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
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.
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!
The laboratory of Dr. Jennifer Trowbridge at The Jackson Laboratory published a paper that describes how a genetic mutation that alters the function of mitochondria may provide a target for slowing aging.
Blood cells routinely wear out and must be replaced. Hematopoietic stem and progenitor cells (HSPCs) are critical to maintaining an adequate supply of mature blood cells. During aging, these long-lived stem and progenitor cells tend to accrue somatic mutations that give them a selective advantage. This condition is clonal hematopoiesis (CH). Most humans develop detectable CH by the age of 60, and this contributes to serious health conditions that occur during aging.
The Trowbridge team examined a mutation in the gene for DNA methyltransferase (DNMT3A) that is commonly associated with CH in humans. The team tested a mouse model that they engineered to carry the Dnmt3a mutation. They found that HSPCs from mice with the mutation had higher levels of mitochondrial activity than the same cells in wild-type mice. This was a surprising result since Dnmt3a had never been associated with mitochondrial function.
They found that molecules that disrupt the enhanced mitochondrial function in mutant cells, such as MitoQ and d-TPP, reduced CH in mice and in human cells. This was also true when using metformin, which impacts mitochondrial metabolism and is commonly used to treat type 2 diabetes. This work enhances knowledge of how blood stem cells contribute to aging and may provide a new therapeutic strategy for treating age-associated diseases, such as cancer, diabetes, and heart disease.
Reference
Young KA, Hosseini M, Mistry JJ, et al. (2025) Elevated mitochondrial membrane potential is a therapeutic vulnerability in Dnmt3a-mutant clonal hematopoiesis. Nat Commun 16: 3306. https://doi.org/10.1038/s41467-025-57238-2
Mito-World talks to Dr. Trowbridge
The metformin result is especially interesting since it is already widely used. Do you think it will become a treatment?
Indeed, the results with metformin were very exciting and provocative. While we have shown this to be effective over the short term in mouse models and in human cells in a dish, more studies are needed in human patients to determine whether there is long-term benefit to metformin. If metformin turns out not to be the best option, the good news is that our work has identified other molecules and drugs that target mitochondrial metabolism that could also be tested for efficacy.
Can you speculate on the mechanism behind this connection? You suggest involvement of DNA hypomethylation and increased gene expression of the electron transport chain and respiratory supercomplex formation.
It appears that hematopoietic stem and progenitor cells that carry somatic mutations that provide them with a selective advantage with aging do so, at least in part, through enhancing mitochondrial metabolism. In our study, we observed a connection between DNA hypomethylation and production of the molecules that drive mitochondrial metabolism. However, other somatic mutations that cause CH also enhance mitochondrial metabolism through what are likely different mechanisms. This may represent an example of ‘convergent evolution’ where the mechanisms may differ but the end result—enhanced mitochondrial function—is the same.
Do you plan to follow up the Phase II clinical studies with the various compounds? Of course, metformin, tamoxifen, and diclofenac are already safe in humans.
We are actively collaborating with clinicians that are doing prospective controlled studies to assess CH in individuals receiving metformin over time. In addition, we are pursuing collaborations to assess CH in ongoing placebo-controlled trials where aged individuals are receiving MitoQ for other indications.
The connection to hematopoiesis is clear, but a connection to other diseases (e.g., cancer, diabetes) is less so. Any thoughts?
The connection between CH and risk of diseases, such as cancer and heart disease, is very well-established. In the field, we have made an educated guess that reducing or controlling the development of CH will reduce the incidence and risk of these other diseases; however, long-term prospective studies in humans are needed to definitively prove this.
Extrapolating from mice to humans has not always been successful. Do you have any plans to look at human cells or tissues?
Our paper does include examination of primary human hematopoietic stem and progenitor cells and shows that DNMT3A-mutant human cells have the same phenotypes as Dnmt3a-mutant mouse cells with respect to enhanced mitochondrial metabolism. We also show that MitoQ is effective in suppressing the competitive advantage and growth of human DNMT3A-mutant cells. What we have found, in my opinion, is a fairly rare example where the phenotypes are remarkably similar in mice and in humans. Moving forward to test these interventions in long-term mouse and long-term human studies are the clear next steps.
Mitophagy in Aging Brains
The brain uses a great deal of energy, and thus, mitochondria are critical to brain health. Damaged or worn-out mitochondria are removed by mitophagy, and impaired mitophagy has been associated with Alzheimer’s and Parkinson’s diseases. The laboratory of Thomas McWilliams at the University of Helsinki showed that mitophagy levels increased differently in different areas of aging mouse brains. They increased in areas responsible for movement, but decreased in those for memory. These results provide insights that may be valuable for healthy brain aging.
Rappe A, Vihinen HA, Suomi F, Hassinen AJ, Ehsan H, Jokitalo ES, McWilliams TG (2024) Longitudinal autophagy profiling of the mammalian brain reveals sustained mitophagy throughout healthy aging. The EMBO Journal 43(23): 6199-6231.
Impaired Mitochondria Affect Skeletal Aging
Patients with impaired mitochondrial respiratory chain capacity often have show reduced levels of skeletal growth that are similar to premature degeneration of cartilage and aging. A research team led by Bent Brachvogel at the University of Cologne in Germany examined cartilage cells in mice with impaired cellular respiration. They found that those cells tended to lose the ability to regenerate and died to accelerate aging. In this way, they identified basic processes that might be therapeutic targets.
Bubb K, Etich J, Probst K, Parashar T, Schuetter M, Dethloff F, Reincke S, Nolte JL, Krüger M, Schlötzer-Schrehard U, Nüchel J (2025) Metabolic rewiring caused by mitochondrial dysfunction promotes mTORC1-dependent skeletal aging. Science Advances 11(16): eads1842.
Balancing Mitochondrial Transcription and Replication
The small mitochondrial genome serves as a template for replicating the DNA genome and for transcribing RNAs that encode proteins. The balance between these two functions is critical for mitochondrial health. However, the mechanism for this balancing is unknown. Recently, a team led by Takehiro Yasukawa at Kyushu University in Japan studied the role of mitochondrial transcription elongation factor (TEFM) in the process. They report that knockout of the TEFM gene resulted in reduced ability to make the transition from transcription to replication. This study provides additional insights into the biology of mitochondria.
Matsuda S, Nakayama M, Do Y, Ishiuchi T, Yagi M, Wanrooij S, Nakada K, Wei FY, Ichiyanagi K, Sasaki H, Kang D (2025) TEFM facilitates transition from RNA synthesis to DNA synthesis at H-strand replication origin of mtDNA. Communications Biology 8(1): 202.
Mitochondria at the Synapse
Mitochondria are important in synaptic transmission and plasticity, but how they do this is unknown. Sannon Farris and her team at Virginia Technical University looked at the mitochondrial calcium uniporter (MCU) that couples neuronal activity to ATP production. There is more MCU in hippocampal CA2 distal than proximal dendrites, and distal dendrites have more plasticity. However, the mechanism is unknown. Mice with a CA2-specific MCU knockout had fragmented mitochondria that might explain their functional deficits a synapses. These differences in MCU expression might be the mechanism used by different cell types to modulate mitochondrial function to different needs.
Pannoni KE, Fischer QS, Tarannum R, Cawley ML, Alsalman MM, Acosta N, Ezigbo C, Gil DV, Campbell LA, Farris S (2025) MCU expression in hippocampal CA2 neurons modulates dendritic mitochondrial morphology and synaptic plasticity. Scientific Reports 15(1): 4540.
Recycling Mitochondria
Cells with damaged mitochondrial DNA have been implicated in numerous diseases and aging. A team led by David Pla-Martín at Heinrich-Heine University Düsseldorf in Germany discovered a mechanism that deals with those mitochondria with damaged DNA. That mechanism depends on a protein complex called the retromer and lysosomes, which contain digestive enzymes. Together they recycle the mitochondrial components and eliminate the damaged mitochondria. The authors speculate that dysfunction in this recycling mechanism might be involved in disease pathogenesis.
Kakanj P, Bonse M, Kshirsagar A, Gökmen A, Gaedke F, Sen A, Mollá B, Vogelsang E, Schauss A, Wodarz A, Pla-Martín D (2025) Retromer promotes the lysosomal turnover of mtDNA. Science Advances 11(14): eadr6415.
How Mitochondria Produce Energy
Mitochondria have long been known to be the organelle that produces energy from sugar in the food we eat. However, the precise machinery that accomplishes this activity is unknown. Now, using cryo-electron microscopy, a team from the laboratory of Edmund Kunji at the MRC Mitochondrial Biology Unit, Cambridge determined the atomic structure of the mitochondrial pyruvate carrier that transports the key molecule pyruvate. This mechanism allows pyruvate to cross the normally impermeable inner mitochondrial membrane. Understanding this machine will allow scientists to develop drugs that interact with it and serve as therapies for a variety of diseases.
Sichrovsky M, Lacabanne D, Ruprecht JJ, Rana JJ, Stanik K, Dionysopoulou M, Sowton AP, King MS, Jones SA, Cooper L, Hardwick SW. (2025) Molecular basis of pyruvate transport and inhibition of the human mitochondrial pyruvate carrier. Science Advances 11(16): eadw1489.
Mitochondria have come to be more appreciated for their roles in health and disease. Mitochondrial dysfunction has been implicated in a direct role in more than 50 diseases. In others, mitochondrial dysfunction is an important contributing factor, including neurodegenerative diseases (e.g., Alzheimer’s disease, Parkinson’s disease), cancer, and metabolic diseases.
Mitochondria have increasingly become the focus of new biotech companies. One of those is Pretzel Therapeutics. Pretzel seeks to harness cellular energetics to treat a wide range of conditions now recognized as having a mitochondrial connection. Mitochondria are the powerhouses of the cell, and each cell contains hundreds of mitochondria. Interestingly, mitochondria have their own small genome that encodes enzymes that control mitochondrial activities. Several of the projects at Pretzel focus on controlling cellular energetics by modulating the cellular copy number of mitochondrial DNA (mtDNA).
The Pretzel researchers hope to restore cellular energetics to treat neurodegenerative and rare diseases associated with low mtDNA levels or to modify bioenergetics to treat obesity. In one program, they hope to restore energetics by activating the mitochondrial DNA polymerase. This program was disclosed in a recent Nature report (Valenzuela et al., 2025). In that publication, the researchers show that a small-molecule activator restored function to the most common mutants of the mtDNA polymerase, PolG. A lead therapeutic in this program was recently entered into Phase 1 clinical study. In another program, they hope to modulate the activity of the mitochondrial RNA polymerase. A third program employs gene editing to reduce mutated mtDNA and increase levels of healthy mtDNA.
Pretzel launched in 2022 with financing of $72.5 million. The founders include Gabriel Martinez, Claes Gustafsson, Maria Falkenberg, Michal Minczuk, Nils-Göran Larsson, and the late Paul Thurk. Their facilities are located in Waltham, Massachusetts, and Mölndal, Sweden.
For more information on Pretzel Therapeutics, visit their website (https://www.pretzeltx.com/).
Reference
Valenzuela S, Zhu X, Macao B, et al. (2025) Small molecules restore mutant mitochondrial DNA polymerase activity. Nature, doi.org/10.1038/s41586-025-08856-9
Questions for Pretzel Therapeutics
Pretzel researchers and others recently published an excellent paper in Nature that supports your therapeutic strategy. Congratulations on that publication.
Mitochondrial dysfunction has been implicated, directly or indirectly, in many diseases. What diseases do you see as the “low-hanging fruit” for treatments?
The lack of treatments for mitochondrial dysfunction and disease indicates to us that there really isn’t any “low-hanging fruit” in this area. That said, diseases with a clear and direct genetic cause, such as POLG disease, offer the clearest mechanistic rationale to drug discoverers.
Are you considering testing approved drugs for potential off-label uses for treating mitochondrial diseases?
We are focused on our own, novel targets and drug candidates. We do not work in re-purposing projects.
Neurodegenerative diseases are projected to increase rapidly with our aging population. Do you have any thoughts about how your therapies might fit into preventing or treating those diseases?
There has been substantial published research on the links between degenerative conditions of aging and declining mitochondrial function, far more than we can summarize here. We are of course interested in investigating how our novel mechanisms may influence these conditions. To this end, we have been awarded a grant from Parkinson’s-UK, a leading charity supporting research, to study our mechanisms in Parkinson’s disease.
Cytotoxic T cells are vital for eliminating cancer cells and thus for restraining tumour growth. However, many types of cancer cell blunt this immune attack by issuing signals that somehow cripple the attacking cell. Like almost everything in immunity, this undoubtedly has multiple dimensions. However, one crucial aspect seems to be centred on mitochondria. By rendering the mitochondria of the cytotoxic cell incapable of energizing the process(es) that kill the target cell, cancer cells survive immune attack. This concept has received support from studies showing that T cells that invade the tumour micro-environment exhibit signs of mitochondrial energetic dysfunction. However, the cellular and molecular mechanisms behind this phenomenon have, until recently, remained obscure.
This phenomenon could have serious consequences. Cancer cells frequently harbour mtDNA mutations that impair their own capacity for oxidative ATP generation (OXPHOS). Surprisingly, mitochondria from T cells use ‘tunnelling nanotubes,’ to transfer into cancer cells [2-4] and promote tumour survival. Even if only a small fraction of tumour cells are ‘empowered’ in this manner, it should be sufficient to protect them from cytotoxic drugs that target cells dependent on non-mitochondrial pathways for their energy supply, DNA repair and cell division. Thus, a pool of chemoresistant cells would survive to reconstitute the tumour in an even more aggressive form that is refractory to future treatments. The phenomenon of intercellular transfer of mitochondria remains somewhat controversial. However, it has been independently documented by multiple reputable laboratories and must now be considered physiological. Nevertheless, it could still be an enhanced property of tumour cells or other cells with metabolic impairment.
A recent paper from the lab of Yosuke Togashi in Japan shed light on one important part of this puzzle [1]. They report that mitochondrial transfer also occurs in the opposite direction, via tunnelling nanotubes and or/extracellular vesicles. OXPHOS-incompetent mitochondria from the tumour, bearing deleterious mutations in mtDNA, were detected in T cells that had invaded the tumour micro-environment. The origin of these mitochondria was confirmed by co-culture experiments with tumour cells expressing a mitochondrially targeted fluorescent reporter protein. Prolonged co-culture resulted in the almost complete replacement of endogenous T-cell mitochondria by those derived from the tumour cells. This replacement reflected the fact that tumour-derived mitochondria were resistant to mitophagy, whereas the original T-cell mitochondria were not.
T cells whose mitochondria had suffered this replacement showed OXPHOS impairment, increased dependence on non-mitochondrial ATP generation, downregulation of T-cell markers associated with cytotoxic functions, and signs of cellular senescence. Importantly, the acquisition of tumour- derived mitochondria impaired their activation and, hence, their ability to kill cancer cells, as shown by an in vivo model.
The work breaks new ground by showing that the interaction of immune cells with cancer cells can facilitate a bidirectional mitochondrial exchange that simultaneously favours cancer cell viability and immune evasion. However, this obviously raises many questions. The authors showed that the exchange can operate in at least three cancer-cell types (melanoma, breast and lung cancer), but does it work for all cancer types? Does the phenomenon depend on which surface markers are expressed by a given cancer cell, or by which antigen-receptors are expressed on the cytotoxic cell with which it interacts? The immune cell repertoire includes many different cell types, each with a role in anti-cancer immunity. Does mitochondrial exchange operate only in cytotoxic T cells, or is it seen in other immune cell-types, such as Treg and other CD4+ cells, dendritic cells, NK (natural killer) cells, phagocytes or B lymphocytes? If so, how is their function modified? Are those other immune cell functions secondarily deranged by impaired cytokine secretion from OXPHOS- deficient T cells? Does tumour mtDNA migrate to other cells in the body than immune cells, and if so, is their function also compromised?
The discovery of the mitochondrial fusion/fission cycle forced us to rethink the mitochondrial content of each cell as being akin to a single entity. The pioneering work of the Togashi lab and others now obliges us to revise another fundamental tenet of mitochondrial biology, recognizing that mitochondria and their DNA are not simply the chattels of single cells, but belong to populations of many cells and to tissues, organs and even the body as a whole.
References
- Ikeda H, et al. (2025) Immune evasion through mitochondrial transfer in the tumour microenvironment. Nature 638: 225–236. doi: 10.1038/s41586-024-08439-0.
- Tan AS, et al. (2015). Mitochondrial genome acquisition restores respiratory function and tumorigenic potential of cancer cells without mitochondrial DNA. Cell Metab. 21: 81-94. doi: 1016/j.cmet.2014.12.003.
- Saha T, et al. (2022) Intercellular nanotubes mediate mitochondrial trafficking between cancer and immune cells. Nat Nanotechnol. 17: 98–106. doi: 10.1038/s41565-021-01000-4.
- Zhang H, et al (2023) Systematic investigation of mitochondrial transfer between cancer cells and T cells at single-cell resolution. Cancer Cell 41: 1788–1802.e10. doi: 10.1016/j.ccell.2023.09.003.
In a new paper in Nature, the laboratory of Martin Picard, PhD, mapped the location and activity of the many mitochondria in a human brain.1, 2 Dr. Picard is associate professor of behavioral medicine at Columbia University Irving Medical Center and directs the Mitochondrial Psychobiology Group. This project was conducted in collaboration with Michel Thiebaut de Shottten, PhD, at Director of research the CNRS in Bordeaux,
When most of us think about burning energy, we think of exercising our muscles. However, small as it is, the brain consumes an outsized proportion of our energy. It needs that energy to perform its myriad functions, and to provide all that energy, each brain cell contains thousands of mitochondria, the organelles that produce energy.
Dr. Picard wondered how the many mitochondria are located in the brain and how they relate to energy production and usage in different areas of the brain. How are the cellular components associated with brain anatomical structures? To explore these and other questions, they developed MitoBrainMap v1.0.3
They began by developing a method to physically divide or “voxelize” a frozen human brain into small cubes or voxels (3x3x3mm). Interestingly, magnetic resonance imaging (MRI) images small cubes of brain, virtually “voxelizing” the brain, but the voxelization of the brain into physical cubes had to await the development of new methods. This was spearheaded by Eugene Mosharov, PhD, first author on the paper.
Next the team had to define the different mitochondrial types across the brain. They found that the different regions of the gray and white matter had quite different mitochondrial densities and activities (measured as oxidative phosphorylation activity). Intriguingly, there was an intriguing correlation: regions with higher activity were those that developed later in evolution.
The final challenge was to create a computational model to assemble the information from a single slice to the whole brain. This was accomplished by Michel Thiebaut de Shotten, PhD, a neuroanatomist from the CNRS in Bordeaux. The team then expanded that model into a prediction model that allowed them to assign predictions to other regions of the brain, based on date from MRIs.
The map is only the beginning. The team can now use that map to further explore the relationship of mitochondria in different regions of the brain with psychosocial and cognitive factors; exploring the mind-mitochondria connection. This new tool will enable them to study how brain energy relates to anatomy, development, behavior, and neurodegeneration, and the nature of the mind and consciousness.
“This is the kind of project that is nearly impossible to do” said Picard, “we had to find an exceptionally high-quality brain, align engineering, computational, molecular biology, and neuroscience expertise, and find the right students courageous enough to undertake this massive effort! I am so grateful for this amazing team that came together to create MitoBrainMap v1.0.”
A Conversation with Martin Picard
How did the idea come about to create the mitochondria brain map?
One November evening in the lab, after discovering the diversity of mitochondria in the mouse brain (Nature Communications 2023) and imaging the brain of our patients with rare mitochondrial diseases. I dreamed of a way to systematically map mitochondria across the whole brain. Chatting with my engineer-at-heart neuroscientist colleague Eugene Mosharov, we came up with the technical approach to turn the brain into cubes to create the MitoBrainMap v1.0.
What were the steps needed to get the data?
1. Find a brain, 2. Develop a hardware/software approach to physically partition, or voxelize the brain, 3. Perform >18,000 laboratory assays, 4. Visualize the massive multi-modal dataset in the brain space, 5. Register that data to the standard human brain space used in neuroscience with Michel Thiebaut de Shotten.
Were there many debates and questions about how to get the right sample sizes and make sure they were representative?
We initially wanted to do the whole brain, but estimated that this would cost >5 million dollars and take multiple years. We abandoned that ambition, and focused on a single section of a single brain hemisphere.
What problems did you have to overcome?
The major challenge was one of scale. This was by far our largest mitochondrial phenotyping project. We developed a higher throughput lab platform and a robust data processing pipeline to overcome this challenge. The other challenge was the working across disciplines, combining molecular and single-cell RNA sequencing, mitochondrial biochemistry, neuroscience, and neuroanatomy.
How did the team work together?
Cohesive teamwork was critical. Students generated a ton of data. Eugene handled and integrated the unique dataset. Orian Shirihai’s team validated and enhanced our mitochondrial assays. And Michel Thiebaut de Shotten mapped this data onto the brain, developing an algorithm to extend to the whole brain.
How long did it take from inception to final paper?
November 2020 to March 2024 – 3.5 years! Plus a year to revise the paper.
What are the next steps on your research?
Cynthia Liu in our lab is now measuring mitochondrial content and OxPhos enzyme activities in 5,000 human samples. This will validate and extend this line of work.
Was there any correlation between mitochondria and regions of known brain functions (e.g., speech, vision, hearing)?
Great question. This is something to explore in future research.
The gap between molecular processes and macro-imaging often contains fascinating information. Your work bridged that gap. Might there be other organelle targets of your work?
Mitochondria are pretty special. They have their own genome, two membranes, and without them, mammalian cells cannot live at all. All cellular and molecular processes converge on their requirements for energy, and the human genome is actively regulated by signals from the Mitochondrial Information Processing System (MIPS) (Cell Metabolism 2022). That being said, one could certainly profile other organelles across the brain.
Can your work be correlated to mitochondrial brain work on neurodegenerative diseases, such as Parkinson’s or Alzheimer’s diseases?
Yes, this is a future direction some of our colleagues are interested in. But when we study diseased brains, it’s like trying to understand the causes of a car crash by looking at the totaled, permanently damaged vehicle. Without looking at the driver, we likely will never know why the vehicle/brain crashed in the first place. In the brain and living organisms, the driver is energy. And energy fluxes through our mitochondria.
You suggest that your method correlates with other imaging methods. Do you think these might have potential to eventually be used in diagnostic methods?
Yes, our hope is that we can quantify mitochondrial content and quality or health with standard neuroimaging methods. In the living human brain, non-invasively.
How did you come to be interested in mitochondria in the first place?
Mitochondria are the dynamic energetic portal between the physical processes that convert food and oxygen into subjective experiences, and consciousness. In graduate school, I became increasingly convinced that mitochondria were going to teach us something meaningful about mind-body processes. Now we study the mind-mitochondria connection, in and outside the brain.
References
1Mosharov EV, Rosenberg AM, Monzel AS, Osto CA, Stiles L, Rosoklija GB, Dwork AJ, Bindra S, Junker A, Zhang Y, Fujita M, Mariani MB, Bakalian M, Sulzer D, De Jager PL, Menon V, Shirihai OS, Mann JJ, Underwood M, Boldrini M, Thiebaut de Schotten M, Picard M (2025) A human brain map of mitochondrial respiratory capacity and diversity. Nature https://doi.org/10.1038/s41586-025-08740-6.
2Thiebaut de Schotten M, Picard M (2025) A map of mitochondrial biology reveals the energy
landscape of the human brain. Nature https://doi.org/10.1038/d41586-025-00872-z.
3Human MitoBrain Map (2025) Michel Thiebaut de Schotten. Retrieved from: http://humanmitobrainmap.bcblab.com/. April 1, 2025.
For more links and videos, visit http://humanmitobrainmap.bcblab.com/
Prediction of whole-brain mitochondrial density visualized along a red (high) yellow (low) gradient projected onto the lateral view of the brain. The map is overlaid on a tractographic representation of the brain, illustrating the connectional organization of white matter pathways.
Prediction of whole-brain mitochondrial density visualized along a standard heat gradient projected onto an axial slice. Warmer colors (e.g., red/yellow) indicate higher predicted mitochondrial density, whereas cooler colors (e.g., green/blue) denote lower density. The map is overlaid on a tractographic representation of the brain, illustrating the connectional organization of white matter pathways.