated.
Mitochondria provide the energy for the production and export of many cellular products. Mutations that affect mitochondrial function can disrupt the production of key molecules, including endocrine hormones. The result might be diabetes, growth hormone deficiency, adrenal insufficiency, hypogonadism, and parathyroid dysfunction. In fact, the authors suggest that the possibility of underlying mitochondrial dysfunction should be considered in all hormonal diseases. Thus, understanding how the mitochondria are involved in those diseases is critical.
Primary mitochondrial disorders (PMDs) are genetic disorders that affect the structure or function of the mitochondria. Because mitochondria are so intimately involved with multiple cellular functions, mitochondrial mutations can manifest in many disorders. The mutation can occur in either the nuclear or mitochondrial genome.
Varughese and Rahman provide an extensive review of how mitochondria can be damaged and of the diseases that can result. They conclude by noting that clinicians should be suspicious of a PMD for any patient who has an atypical presentation or seemingly unrelated comorbidities. The treatment of PMDs can be complex and quite different than the “normal” treatment for a particular endocrine manifestation.
A conversation with Rahman and Varughese
MitoWorld: Since there is no cure for PMDs right now, are clinicians left with treating the symptoms?
Rahman: Yes, symptomatic management is the mainstay of managing PMDs at present. This means being vigilant and monitoring for known complications of the disease and acting promptly with symptomatic measures when these complications arise.
MitoWorld: You seem to be suggesting that clinicians should be aware of multiple, possible unusual combinations of symptoms that might indicate a PMD. Are there key diseases other than diabetes that should raise suspicion?
Rahman. Table 6 in our paper gives several examples of combinations of symptoms that should arouse suspicion of an underlying PMD. For example, the combination of adrenal insufficiency or growth hormone deficiency with progressive external ophthalmoplegia, pigmentary retinopathy and heart block should alert the clinician to the possibility of Kearns-Sayre syndrome, while the combination of premature ovarian insufficiency and sensorineural hearing loss is suspicious of Perrault syndrome.
MitoWorld: What are the most promising treatments that you are aware of?
Rahman: Unfortunately, there are no disease-modifying therapies that are licensed for PMDs. Many treatments are in development at the preclinical stages, including pharmacological and genetic approaches. Currently, genetic approaches seem more promising as strategies to provide personalized tailored curative treatments, but are not yet available for PMDs, with the exception of Leber Hereditary Optic Neuropathy.
MitoWorld: What interested you in mitochondrial in the first place?
Rahman: I first began caring for patients with mitochondrial diseases as a junior doctor (paediatric trainee) in the early 1990s. Deeply moved by the challenges faced by affected patients and their families, I have devoted my career to improving the diagnosis and management of these conditions.
Varughese: I am a paediatric endocrinologist. As a paediatrician, I was drawn to endocrinology by the opportunity to make lasting impacts on children’s growth and development through targeted, evidence-based care. My interest in mitochondrial disease emerged from seeing its intricate interplay with multiple organ systems, including endocrine function. Writing this article was a way to bridge both interests, aiming to improve both early recognition of endocrine issues in affected children and the identification of underlying mitochondrial disease in patients with atypical constellations of symptoms.
Reference
Varughese R, Rahman S (2025) Endocrine dysfunction in primary mitochondrial diseases. Endocrine Reviews 46: 376–396.
The special issue of Journal of Cell Science (JCS) on the “Cell Biology of Mitochondria” looks to be one of the most comprehensive open series of papers, opinions, perspectives, interviews, reviews and posters on the subject of mitochondria biology, perhaps ever.
This incredibly in-depth examination of mitochondria covers the subject in research, interviews and commentary and does so in what can only be described as a community spirit from the Journal of Cell Science (JCS) a publication of the Company of Biologists, which is “dedicated to supporting and inspiring the biological community.”
A Good Place to Start [Editorial]
The Cell Biology of Mitochondria Special Issue is a collaboration led by Ana J. Garcia-Saez, Max Planck Institute of Biophysics and Heidi McBride, Department of Neurology and Neurosurgery McGill University, guided by Cell Biology Executive Editor Seema Grewal, who has a deep publishing and research biology background. McBride is also a member of the MitoWorld Scientific Advisory Board (SAB).
MitoWorld was so impressed with this collection, enough reading for a month, that the questions arose of how does such an issue come together and how does it stand to help the mitochondrial research world as the subject becomes more popular. To get a sense of this, Executive Editor Seema Grewal answered a few questions.
MitoWorld: What prompted the special issue?
Grewal: JCS has a long and rich history of publishing papers in the field of mitochondrial cell biology; indeed, some of the early papers examining the factors that contribute to mitochondrial fusion and fission were published in JCS. We wanted to remind the community about this, so what better way to do this than to coordinate a special issue on the topic.
MitoWorld: This was a huge undertaking, how did this get going and how long has it taken?
Grewal: We started discussing the idea at the journal’s annual gathering of editors back in February 2024. Heidi and Ana are on the journal’s Editorial Advisory Board and are experts in the field, so the team felt that they would be well-placed to serve as Guest Editors for the issue. After some discussion with them, we decided on the aim, scope and timeline for the special issue. We put out a call for papers in the Spring of 2024 and had an encouraging response from the community, resulting in lots of research articles being submitted for consideration in the special issue. In parallel, we also identified and invited experts from across the field to contribute review-type articles.
MitoWorld: Can you talk about the Journal and its mission and how you are able to put together projects at this scale.
Grewal: JCS prides itself in being a community journal that is published by a not-for-profit publisher (The Company of Biologists) that exists to benefit scientists not shareholders. Coordinating a special issue is hard work, but we’re fortunate to have an in-house team that can support Guest Editors in coordinating the issue, so that they can focus on the science. This team works closely with the Guest Editors to ensure the smooth and efficient handling of articles.
MitoWorld: What do you hope comes from such a publication? Who should be reading this issue?
Grewal: We’re hoping that the issue will inspire the community and stimulate debate and discussion. It contains a range of research and technical articles that showcase the advances in the field. It also contains some in-depth reviews that synthesize the latest findings. We’ve also included some perspective and opinion articles that challenge our view of mitochondria. Finally, we strongly believe that it’s important to highlight the scientists that actually do the work, so the issue includes some interviews with researchers at different career stages. We’re hoping there’s something in the issue for everyone. It’s also worth pointing out that, thanks to our ‘Forest of Biologists’ initiative, we planted 24 trees to represent the 24 peer-reviewed articles published in the issue, so that’s another really positive outcome!
MitoWorld: There is so much material, do you have suggestions on what busy people should concentrate on or how to best use the whole resource.
Grewal: The Opinion piece is a good place to start, as it provides an over-arching view of mitochondria. After that, we suggest that people just bookmark the full table of contents and dip in and out of any reviews or research articles that appeal to them
MitoWorld: What do you hope the take-aways are for the serious reader of this special issue?
Grewal: That we’ve made lots of progress, largely thanks to new technologies…but there’s still so much to learn!
Columbia University mitochondria researcher Martin Picard’s life changed in 2014 when he peered through a microscope in Douglas Wallace’s lab at the Children’s Hospital Philadelphia. He saw something that didn’t fit the textbook “powerhouse of the cell” picture. Mitochondria are tiny elongated and sometimes spherical energy-producing organelles. While many times thinner in diameter than a human hair, hundreds to thousands of mitochondria populate the interior of each human cell.
After 20 years of wonder, Picard’s personal and professional journey was picked up by Scientific American, which has just published his article, The Social Lives of Mitochondria: When These Energy-Giving Organelles Thrive, So Do We (Scientific American June 2025). The online version of the print article, viewed here, is entitled Mitochondria Are More Than Powerhouses—They’re the Motherboard of the Cell.
Picard writes, “Under the high-power microscope, mitochondria have many tiny generally horizontal “baffles”, called cristae, the site of ATP production, the cellular energy currency. Energy transformation within cristae involves the stripping of electrons from food and allows them to flow onto the oxygen we breathe”.
With hundreds to thousands of mitochondria bunched together, it is hard to know if they are acting in concert or as random lone operators. What Picard saw through the microscope, featured here and below was the alignment of the cristae between mitochondria. “The first physical evidence of non-molecular information exchange between mitochondria,” says Picard.
https://www.nature.com/articles/ncomms7259/figures/3
Since then, Picard and others have probed this mitochondrial behavior to the point that it appears mitochondria are operating communally or failing to do so. Different organs, researchers have found, have different types of mitochondria. “Mitochondria have a bacterial origin in evolution, and there is ample evidence from bacteria today that they do what is called “quorum sensing” where they signal and align to perform tasks a single bacterium or mitochondrion could not accomplish on its own,” Picard explains.
For more background and context, MitoWorld talked with Picard:
MitoWorld: Can you show us any microscopy or artistic renditions or video that shows the “social” nature of mitochondria?
Picard: The best video is this. Also this video showing cristae align between mitos changed my life. This picture shows mitochondria networking.
MitoWorld: What led to your thoughts about the social nature of mitochondria?
Picard: Everything in biology has somewhat of an interactive nature to it. And across the universe, everything is interconnected, from electrostatically attracted protons and electrons within atoms, to attracted social human beings, to planets attracted to each other by gravitational forces. Why would our biology be different? And could there be some kind of “social” behavior deep within our cells that led to our organs, bodies, and to our mind to becoming “social”. And it could have started with the endosymbiosis of mitochondria.
MitoWorld: Has this been on your mind for a while, how did you begin to verify the social conjecture?
Picard: Early work by David Chan on mitochondrial fusion. In 2012 I wrote a piece called “Mitochondria: Starving to Reach Quorum” that touched on their “social” nature, like bacteria that talk to each other to do “quorum sensing” and increase their virulence. Then in 2014, I saw cristae alignment between mitochondria. Since then, many labs have observed that, if you prevent mito-mito interactions (disrupt their social interactions), they go bad, as do the cells that house them too. My neuroscientist colleague Carmen Sandi and I detailed this in a paper in 2021.
MitoWorld: Help readers understand how important mitochondria are to the life of cells.
Picard: Without mitochondria, we would not exist. When they appeared in evolution, the result of a merger. This was the click—the beginning of a new phase of life. Somehow their presence allowed a type of multicellular life that wasn’t possible before. My hunch is that mitochondria provided the ability to process information: they made cells smarter and elevated their “social” behavior to a next level. With this, cells could come together into larger collectives, hold larger goals, and grow organisms that behave, think, and feel. This may all have been possible because the Mitochondrial Information Processing System (MIPS) became the “brain” of the cell.
MitoWorld: What are the behaviors of mitochondria that are “social”?
Picard: Mitochondria 1) communicate with each other and other organelles, 2) exhibit group formation, 3) are interdependent, 4) synchronize their behaviors, and 5) functionally specialize to accomplish specific functions.
MitoWorld: What are the health, medical and research avenues that open as a result of the mounting evidence of the social nature of mitochondria?
Picard: I think it’s time to see ourselves energetically. We are not just molecular machines. That mechanical, somewhat static view has been propagated for too long without seeing the wider energetic context. Understanding the “social” layer of biological organization makes it clear that there are biological processes and forces, including “goals” that cells and organisms have, that aren’t just the product of cogwheels. For example, the healing process is a completely untapped area of medicine and science that needs attention. I would suggest that, alongside our mitochondrial research, we need Healing Science, a new area of science that will map out how we manage to heal, every day. Charting this new territory of health and healing science has to be grounded in first principles. The interconnectedness of our biology, together with our fundamental energetic nature, are those first principles. Realizing that mitochondria are “social” is a step towards a more accurate view of how life works, and of what keeps us healthy day after day.
Next-generation sequencing has become the method of choice diagnosing diseases and risks, but the size difference between the nuclear and mitochondrial genomes complicates its value for mitochondrial diseases. A new study led by Rita Horváth at the University of Cambridge offers new hope for this technology.
Mitochondrial diseases affect about 1 in 4,300 people. Unfortunately, they have different manifestations at different times in development. They also overlap with other common diseases. Finally, there are only a limited number of biomarkers for blood samples.
The Horváth laboratory developed the MitoPhen database that includes genotype-phenotype information and mitochondria (mt)DNA variant levels in blood and tissues from published reports. They test MitoPhen for its ability to determine phenotype similarity scores for patients with mitochondrial diseases and then in a large European Solve-RD rare disease cohort. They then used those data to develop a workflow to identify mtDNA variants using MToolBox and annotated them with the MITOMAP database.
Using these data-management tools, the team was able to identify additional patients with mtDNA mutations. Other methods leave significant uncertainty. The workflow developed here allows analysis of DNA samples for possible mtDNA-based diseases to reveal rare mitochondrial diseases in patients not suspected of those diseases. Thus, the workflow and analysis provide another tool for diagnosing these rare disorders.
Reference
Ratnaike T, Paramonov I, Olimpio C, Hoischen A, Beltran S, Matalonga L, Solve-RD Consortium, Horváth R (2025) Mitochondrial DNA disease discovery through evaluation of genotype and phenotype data: The Solve-RD experience. Am J Hum Genet https://www.cell.com/ajhg/fulltext/S0002-9297(25)00144-2?rss=yes.
A discussion with Dr. Horváth:
What are the likely next steps in your research?
Thiloka: It will be really interesting to expand this phenotype-based prioritisation techniques to other primary mitochondrial diseases, and we have indeed compiled a large manually curated updated version of MitoPhen for this purpose. We are now looking at nuclear genes that cause mitochondrial diseases to see whether we can highlight patients with phenotypes that are suggestive of mitochondrial diseases, to prioritise known or novel variants for further evaluation.
You found a deceptively small additional number (0.4%) of patients where no disease was expected. Of course, that number spread across a large population would become a big number. Do you think it will expand interest in mitochondrial diseases?
Thiloka: Absolutely! Mitochondrial diseases are known to affect in 1 in 4300 individuals, so this group of conditions is one of the largest in the field of inherited metabolic conditions. Being able to confidently diagnose individuals affected by these conditions mean that our pool of families to invite for potential therapeutic strategies or clinical trials will grow, enabling advancements in this challenging field.
As you noted, there is overlap with some diseases (e.g., diabetes). Will your technique help to parse the different diseases?
Thiloka: Great point. We believe this technique can help understand contribution of the variant to the clinical features. For example, in our study, we diagnosed individuals with sensorineural hearing loss with mitochondrial DNA variants that cause this presentation, however, there was one individual where the mitochondrial DNA variant didn’t fully explain the phenotype which consisted of several more features than just sensorineural hearing impairment. That is important to know as well because we are increasingly finding dual genetic diagnoses in this era of genetic testing. We can only try to achieve this level of phenotypic certainty by adding to existing genotype-phenotype databases with curated data at the individual level.
Can your workflow be “translated” so that it can be transitioned into the clinic? What would that take?
Thiloka: I am aiming to a tool which could be used in the clinical setting to understand the probability of a person having a primary mitochondrial disease based on their clinical features. A tool such as this could be helpful in utilizing resources effectively to prioritise advanced genetic testing for individuals with a high likelihood of this diagnosis. However, to get to this stage we would need to have a comprehensive resource that has compiled individual level data on primary mitochondrial diseases and have been tested in the setting of individuals with other genetic conditions (non-mitochondrial). We are trying to achieve this currently with our updated MitoPhen database that now contains data on 117 genotypes of primary mitochondrial diseases, and we are testing the utility of this dataset in large datasets including the 100,000 Genomes Project and RD-Connect. The unexplored situation is that of ‘real world’ clinical data extracted from electronic health records, which is likely to contain more ‘noise’ in the sense of phenotypic features which may not be relevant to mitochondrial disease, but is very much the next major step to take in this research.
How did you first become interested in mitochondria?
Thiloka: I became interested in mitochondria because I wanted to understand the processes behind what caused my cousin’s fatal degenerative condition, known as Kearns-Sayre Syndrome (a primary mitochondrial disease). I undertook my PhD at Newcastle University where I worked on understanding what we could learn from muscle biopsy findings from patients, to explain disease progression in different primary mitochondrial diseases, but also how muscle mitochondrial function changes with exercise. Since the PhD, I have remained committed to trying to streamline the diagnostic process for families because I realized we could better use the clinical record to inform their disease profile. It has been challenging trying to juggle this with clinical and family commitments, while I train to become a Paediatric Neurologist, but keeping in close contact with the amazing Lily Foundation maintains my motivation and desire to help add to this scientific domain!