TRiMAD 2026, Early registration ends September 14 for an unusually accessible two-day gathering of leading mitochondrial researchers.
There are not many opportunities to spend two days in one place with mitochondrial researchers from the NIH, Harvard Medical School, Dana-Farber Cancer Institute, Memorial Sloan Kettering Cancer Center, The Wistar Institute, University of Pennsylvania and Boston Children’s Hospital — alongside three of the major mitochondrial research centers in Philadelphia.
TRiMAD 2026 is one of them.
The Translational Research in Mitochondria/Metabolism, Aging and Disease Conference — TRiMAD — returns to Philadelphia November 14–15 for two concentrated days of mitochondrial science, from fundamental mitochondrial biology to cancer, cardiovascular and neurological disease, aging, metabolism and primary mitochondrial disease.
And unlike many major scientific meetings, TRiMAD remains deliberately accessible: early registration is just $125 for trainees and $200 for faculty. The early-registration deadline is September 14.
Three Philadelphia Centers Bring the Meeting Together
TRiMAD is organized by three institutions that have built significant mitochondrial research programs within a few miles of one another:
Thomas Jefferson University’s MitoCare Center, directed by György Hajnóczky, MD, PhD, brings together advanced imaging, mitochondrial phenomics and disease models to understand mitochondrial function and dysfunction across cells, tissues and disease.
Children’s Hospital of Philadelphia’s Center for Mitochondrial and Epigenomic Medicine, directed by Douglas C. Wallace, PhD, spans mitochondrial genetics and basic research through advanced diagnostics, translational science and clinical mitochondrial medicine.
Temple University’s Aging + Cardiovascular Discovery Center, led by John Elrod, PhD, brings mitochondrial biology into the study of cardiovascular disease and aging.
Together, these centers make Philadelphia an unusual concentration of mitochondrial research — and provide TRiMAD with a scientific range that extends well beyond any single definition of “mitochondrial disease.”
A Remarkable Group in One Room
The 2026 program brings some of the best-known names in mitochondrial science together with investigators pushing the field into new areas of medicine.
Dario C. Altieri, MD — The Wistar Institute. Dr. Altieri brings cancer squarely into the mitochondrial conversation. President and CEO of Wistar and Director of its Ellen and Ronald Caplan Cancer Center, his research explores mitochondrial mechanisms that allow cancer cells to adapt, survive and progress.
Zoltan Arany, MD, PhD — University of Pennsylvania. Chair of Penn’s Department of Physiology. Dr. Arany studies the molecular mechanisms linking metabolism and mitochondrial function with cardiovascular physiology and disease.
Edward Chouchani, PhD — Harvard Medical School, Dana-Farber Cancer Institute and HHMI. Dr. Chouchani is helping define a newer generation of mitochondrial research connecting metabolism, redox biology and mitochondrial signaling to cancer and metabolic disease.
Agnel Sfeir, PhD — Memorial Sloan Kettering Cancer Center. The PaineWebber Chair in Cancer Genetics at MSK. Dr. Sfeir investigates genome stability and mitochondrial DNA biology, bringing another important connection between mitochondria and cancer to TRiMAD.
Richard J. Youle, PhD — National Institutes of Health. An NIH Distinguished Investigator, Youle has been central to the discovery and understanding of mitochondrial quality control, including PINK1/Parkin-mediated mitophagy and its relationship to Parkinson’s disease.
Thomas Schwarz — Boston Children’s Hospital and Harvard Medical School. Dr. Schwarz studies how neurons maintain mitochondrial health, with a particular focus on mitochondrial transport, positioning, and local quality control/mitophagy in axons.
Rebecca Ganetsky — Children’s Hospital of Philadelphia. Dr. Ganetsky is a physician-scientist focused on primary mitochondrial diseases, particularly mitochondrial Complex V/ATP synthase disorders and mtDNA deletion syndromes, with an emphasis on connecting molecular defects to clinical phenotypes. Her translational work also develops new biochemical diagnostics and functional biomarkers of mitochondrial activity to improve diagnosis, disease monitoring, and ultimately therapeutic development.
Dmitry Temiakov — Thomas Jefferson University. Dr. Temiakov studies the molecular machinery that controls mitochondrial gene expression, using structural biology and biochemistry to define the mechanistic principles of mitochondrial DNA replication and transcription initiation. His work also examines how these processes are altered in disease or involved in physiological processes, like maternal inheritance of mitochondrial DNA.
John Elrod of Temple — Temple University. Dr. Elrod studies mitochondrial calcium signaling, metabolism, fibrosis, and cell death, particularly in the context of cardiac injury, heart failure, aging, and neurodegeneration. His lab is especially known for defining mechanisms of mitochondrial calcium transport and how altered calcium handling reshapes energy metabolism and contributes to disease.
More Than Keynotes
TRiMAD is designed for scientific exchange rather than simply a sequence of major lectures. Nine invited speakers will be joined by 20 short talks selected from submitted abstracts, two poster sessions and an opportunity to tour Jefferson’s MitoCare Center.
That makes the meeting particularly attractive for trainees and younger investigators who want their work seen and discussed alongside established leaders in the field.
TRiMAD began in 2011 as a way of bringing together mitochondrial researchers across the Pennsylvania-New York-Ohio-Michigan region. In 2026, its reach — and the range of mitochondrial biology represented — is considerably broader.
For MitoWorld, that breadth is particularly important. Mitochondria are increasingly being investigated not only in primary mitochondrial disorders, but across cancer, cardiovascular disease, neurological disease, metabolism, aging and other major areas of medicine. TRiMAD puts many of those conversations under one roof.
Don’t Miss the Early Registration Deadline: September 14, 2026
TRiMAD 2026
November 14–15, 2026
Dorrance H. Hamilton Building
Thomas Jefferson University
Philadelphia, Pennsylvania
Early registration through September 14:
Trainees — $125
Faculty — $200
Registration remains open through October 31, and abstracts may be submitted through October 14. Abstract presenters must be registered for the meeting.
MitoWorld will be following TRiMAD closely. This is the first of three MitoBlog posts leading up to the conference, including conversations with some of the scientists and organizers who are helping expand where mitochondrial science goes next.
All living organisms live in an environment shaped by gravity and other forces, but how do these forces affect gene expression? A multi-institute research team, led by Shintaro Iwasaki of RIKEN/the University of Tokyo, explored how mitochondrial translation is influenced by gravitational and mechanical forces. The study was published in Nature Communications.
After space flights, astronauts return to Earth with weak muscles. The mechanical stresses of gravity on Earth stimulate mitochondrial function, but without gravity, muscles atrophy from disuse. Previous research had documented damage to mitochondria during spaceflight. Multiple experiments on many space flights have shown various kinds of damage to cells and tissues. However, our understanding of those challenges is limited.
The Iwasaki research team sought to leverage and expand our knowledge of the effects of spaceflight on living organisms. They obtained samples that had flown in space. Frozen mammalian cells were flown to the International Space Station. In space, the samples were thawed, subjected to various treatments, and refrozen to return to Earth. Back on Earth, the researchers then used genome-wide ribosome profiling to compare mitochondrial translation in the spaceflight samples under microgravity and 1 G in the International Space Station. Caenorhabditis elegans samples were obtained from previous space flights.
They found that the samples had lower metabolic activity than Earth-bound samples. More specifically, mitochondrial translation was disrupted. Other cellular functions were affected, including loss of cell adhesion and radiation damage to the ECM. They looked at a poorly understood cell signaling pathway that connects cell adhesion sensing, mitochondrial malonyl-CoA balance, and translation. ATP production might still be found in the human cells, but mitochondrial translation was clearly affected in C. elegans. Other affected cell components included intermediate filaments and the apoptotic cascade.
While the connection between spaceflight and muscles atrophy was well-known, this study advances our understanding of how cells use gravity and other mechanical forces to regulate mitochondrial translation. It also provides valuable information that will help future astronauts to preserve muscle strength during extended space flights.
Statement of Significance by Dr. Iwasaki:
Gravity is a constant part of life on Earth, but we still know surprisingly little about how cells sense it. Our study shows that microgravity reduces mitochondrial translation. We also identified a pathway linking mechanical forces outside the cell to protein synthesis inside mitochondria. This may help us understand not only the effects of spaceflight, but also muscle disuse, aging, and mitochondrial disease.
A Conversation with Dr. Iwasaki:
MitoWorld: Can you give us an idea of how you might be thinking to extend the findings of this study?
Dr. Iwasaki: We would first like to identify the exact molecular mechanisms that could be affected by malonylation and control mitochondrial translation in response to mechanical forces. We are also interested in whether the same mechanism works in other tissues, such as the heart, bone, and blood vessels. Another important question is whether exercise, mechanical stimulation, or drugs could help maintain mitochondrial function during long-term spaceflight or physical inactivity.
MitoWorld: You mention in your Limitations to the Study section that you cannot eliminate other possible mechanisms that might affect mitochondrial translation. Can you speculate on what those might be?
Dr. Iwasaki: Malonylation is probably only one part of the story. Microgravity can also affect ATP/GTP energy balance, membrane potential, calcium signaling, redox balance, and many other metabolites. Changes in mitochondrial shape, protein import, RNA processing, or ribosome assembly could contribute as well. These are still open questions, and we will need more detailed biochemical and genetic studies to test them.
MitoWorld: How were you able to arrange to be a part of the experiments on the International Space Station?
Dr. Iwasaki: We applied to an open call from JAXA with a proposal to study how microgravity affects protein synthesis. The proposal was selected, and we then worked closely with JAXA and our collaborators to adapt the experiment for the ISS. We acknowledge the support from Japan Space Forum and Japan Manned Space Systems Corporation. The actual experiment was carried out in the Japanese “Kibo” module in 2021. Astronaut Soichi Noguchi performed the cell-culture work, and the samples were later returned to Earth for analysis. It was a long-term team effort involving researchers, engineers, and astronauts. We truly appreciate their extensive support that makes this project possible.
MitoWorld: The implications of your work for astronauts are clear. Might there be other clinical applications? For example, could the findings from the mouse experiments be useful to patients with limited mobility?
Dr. Iwasaki: Possibly, although we still need direct evidence from human studies. In mice, reducing mechanical load lowered mitochondrial translation in muscle. This suggests that a similar mechanism may operate during bed rest, limb immobilization, or age-related muscle loss. We are actively working to survey small-molecule compounds that may increase mitochondrial translation, as a potential means to treat sarcopenia.
MitoWorld: Mitochondria were found in many of the effects of spaceflight. Can you expand on why this might be?
Dr. Iwasaki: Because mitochondrial translation was already reduced within 24 hours of microgravity exposure, we suspect that this early response may contribute to other mitochondrial defects observed during spaceflight. To test this idea, we need more detailed and comprehensive time-course studies under microgravity conditions.
Reference
Wakigawa T, Kimura Y, Mito M, Tsubaki T, Lee M, Nakamura K, Khan AH, Saito H, Yamamori T, Yamazaki T, Higashibata A, … Iwasaki S (2026) Gravitational and mechanical forces shape mitochondrial translation. Nature Communications 17(1): 5552.
https://www.nature.com/articles/s41467-026-74493-z
Extended spaceflight presents many challenges to the human body, including the immune system. Effects have been particularly well-documented in the immune system. Recently, a team, led by Daniel Winer, Alexander Chouker, Christopher Mason and Brian Crucian, described those challenges and strategies for maintaining immune health in future astronauts. The review was published in Nature Reviews Immunology.
Humans evolved in an Earth-bound environment that featured gravity and a degree of protection from radiation. However, extended spaceflight presents many challenges to the human body. One of the most critical systems that might be negatively affected is the immune system. The many existing studies on space and the immune system, which have been elaborated by recent multiomic analyses, established the foundations of a new research field called astroimmunology.
For humans, space is a hostile environment with many threats, such as microgravity and cosmic radiation. In addition, microbes of the human microbiome display increased virulence, antibiotic resistance, biofilm formation and more. Space travel increases psychological stress and disturbances to circadian rhythms that affect the immune systems. For example, even minor respiratory infections seemed to be more common among early space station residents. If we are able to establish ourselves on the moon or Mars, new challenges from those environments will appear. All of these can impact our cellular health.
Unfortunately, it is hard to study these on the ground. There really is no substitute for experiments in space. It will be important to continue to explore the effects of space on human health as the number of flights increases. This outstanding review covers the many challenges and possible strategies to mitigate those effects. As spaceflights grow longer and longer, these studies will become even more important
A Statement of Significance by Dr. Winer.
The immune system is one of the body’s systems most impacted by spaceflight, typically showing a combination of basal low-grade inflammation from innate cells, coupled to reduced robustness, including by some adaptive immune cells, such as T cells. Since the immune system influences many physiological processes across the body, and its dysfunction contributes to most chronic diseases of aging, it is important to understand how changes to the immune system during spaceflight will ultimately contribute to astronaut health. Our work provides a comprehensive contemporary guide to understand how and why the immune system changes from stressors linked to spaceflight. It also covers pertinent topics like host-microbiome interactions, aging, clinical risks, countermeasures to boost immune function in space, immune monitoring, and how risks associated with living on the Moon or Mars could impact immunity.
A Conversation with Dr. Winer.
MitoWorld: Can you tell us the particular directions that your own research might take to further the findings described in this outstanding review?
Dr. Winer: We are currently working on a number of projects to better understand how changes in gravity, including simulated microgravity, impact immune cell function. We are also particularly interested in understanding how simulated microgravity can be used to recapitulate aspects of biological aging in the immune system. Working with the David Furman lab and Cosmica Biosciences, we have shown that 24 hours of simulated microgravity can induce aging trajectories in cells that overlap with natural processes as far as 9 years out. Thus, microgravity offers a chance to develop interesting new forms of prognostic markers in aging research. This test is the BeyondAge biological aging recently released by Cosmica Biosciences.
MitoWorld: The immune system is obviously critical to human health. Are you aware of other systems that are affected by spaceflight? For example, astronauts typically return from extended flights with atrophied muscles?
Dr. Winer: Spaceflight impacts most physiological systems, and in addition to the immune system, many astronauts will experience some declines or changes in musculoskeletal, endocrine, cardiovascular, and neurological systems (including sensorimotor), among others. We are particularly interested in the immune system since in theory, it plays a role in modulating so many diseases, such as cardiovascular diseases, musculoskeletal, metabolic, cancer, and neurodegenerative diseases. Thus, by studying the immune system, we can find potentially useful applications across many different diseases of aging, and complications of spaceflight.
MitoWorld: While you are focusing on space travel, could your findings have implications for clinical work here on Earth?
Dr. Winer: Yes. Since spaceflight stressors like microgravity and radiation alter fundamental cellular properties, such as DNA damage repair, mitochondrial function, cytoskeletal regulation, and inflammatory signaling, among others, all of which impact human diseases on Earth, we may learn more about fundamental processes driving such diseases. Such knowledge could be useful in designing new therapies, or biomarkers as alluded to previously.
MitoWorld: Can you briefly summarize the involvement of mitochondria in the effects on the immune system during spaceflight?
Dr. Winer: Mitochondria are key organelles that control immune cell activation, polarization, and programming. Through metabolic reprogramming, they can dictate the type of immune response that occurs in cells. For instance, pro-inflammatory macrophages and T cells often exhibit disturbed tricarboxylic acid cycles in the mitochondria, leading to increased usage of other pathways, such as glycolysis and the pentose phosphate pathway, that can support inflammation. During spaceflight stressors, we see a number of similarities. With simulated microgravity exposures, we see reduced mitochondrial oxidative phosphorylation across many immune cells, and this mitochondrial dysfunction can hamper immune cell functions. In addition, mitochondrial dysfunction in immune cells can lead to increased reactive oxygen species production which can also fuel inflammation. Finally, mitochondrial damage due to radiation from spaceflight can cause danger molecules to leak from the mitochondria and either lead to cell death or incite inflammation from cells. Thus, the mitochondria are a central hub impacted by spaceflight stressors on cells.
MitoWorld: Given the many challenges that you have cataloged with spaceflight, are you still hopeful about long-term space existence?
Dr. Winer: Yes! The study of astroimmunology and the impact of spaceflight on other physiological systems is still very young. For many years, due to technological limitations, most of these studies centered on basic phenotyping work, where we would see things, such as immune dysfunction, but not really understand fully in depth why the changes were occurring. However, now with more advanced techniques, such as many of the multiomic analyses as well as equipment that can perform terrestrial-like workflows in space, coupled to the increase of commercial spaceflights, we are seeing a major rapid expansion in knowledge understanding how spaceflight influences the body. With this new emerging knowledge, combined with other technologies, such as AI, I think that humanity will be in good position to develop robust countermeasures to facilitate safe space travel. Long-term space existence will no doubt continue to offer new challenges, but I am hopeful that such challenges can be overcome through interdisciplinary modern, and even futuristic approaches.
Reference
Winer DA, Du H, Kim J, Chang V, Burke M, Winer S, Costes SV, Frippiat JP, Sams C, Paul AM, Wu H, Ullrich O, Baatout S, Beheshti A, Mason CE, Choukér A, Crucian BE (2025) Astroimmunology: The effects of spaceflight and its associated stressors on the immune system. Nat Rev Immunol 26:189–212.
doi: 10.1038/s41577-025-01226-6.
The shapes and sizes of tissues and organs are critical to multicellular organisms, but the mechanisms controlling the different processes that generate them are only partially understood. A research team, led by Celeste Nelson at Princeton University, linked one of these shape-generating processes, apical constriction, to ATP production by mitochondria. The findings were published in Science Advances.
Apical constriction occurs when cells shrink on one surface to fold epithelial tissues. The force is provided by the contraction of actomyosin, and those actions require ATP hydrolysis. Thus, the pattern of ATP hydrolysis is critical. Dr. Nelson and her team sought to determine if the generation of that energy is also spatially patterned.
The team examined ventral furrow formation during gastrulation in Drosophila, neural tube closure during neurulation in chicken, branch formation during lung development in chicken, and lens placode invagination during eye development in mouse embryos. During development, these tissues use apical constriction to fold the epithelium in a well-characterized pattern. The researchers determined mitochondrial density by immunofluorescence staining for Tom20, an outer mitochondrial membrane protein. Using that and other tools (e.g., time-lapse imaging, spatial transcriptomics, oxygen consumption rate), they found that mitochondrial density, membrane potential, and ATP production are greater on the apical sides of epithelial cells during apical constriction. In fact, mitochondrial density can be used to predict which cells will undergo apical constriction before they initiate the fold.
During development, tissue shape depends on multiple factors, including gene expression, mechanical forces, and energy. These processes are remarkably conserved. The Nelson team demonstrated that the location of mitochondria predicts apical constriction and is upstream of other activities. Their findings implicate the spatial distribution of bioenergetics in development.
A Statement of Significance by Dr. Nelson
Many developing tissues generate their final shapes through a series of highly reproducible and stereotyped folds, akin to origami patterns. Over the past few decades, the field has uncovered many of the gene expression changes and biochemical signals that are necessary to generate the forces to fold these tissues. Our work now shows that ATP is generated at the site of folding before it begins by oxidative phosphorylation, and that mitochondria concentrate at these sites. So now we need to figure out whether the same genetic and biochemical signals are leading to both mitochondrial localization as well as force induction, or whether there are parallel signals.
A Conversation with Dr. Nelson
MitoWorld: Can you give us an idea of what direction your research might take to further your findings here?
Dr. Nelson: There is an increasing recognition in the field that energy metabolism and mechanical forces are interacting with each other on some scale within cells and tissues, and we’re seeing more and more research groups exploring these interactions, which is very exciting! Our group is primarily focused on branching epithelia, so we’re currently exploring the different ways in which epithelial branching morphogenesis is fueled across systems, whether it’s primarily by mitochondrial oxidative phosphorylation, or by glycolysis, or both.
MitoWorld: You focused on apical constriction in this work. Do you think the findings here can be extrapolated to other mechanisms involved in tissue morphology?
Dr. Nelson: Our data suggest that there’s an interesting coupling between energy metabolism and tissue folding. Since we published our findings, several other scientists have mentioned that they’ve also observed mitochondria at the apical side of their apically constricting tissues! So we think this observation might represent a conserved energetic-mechanical motif. But as your question suggests, tissues can fold in ways that don’t involve apical constriction. It makes sense to assume that other folding mechanisms require energy metabolism, but I wouldn’t be so bold as to predict that spatially patterned mitochondria are universal across types of folding events.
MitoWorld: Can you speculate on how mitochondria are controlled by the other elements of the signaling apparatus that determines tissue morphology? Your last sentence in the Discussion suggests the complexity of this question.
Dr. Nelson: The most stunning observation that we made, in my opinion, was that mitochondria appear at sites where energy is needed before the tissue folds. How do they know to get there? What moves them there? I wish that I could say we know the answer to those questions, but we don’t. The fact that we observe this patterning across species and systems suggests something fundamental to me. It’s probably not dependent on a specific growth factor or morphogen, but rather coupled to the subcellular changes necessary for a block-like epithelial cell to change shape in the first place.
MitoWorld: This is somewhat related to the previous question. Do you have any idea of how the mitochondria are held in position at the apical side of the cell?
Dr. Nelson: I’m not sure they’re actually held there, per se. We have some timelapse imaging data that suggest the mitochondria are fairly dynamic, moving along the apical-basal axis of the cell. It would be really cool to do a pulse-chase experiment with mitochondria to see how many persist on the apical side and how many move back and forth.
MitoWorld: You note an interesting balance between glycolysis and oxidative phosphorylation. Can you elaborate on that relationship?
Dr. Nelson: In many systems, it’s been reported that cells use either glycolysis or oxidative phosphorylation (oxphos) in lieu of the other. We don’t see that to be true for apical constriction, at least for the developing chicken lung where we conducted seahorse experiments. In that system, we found both increased oxphos and increased glycolysis in the regions of tissue undergoing apical constriction. So there’s certainly more to be learned about the energetics of apical constriction, and about how the cell budgets energy generated by oxphos versus glycolysis.
Reference
Lemma B, Rothstein M, Zhang P, Waas B, Kilwein M, Topiwala S, Zhang SX, Sudhakar A, Goodwin K, Gavis ER, Mallarino R, Kosmrlj A, Nelson CM (2026) Patterns of mitochondrial ATP predict tissue folding. Science Advances 12(17): eaee6175.
Shout out from www.MitoWorld.org to the Cell Metabolism team led by editor Salvatore Fabbiano for recognizing and facilitating our Mito-Cancer session at the Multifaceted Mitochondria Symposium (June 21-23, Glasgow). This included Cell Metabolism publishing our Commentary, Cancer as a window into mitochondrial biology.
For the Cell Metabolism Commentary and Symposium session, editor Fabbiano selected Gordon Freedman from Mitoworld and Kelsey Fisher-Wellman, PhD, Wake Forest University, to moderate a panel of experts including Thomas MacVicar, PhD, Professor of Mitochondrial Biology, University of Glasgow; Laura C. Greaves, PhD, Professor of Mitochondrial Biology, Newcastle University; Payam A. Gammage, PhD, Professor of Mitochondrial Biology, University of Glasgow; Stephen W. G. Tait, PhD, Professor of Cancer Biology, University of Glasgow.
This topic arose from questions we had at www.MitoWorld.org about the hundreds of millions of years cancers and tumors have had to evolve to import mitochondria, reprogram them, and make them more efficient to drive their growth. While these lines of research are simultaneously being investigated by cancer researchers and mitochondrial researchers, there has been very little cross-fertilization. This intersection of fields has much to teach us with regards to understanding cancer, mitochondria, and applications across not only mitochondrial disease, but also a broader base of diseases, dysfunctions and aging.
MitoWorld had been in the crossfire of conversations and contentions about whether mitochondria meaningfully move between cells or whether this reported behavior is anecdotal. It occurred to us that cancer is an evolutionary and physiological laboratory for this question, and others of mitochondrial plasticity. Given that mitochondria composition, state and function can differ from organ to organ, within organs, and across the range of cancers and tumors, we further wondered if this variation could be classified, stored in aggregate databases and be made of use to any community exploring mitochondria roles in disease, health and physiology. Hence, the birth of the Mito-Cancer Atlas Project, which aims to do just that.
We were not alone in this line of reasoning. Kelsey Fisher-Wellman, PhD, is at Wake Forest University and Atrium Health, where he runs his Cancer Metabolism Lab. Kelsey was well underway in building a mito-cancer atlas and typecasting mitochondrial differentiation looking for targeting windows.
“Nearly a decade ago, I started my laboratory on a simple premise: not all mitochondria are the same. Rather, mitochondria are specialized according to the physiological demands of their host cell. Before we ever made a measurement in cancer, we proved this concept using a first-of-its-kind physiological omics platform that we termed Mitochondrial Diagnostics. Our work has defined mitochondrial specialization across normal tissues and our discovery of exploitable mitochondrial vulnerabilities in AML provide proof-of-concept for a much larger vision. The Mito-Cancer Atlas is the logical next step: a systematic effort to map the physiological diversity of cancer mitochondria across all tumor types.” Kelsey Fisher-Wellman, PhD, Wake Forest University, Atrium Health
MitoWorld also joined forces with Phillip West, PhD, at the Jackson Laboratory, where he is Associate Professor, Co-Program Leader, JAX Cancer Center and Principal Investigator of the West Lab, which explores immune and inflammatory responses to genetic disorder and aging related diseases.
“I see The Jackson Laboratory as a natural strategic partner for the Atlas. JAX is supported by an NCI-designated Cancer Center and has the genetic model infrastructure, computational scale, and translational reach to move nominated targets from hypothesis to validated biology. My laboratory has spent the past decade studying how mitochondria impact immunity and inflammation in cancer and other aging-related diseases. Overall, our work argues that mitochondria are key to every aspect of cancer growth, metastasis, treatment toxicity, and long-term survivorship.” Phillip West, PhD, the Jackson Laboratory
To make a mitochondria-cancer typecasting and a mitochondrial atlas for this activity possible, MitoWorld and its collaborative platform, MITOS Global, formed a formal partnership with Heureka Labs, a Duke University spinout of Matthew Hirschey, PhD, where the Hirschey Lab investigates cellular nutrient sensing and metabolism using computational approaches to understand how metabolic pathways regulate health and disease.
“Modern cancer research labs generate biological data faster than they can process it. Insights sit buried in archives, experiments are repeated in silos, and findings aren’t structured for reuse across scientific networks. Institutions have turned to AI for a solution, but general-purpose language models are built to summarize what is already written, not to reason over what a lab has actually measured — and when pushed toward scientific inference, they aren’t able to identify the novel relationships in underexplored domains that drive impactful discoveries. That gap is exactly why Heureka exists. Our platform lets scientists run end-to-end projects — generating hypotheses, mining the literature, designing experiments, analyzing results, and interpreting findings — using models grounded in empirical biology for deeper insights.” Ioan Bolohan, CEO, Heureka Labs
MitoWorld, Fisher-Wellman and our Mito-Cancer Atlas project welcome mitochondria and cancer researchers interested in cataloging the richness of mitochondria states and plasticity in the range of cancers and tumors. We are currently working on a new website called the MitoCancer Frontier.
Previous Mito-Cancer www.MitoBlog posts are found here.
Proteostasis, the maintenance of a healthy, correctly folded protein network, is essential for cellular function. When mitochondrial proteins are damaged or misfolded, cells activate the mitochondrial unfolded protein response (UPRmt), a quality-control program that induces chaperones and proteases to help restore mitochondrial proteostasis. In simple model organisms, mild UPRmt activation has been linked to increased stress resistance and longer lifespan. A recent study led by María José Pérez and Michela Deleidi asked whether this response is equally protective in the human brain. The findings were published in Nature Neuroscience.
The team wondered how mitochondrial proteostasis is maintained in the aging human brain, how mitochondrial proteostasis is maintained in different human brain cell types and whether UPRmt activation has the same consequences across neurons and glia. Using human induced pluripotent stem cell-derived neurons, astrocytes and microglia, as well as neuronal-glial tricultures and microglia-containing brain organoids, they modeled mitochondrial proteotoxic stress in a human cellular context. Pharmacological inhibition of the mitochondrial protease LONP1 was used to induce mitochondrial protein misfolding and activate the UPRmt. This stress caused mitochondrial fragmentation and reduced mitochondrial membrane potential across cell types, but the downstream responses were markedly different.
The team found that mitochondrial stress profoundly altered human microglial metabolism, causing lipid remodeling, lipid-droplet accumulation and depletion of S-adenosylmethionine (SAM), a key metabolite involved in methylation and antioxidant defense. These changes were associated with DNA damage, inflammatory signaling and increased senescence. By contrast, neurons and astrocytes mounted more adaptive stress responses, whereas microglia showed impaired quality control and accumulated misfolded proteins.
The study shows that mitochondrial stress responses are highly cell-type specific in the human brain. Although the UPRmt can support proteostasis under some conditions, chronic activation in microglia can become maladaptive, promoting senescence and disrupting neuronal homeostasis. These results suggest that therapeutic strategies aimed at modulating mitochondrial stress responses will need to be carefully tuned by cell type, duration and disease context.
Statement of Significance by Drs. Pérez and Deleidi
Reports on the mitochondrial unfolded protein response, or UPRmt, have been contradictory, with protective effects in some settings and damaging effects in others. Our findings suggest that this depends, at least in part, on cellular context. Brain cells do not mount a uniform mitochondrial stress response: microglia responded earlier and more strongly than neurons, suggesting that they may act as key sensors of mitochondrial stress.
In microglia, however, sustained UPRmt activation was maladaptive, driving metabolic dysfunction, senescence and impaired communication with neurons and astrocytes. Microglia carrying a mitochondrial proteostasis defect were sufficient to induce senescence, reduce neuronal integrity and increase amyloid accumulation in brain assembloids. This signature overlapped with disease-associated microglial states found in aging and Alzheimer’s disease brain. These findings reveal how defects in mitochondrial quality control may contribute to neurodegeneration by altering the brain’s immune environment. They also highlight rare mitochondrial diseases as powerful models to uncover mechanisms relevant to common age-associated disorders, including Parkinson’s and Alzheimer’s disease. Overall, our study identifies microglial metabolism and mitochondrial proteostasis as potential therapeutic targets and underscores the need for cell-type-selective approaches rather than indiscriminate activation of mitochondrial stress pathways.
A Discussion with Drs. Pérez and Deleidi
MitoWorld: Can you give us an idea of where you might direct your future research to expand on the findings in this paper?
Authors:
One important direction will be to understand whether the mechanisms we identified in human microglia also operate in the context of specific neurodegenerative diseases. In this study, we found that chronic activation of the mitochondrial unfolded protein response can push microglia toward a senescent and inflammatory state. We now want to explore how this process interacts with disease-associated protein aggregates, such as α-synuclein in Parkinson’s disease or amyloid and tau pathology in Alzheimer’s disease.
We are also interested in defining whether the metabolic vulnerabilities we identified, particularly lipid remodeling and the SAM-polyamine axis, can be targeted to restore healthier microglial function. Ultimately, our goal is to understand whether correcting mitochondrial stress responses in microglia could help preserve neuronal homeostasis and slow disease progression.
MitoWorld: It is interesting that the mitochondria in different cell types had such different responses. Do you have any thoughts on why that might be? Is this just another case of how mitochondria are regulated by the nuclear genes?
Authors:
Yes, nuclear regulation is certainly part of the answer, but we think the explanation is broader. Mitochondria are deeply shaped by the identity, function and metabolic state of each cell type. Neurons, astrocytes and microglia have very different energetic demands, stress-response programs and roles within the brain. Therefore, the same mitochondrial stress can be interpreted very differently depending on the cellular context.
In our study, neurons and astrocytes appeared better able to activate adaptive compensatory pathways, whereas microglia showed a more maladaptive response, with impaired proteostasis, metabolic rewiring and senescence. This suggests that mitochondrial stress responses are not uniform across the brain. They are integrated with cell-type-specific transcriptional programs, metabolic wiring and immune functions.
MitoWorld: Each neurodegenerative disease features its own misfolded protein (e.g., Parkinson’s disease, a-synuclein; Huntington’s disease, huntingtin) and affects specific neurons. Could those be other examples of the type of cell-specific results of the UPR?
Authors:
Absolutely. One of the important lessons from our study is that proteostatic stress responses are highly cell-type specific. Different brain cells may have different thresholds for coping with misfolded proteins, and different diseases may expose vulnerabilities in distinct cellular populations.
In Parkinson’s disease, for example, dopaminergic neurons are particularly vulnerable, but microglia and astrocytes also shape how α-synuclein pathology spreads and how the tissue responds. Similarly, in Huntington’s disease or Alzheimer’s disease, the affected neurons and glial cells may engage different stress-response pathways depending on their metabolic state, proteostatic capacity and local environment. We think that understanding these cell-specific responses will be essential for designing therapies that do not simply activate or inhibit a pathway globally, but modulate it in the right cell type and at the right time.
MitoWorld: Do you have any speculation on the mechanism involved in the lipid remodeling?
Authors:
Our data suggest that lipid remodeling is not just a secondary consequence of mitochondrial stress, but part of the mechanism driving microglial dysfunction. When mitochondrial proteostasis is impaired, microglia appear to reorganize their lipid metabolism, leading to the accumulation of lipid droplets and changes in glycerophospholipid and glycerolipid pathways. One possibility is that lipid droplets initially form as a protective response to buffer damaged membranes, oxidative stress or excess fatty acids. However, when the stress is chronic, this adaptive response may become maladaptive. Lipid-droplet accumulation has been linked to impaired phagocytosis, increased inflammatory signaling and reduced cellular fitness in aging microglia. In our models, interfering with lipid-droplet formation reduced senescence markers, suggesting that lipid remodeling actively contributes to the senescent phenotype.
MitoWorld: As you note in the Discussion, your findings have significant implications for cancer treatments? Do you have plans to follow up on these possibilities?
Authors:
This is an important point. Some therapeutic strategies, including in oncology, aim to manipulate mitochondrial stress responses or proteostasis pathways. Our findings suggest that these approaches may have cell-type-specific effects that need to be carefully considered. In particular, chronic activation of mitochondrial stress responses in immune cells could potentially promote senescence or inflammatory dysfunction. Our main focus remains neurodegeneration, but we think the broader implication is that mitochondrial stress pathways should be studied in a tissue- and cell-type-specific manner. It will be important to understand when activation of the UPRmt is beneficial and when it becomes maladaptive. This principle could be relevant not only for brain diseases, but also for cancer and other age-associated conditions in which senescence, inflammation and mitochondrial dysfunction intersect.
MitoWorld: Can you tell us how you came to be interested in mitochondria?
Authors:
Our interest in mitochondria came from trying to understand why certain brain cells are especially vulnerable in neurodegenerative diseases. Mitochondria sit at the intersection of several processes that are central to these diseases: energy metabolism, inflammation, protein quality control, oxidative stress and cellular aging. For our group, mitochondria became particularly interesting because they provide a way to connect rare genetic disorders with broader mechanisms of neurodegeneration. Studying defects in mitochondrial proteostasis can reveal fundamental biological pathways that may also be relevant to common age-associated diseases. Over time, this led us to focus not only on neurons, but also on glial cells, especially microglia, and to ask how mitochondrial stress in these cells affects the entire brain environment.
Reference
Perez J MJ, Lam A, Weissleder C, Bertoli F, Raji H, Bosch M, Nemazanyy I, Kalb S, Kehili M, Hirschberg I, Brunetti D, Heckenbach I, Scheibye-Knudsen M, Deleidi M (2026) The mitochondrial unfolded protein response in human microglia disrupts neuronal–glial communication and promotes senescence. Nature Neuroscience https://doi.org/10.1038/s41593-026-02320-1.
Chemotherapy resistance accounts for more than 80% of cancer deaths, and so, preventing its development is a significant challenge in cancer treatment. Resistance comes from multiple sources. Some are related to the cancer cells themselves, and others are in reaction to the therapy. New ways to prevent the development of resistance are urgently needed to improve patient outcomes.
Recently, a multi-institute research team, led by Emma M. Kerr of Queen’s University Belfast, sought to better understand the cellular mechanisms related to resistance. To do this, they studied the cellular effects of chemotherapy in colorectal cancer. Their findings were published in a paper in Nature Metabolism.
To promote tumor progression, cancer cells reprogram cell energetics. Thus, the Kerr team chose to examine therapy resistance in colorectal cancer. They wanted to determine how mitochondria facilitate the acute stress response to 5-fluorouracil (5FU) in cells that survived treatment. That cancer is commonly treated with 5FU, but the effects are not fully understood. 5FU causes great metabolic stress to cells, and so, the research team examined its effects on mitochondria because of their deep involvement in cell metabolism.
Their results show that 5FU has multiple effects on mitochondria. Specifically, 5FU promotes mitochondrial adaptation at multiple levels. It changes the number, the communication and the activity of mitochondria, all of which mean that the cell can survive the metabolic stress caused by the drug. It does not inhibit complex I, it increases it’s activity, and the activity of the mitohcondria, and cell metabolism in general to delay tumor growth and prolong cell survival in preclinical models. They also found that oxidative metabolism signatures might predict the response to 5FU therapy.
This study enhances our understanding of how resistance to 5FU is driven by a coordinated mitochondrial response, but this can be blocked to deepen responses to 5FU. The increase mitochondrial activity was key to the ability of cancer cells to survive treatment with 5FU. Importantly, the findings suggest that this therapy can be used as part of combination therapy for colorectal cancer.
A Statement of Significance by Dr. Kerr.
Our work establishes mitochondrial plasticity as a central mechanism of acute chemotherapy tolerance in colorectal cancer. We show that, in response to 5FU-induced metabolic stress, cancer cells increase mitochondrial biogenesis, organisiation and respiratory activity to restore pyrimidine balance. This adaptation reveals a previously unrecognised mechanism of treatment tolerance and creates a targetable vulnerability that could inform patient stratification and rational combination therapies.
A Conversation with Dr. Kerr and Dr. Shaw
MitoWorld: Can you give us an idea of the direction your research might take to further your findings in the current paper?
EK: Our next step is to investigate how mitochondrial, and more broadly metabolic, plasticity influence treatment response and resistance in metastatic colorectal cancer. We are particularly interested in how the distinct environments of different metastatic sites reshape tumour metabolism, alter mitochondrial adaptation and ultimately determine sensitivity to 5FU-based therapy.
AS: From a fundamental biology standpoint, I’m particularly keen to map the precise molecular pathways that bring about the acute burst in mitochondrial biogenesis and structural reorganization that we observe. Chemotherapy-induced metabolic disruption acts as a powerful stress test. By studying how mtDNA copy number, organelle turnover, and quality control mechanisms are regulated during acute 5FU survival, we can uncover basic principles of mitochondrial plasticity that dictate how mammalian cells endure severe metabolic insults.
MitoWorld: Do you think the increased need for mitochondrial activity is related to the need for more energy production or is there a more complex mechanism at work?
EK: We think the mechanism is more complex than simply producing additional energy. 5FU disrupts pyrimidine balance, and our data indicate that surviving cancer cells increase mitochondrial activity to support UCK2-dependent uridine salvage and the restoration of nucleotide pools. Because this process involves several ATP-dependent phosphorylation steps, increased mitochondrial capacity may help sustain the response. However, mitochondria are likely supporting a broader metabolic programme, rather than acting solely as a source of ATP.
AS: I completely agree that it goes far beyond ATP generation. Mitochondria are fundamental metabolic integrators. When 5FU disrupts pyrimidine synthesis, mitochondria respond not just by ramping up bioenergetics, but by dynamically rewiring metabolic fluxes to feed nucleotide recovery and maintain redox balance. It highlights that mitochondria act as dynamic homeostatic sensors, they adapt their structure and function under extreme environmental stress to prioritize critical cellular salvage pathways over baseline energy production.
MitoWorld: This research has clear clinical implications. You note several in the Discussion. Do you plan to follow up with some of these?
EK: Yes. Our immediate priority is to translate these findings towards clinical testing by evaluating drugs that can disrupt the mitochondrial adaptations induced by 5FU. This could include repurposing existing medicines, as well as testing newer metabolism-targeted agents in combination with chemotherapy. In parallel, we want to refine mitochondrial activity signatures as biomarkers, so that future trials can focus on patients whose tumours are most likely to benefit from these combinations.
AS: Yes, and what excites me about the translational side is that targeting these adaptive mechanisms relies on dissecting fundamental mitochondrial biology. By understanding the specific mechanisms of mitochondrial biogenesis and respiratory reliance that surviving cells depend on, we can identify and exploit precise metabolic vulnerabilities in patients.
MitoWorld: Your work here was specific to colorectal cancer and 5FU. Can you speculate on whether your findings might have applications for other cancers? For example, 5FU is also commonly used to treat actinic keratosis and superficial basal cell carcinomas.
EK: Although our study focused on colorectal cancer and 5FU, the mechanism we identified appears to be linked more broadly to thymidylate synthase inhibition and the resulting pyrimidine stress, rather than to colorectal cancer alone. More than five million patients each year receive thymidylate synthase–targeting treatments, including fluoropyrimidines across gastrointestinal and other cancers, and antifolates such as pemetrexed in lung cancer. In our study, several TS-targeting drugs triggered similar mitochondrial adaptation across different cancer models, including lung cancer cells, suggesting that mitochondrial plasticity may be a wider mechanism of treatment tolerance. It is therefore also plausible that related responses could occur in conditions treated with topical 5FU, such as actinic keratosis or superficial basal cell carcinoma, although the route of drug delivery and tissue environment are very different and would need to be studied directly.
AS: It’s a fascinating prospect. Mitochondria possess a core, conserved toolkit for responding to extreme physiological pressure. Whether a cell is an exercising muscle fiber adjusting to oxygen debt, a neuron undergoing mitochondrial quality control under neurodegenerative stress, or a cancer cell enduring high-dose antimetabolite therapy, the underlying rules of mitochondrial adaptation are widely conserved! Whether these findings translate to other cancers in the context TS targeting therapies is an exciting area of future discovery for sure!
MitoWorld: Mitochondria are such deceptively simple organelles with an extraordinary range of activities. Can you comment on how they have evolved to be so critical in so many diseases?
EK: Mitochondria are involved in so many of the processes that shape how a cell behaves that it is not surprising they are linked to such a wide range of diseases. They do far more than generate energy, helping to coordinate metabolism, redox balance, signalling, immunity and the decisions that determine whether a cell survives or dies.
What makes mitochondria especially interesting is how adaptable they are. In cancer, tumour cells can take advantage of that flexibility to keep growing, cope with difficult environments and survive treatment. In other diseases, when those same mitochondrial processes go wrong, they can contribute to inflammation, degeneration or metabolic dysfunction. Their importance comes from the fact that mitochondria do not just support what a cell is doing; they help determine how that cell behaves.
That is why it is so important that we continue to study mitochondria in the right biological context. Advances in imaging, metabolic profiling and single-cell technologies are only now allowing us to appreciate how dynamic and context-dependent their roles really are. At the same time, disease-specific models, like genetically engineered mouse models used for CRC, let us examine mitochondrial behaviour within complex tumours that retain their surrounding tissue and immune environment. The more closely we study mitochondria in these realistic settings, the clearer it becomes that they are not simply affected by disease – they can actively shape how disease develops, progresses and responds to treatment.
AS: Their central role in disease stems directly from their evolutionary origin as endosymbionts and their function as primary metabolic and signaling integrators. Rather than serving merely as static ‘powerhouses,’ mitochondria evolved to sense physiological cues and coordinate crucial cell fate decisions as Emma mentioned. Given such broad control over cellular survival, their widespread involvement across disease indications is entirely expected.”
MitoWorld: How did you come to be interested in the involvement of mitochondria in cancer?
EK: My interest in mitochondria grew from a broader question: how do cancer cells survive extreme stress, and can we use that to expose new therapeutic weaknesses?
During my PhD, I studied how to increase cancer cell death, both through mitochondrial dependent, and independent, apoptosis. In my postdoctoral work I then explored the other side of that biology: how cells survive very high levels of KRAS-driven stress. We found that cells with the highest KRAS activity had fundamentally reprogrammed their mitochondria.
This context specificity really shaped the direction of my own lab. Mitochondria have this Janus-like role in controlling both life and death, and both sides create vulnerabilities we can exploit. Our current work asks how mitochondrial plasticity supports treatment tolerance and how we can turn that adaptation against the tumour.
AS: My interest in mitochondria stems from my early background in muscle biology and exercise physiology, where I became fascinated by how dynamically these organelles adjust to metabolic demand. When searching for PhD opportunities, I was struck by how many distinct human pathologies, from neurodegeneration to metabolic disorders,trace back to mitochondrial dysfunction. My PhD focused on unravelling a critical mitochondrial quality control pathway dysregulated in Parkinson’s disease, but my postdoctoral research shifted toward oncology, examining mitochondrial DNA copy number regulation in cancer.
What continues to stimulate my curiosity is a desire to understand the fundamental, basic biology of mitochondria more broadly, rather than viewing them strictly through the lens of a single disease. However, extreme pathological states, such as a cancer cell enduring high-dose chemotherapy stress, provide an unparalleled experimental window. They push mitochondrial plasticity to the limit, allowing us to uncover core mechanisms of organelle dynamics and stress tolerance that might otherwise remain hidden in homeostatic tissue.
Reference
Moss DY, Brown CN, Shaw AM, … Kerr EM (2026) Mitochondrial metabolism determines chemotherapy sensitivity in colorectal cancer. Nat Metab.
The importance of human biome to our overall health is well-established. Disruptions in the flora and fauna of the human gut can cause serious problems. The most common of these is irritable bowel syndrome (IBS), but the associated disorders of small intestinal bacterial overgrowth (SIBO), intestinal methanogen overgrowth (IMO), and intestinal sulfide overproduction (ISO) are associated with IBS. Patients with these conditions have higher levels of breath hydrogen sulfide or methane, and higher bacterial colony counts, but they are not well defined.
A study led by Mark Pimentel and Juliana de Freitas Germano sought to bring more clarity to these disorders. The study was recently published in mSystems. The team examined gene transcriptomics of biopsies from several different groups. The groups included the small bowel of patients with IMO, ISO, and SIBO and from rats who were gavaged with bacteria that produce hydrogen sulfide.
Interestingly, each condition yielded unique results. For example, the genes linked to H₂S toxicity (e.g., electron transport chain and redox balance genes) of ISO patients were significantly affected, but the gene expression patterns of those with IMO and SIBO were affected much less. Results from the rat studies were similar to the ISO findings (e.g., dysregulation of mitochondrial respiration, redox balance, water homeostasis, immune response, and gut motility). Similar gavages with non-sulfide bacteria had no effect.
This study offers new insights into these disorders. The findings suggest that ISO symptoms are associated with bacterial H2S effects. Furthermore, it emphasizes the need for therapeutic strategies targeted specifically to each condition.
A Statement of Significance by Dr. Pimentel:
Our transcriptomic profiling study of small bowel biopsies revealed potential mechanisms underlying the pathophysiology of ISO, IMO, and SIBO and suggested that these are three distinct gut disorders that should be treated differently, with special attention to ISO and its broad effects on gene expression.
A Conversation with Dr. Pimentel:
MitoWorld: Can you give us an idea of how you will continue with this line of research?
Dr. Pimentel: We have expanded our use of omics techniques to better understand alterations in the small bowel ecology and environment associated with SIBO, IMO, and ISO, to improve not only diagnosis but also treatment.
MitoWorld: H2S controls an amazing array of activities. The involvement of mitochondria in its regulation is yet another aspect of cell biology moderated by these organelles. Were you surprised by this connection?
Dr. Pimentel Even though we know that H2S affects mitochondria, we wanted to explore whether this could be identified by classifying groups based on their H2S levels in exhaled breath. We were surprised that changes in mitochondrial biological processes, such as those related to mitochondrial ATP synthesis, were already happening at 1.5 ppm of H2S.
MitoWorld: Do you have any idea of what causes the dysregulation of the organisms that cause these disorders?
Dr. Pimentel: Dysregulation of organisms causing ISO, IMO, and SIBO can occur when the intestine loses its ability to clear them. In many patients, that loss begins after an episode of food poisoning, which triggers an autoimmune response in the gut’s motility system. Once gut motility is impaired, these organisms can persist or thrive where they shouldn’t, leading to ISO, IMO, and/or SIBO.
MitoWorld: You noted that further studies with larger sample sizes might identify the more important genes that are affected. Do you have any leading candidates?
Dr. Pimentel: I will focus specifically on ISO (no co-occurrence of SIBO and/or IMO) since it showed broad changes in gene expression. We analyzed small bowel transcriptomics from subjects with a minimum of 1.5 ppm but below 2.0 ppm of exhaled H2S (n=16) and those with ≥ 2.0 ppm of exhaled H2S (n=12), separately. When comparing these groups against subjects without ISO/SIBO/IMO (n=19), both comparisons showed, for example, downregulation in SLC7A11, which is involved in redox balance and ferroptosis regulation, and IL1B, which encodes a proinflammatory cytokine. When these H2S groups were combined (n=28), these changes were still there and more significant. Also, we identified dysregulation of several mitochondrial-associated genes, upregulation of CYP1A1 (redox balance), downregulation of CTH (endogenous H2S production), and upregulation of SST (gut motility and pain) in one of the H2S subgroups and in the combined group comparisons. Thus, we strongly believe that further studies with larger sample sizes will continue to show redox balance-, endogenous H2S production-, gut motility and pain- and mitochondrial-associated mechanisms and genes as important findings in ISO, independent of SIBO and/or IMO.
MitoWorld: Are there any interactions among the various sulfide, methanogenic, and other organisms that might complicate the situation?
Dr. Pimentel: In terms of transcriptomics, most differentially expressed genes and significant changes were found in ISO when combined with SIBO and/or IMO. These findings may suggest that interactions among the organisms associated with these different disorders are affecting the small bowel tissue more deeply. In other words, most changes were found in ISO, and we believe this is the leading cause of alterations in gene expression; however, these alterations can be intensified when co-occurring with SIBO and/or IMO. We haven’t proved that hypothesis in this manuscript, but this is within the scope of our future investigations.
MitoWorld: Do you see any clinical applications of your findings, and might you follow up on those?
Dr. Pimentel: Our findings demonstrate that SIBO, IMO, and ISO are distinct disorders that should be managed differently in clinical practice. The most pronounced transcriptomic alterations were observed in ISO, which is also usually associated with greater symptom severity, including diarrhea and urgency. These findings may contribute to the development of targeted or combination therapies for small bowel disorders, representing an important direction for future research.
Reference
de Freitas Germano J, Leite G, Villanueva-Millan MJ, Brimberry D, Rashid M, Hosseini A, Flor D, Bogatyrev S, Morales W, Weitsman S, Sanchez M, … Pimentel M (2026) Transcriptomics profiles in intestinal sulfide overproduction, small intestinal bacterial overgrowth, and intestinal methanogen overgrowth. mSystems 11: e00458-26.
Leigh syndrome (LS) is an untreatable mitochondrial disorder that leads to psychomotor regression and early death. Recently, an international research team, led by Antonio Del Sol and Alessandro Prigione, screened approved drugs to find those that could be repurposed to treat LS. They identified two strong candidates that validate the screen and that might point to therapies for LS. The findings were published in Nature Communications.
Repurposing approved drugs is an efficient method for developing new therapies, especially in the context of rare diseases. Those drugs have already been shown to be safe for use in humans. The Del Sol-Prigione team took advantage of this strategy and previous findings that implicated the SURF1 gene variants in LS. They used a brain organoid model of LS that contained SURF1 variants. The atypical progenitor organization of the organoids suggested defective neuronal morphogenesis, and the LS iPSC-derived dopaminergic neurons also showed improper features.
Using the organoids, they developed a deep learning algorithm for cell type-specific drug repurposing screening. In parallel, they used a survival screen in a yeast model of LS. Two drugs stood out in the tests. Talarozole and sertaconazole rescued neuronal morphogenesis, reduced lactate release, and improved growth in the midbrain organoids.
The results validate the use of in silico screens with human brain organoids for finding new therapies for LS and potentially other mitochondrial diseases. They also give new hope for patients with this tragic disease. This paper also complements another recent study by Dr. Prigione that was published in Cell.
Statement of Significance from Dr. Prigione
Identifying new treatment options is crucial for an incurable disease, such as LS. Here we took advantage of so-called New Approach Methodologies (NAMs), including human organoids and artificial intelligence (AI), and discovered two drugs that may be used for treating individuals with LS. This powerful platform can now be employed also in the context of other rare neurodevelopmental diseases.
A Conversation with Dr. Prigione:
MitoWorld: Can you give us an idea of the directions you might take to extend these findings?
Dr. Prigione: We are following these results on two different paths. First, we are exploring ways to bring these treatments to LS individuals. In particular, we are focusing on talarozole since it showed stronger effects in the models and has already been tested in humans as oral formulation in a trial that was conducted last year for osteoarthritis. Unfortunately, the company that developed the oral formulation for the trial did not agree to provide the drug for us. Therefore, we are looking into alternative options, including manufacturing the compound ourselves.
The second path is back to research. We are going to assess the effect of these two compounds in other LS models both humans and animals and determine their potential synergy with other drugs that we have identified, such as sildenafil (see Zink et al., Cell 2026). We are also further developing the deep learning and AI strategy to extend the computational screen to additional brain organoid models to possibly identify additional repurposable candidates and better understand the underlying mechanisms of actions in this disease context.
MitoWorld: In this paper, you focused on brain organoids. Might your overall strategy be useful with other tissues?
Dr. Prigione: Yes, combining AI and organoid models may represent a powerful approach to take advantage of NAMs and possibly reduce the reliance on animal models, especially for those disease conditions for which animal models are not available. For example, SURF1 variants cause a severe form of LS but mice without Surf1 do not show defects and even live longer than healthy animals. Therefore, human iPS models may represent an important strategy to advance drug discovery for these gene defects.
MitoWorld: You identified two potential drugs for LS. Do you plan to pursue any clinical studies to advance those treatments?
Dr. Prigione: As mentioned above, we are very much interested in exploring ways to assess these drugs (and particularly talarozole) in clinical settings. For this, we are partnering with the patient organization Cure Mito. Together, we are considering manufacturing the drug ourselves to develop an ethical path that would follow us determining the potential effectiveness of talarozole in LS individuals.
MitoWorld: You have a great strategy for repurposing drugs. On the other hand, those drugs also provide information about the disease process itself. You describe some of those implications in your Discussion.
Dr. Prigione: Yes, we speculate that drug function may be important for two aspects beyond energetics. First, they may act on retinoic acid pathway to improve neuronal development. Second, they may act on PPARγ, which may impact inflammation and was previously implicated in the positive effects seen in LS mice treated with cannabidiol (CBD). These results highlight the complexity of the disease processes and suggest that combinatorial treatment strategies might also be considered to combat both neurodevelopmental and neuroinflammatory components.
MitoWorld: We are always interested in what first interested you in mitochondria.
Dr. Prigione: During my PhD, I worked in the lab of Gino Cortopassi at UC Davis and started working on mitochondrial DNA deletions in human cellular models. That project and that experience were essential for me, as I was struck by the complexity and essentiality of mitochondria. During my postdoc, I changed the field and worked on iPS cells. Therefore, when I started my independent laboratory, I decided to combine these two topics and began using iPS models to study mitochondria-related diseases.
References
Menacho C, Okawa S, Álvarez-Merz I, Wittich A, Muñoz-Oreja M, Lisowski P, Martín ML, Pentimalli TM, Zakin S, Thevandavakkam M, Jerred C, … Del Sol A, Prigione A (2026) Accelerating Leigh syndrome drug discovery through deep learning screening in brain organoids. Nature Communications 17(1): 3570.
https://www.nature.com/articles/s41467-026-71391-2
Zink A, Dai DF, Wittich A, Henke MT, Pedrotti G, Heiduschka S, Santamaria G, Pentimalli TM, Brueser C, Notopoulou S, Umar AR, … Prigioni A (2026) Pluripotent stem-cell-based screening uncovers sildenafil as a mitochondrial disease therapy. Cell 189: 1656–1679.
Aging kidneys exhibit mitochondrial structural defects, oxidative stress, fibrosis, and altered metabolism. A new study published in Aging Cell suggests that alterations in the mitochondrial contact site and cristae organizing system (MICOS) may contribute to these defects.
Kidney function commonly declines with age, and aging is a major risk factor for acute and chronic kidney disease. Because many kidney cell types, especially tubular epithelial cells, have high energetic demands and rely heavily on mitochondrial function, the research team asked whether age-related changes in mitochondrial architecture contribute to this vulnerability.
Using transmission electron microscopy (TEM) and serial block-face scanning electron microscopy (SBF-SEM), the investigators examined mitochondria from the kidneys of young versus old mice. In the aged cohort, they found fragmented mitochondrial morphology, and, notably, the folds of the inner mitochondrial membrane that promote energy production, known as cristae, were disorganized, shorter, and smaller by volume. At the molecular level, aging was correlated with decreased expression of MICOS components and of OPA1, another key regulator of inner mitochondrial membrane structure.
To test whether MICOS disruption could affect mitochondrial function, the authors perturbed MICOS components in cellular models. Loss of MICOS proteins altered mitochondrial calcium handling, increased reactive oxygen species, and impaired aspects of mitochondrial respiration. Human genetic and biobank analyses further linked CHCHD6 and OPA1 with kidney and genitourinary disease phenotypes, although these findings remain associative.
Together, the study supports a model in which age-related decline of MICOS and related cristae regulators contributes to deterioration of mitochondrial inner membrane architecture. These changes are associated with oxidative stress, altered calcium regulation, metabolic remodeling, fibrosis, and increased vulnerability to kidney dysfunction during aging.
A Statement of Significance from Dr. Hinton, Jr.:
Aging is the greatest risk factor for chronic kidney disease, yet the mechanisms linking aging to renal dysfunction remain poorly understood. In this study, we demonstrate that aging is associated with profound remodeling of mitochondrial ultrastructure in the kidney, characterized by disrupted cristae architecture, altered mitochondrial morphology, increased oxidative stress, and widespread metabolic dysregulation. Using advanced three-dimensional electron microscopy, human kidney samples, large-scale biobank analyses, and mechanistic studies targeting the mitochondrial contact site and cristae organizing system (MICOS) complex, we identify age-dependent loss of MICOS components as a conserved feature of kidney aging. Furthermore, disruption of MICOS proteins directly impairs mitochondrial function, calcium handling, and redox homeostasis, recapitulating key features of the aged kidney phenotype. These findings establish MICOS complex dysfunction as a central regulator of mitochondrial structural integrity during renal aging and suggest that preserving cristae architecture may represent a therapeutic strategy to mitigate age-related kidney disease and preserve renal healthspan.
A conversation with the authors:
MitoWorld: What initially led your group to investigate the MICOS complex during kidney aging?
Hinton et. al.: This study grew from a broader question that has guided our work for many years: Does mitochondrial architecture actively influence aging, or is it simply a consequence of aging? For decades, mitochondrial dysfunction has been widely recognized as a hallmark of aging, but most studies focus on metabolism, ATP production, and oxidative stress. The primary focus was on the functional aspect, with the structural aspect given a back seat. We wanted to determine whether mitochondrial structural organization also contributes to tissue decline. This study draws the field’s attention to the role of structural organization in cellular aging.
Our laboratories had previously observed age-associated declines in MICOS proteins in skeletal and cardiac muscle, along with disrupted cristae organization, altered mitochondrial morphology, oxidative stress, and metabolic dysfunction. These recurrent observations from our lab and elsewhere suggested that MICOS decline might represent a broader biological phenomenon rather than a tissue-specific event. The kidney was compelling because it is highly energetic and densely packed with mitochondria. Even subtle changes in mitochondrial architecture could have major consequences for kidney function. Also, independent human genetic observations from our lab and Dr. Katti’s lab provided additional evidence supporting the rationale for investigating MICOS biology in renal aging.
MitoWorld: What was the major discovery of the paper?
Hinton et. al.: The major discovery was that kidney aging is accompanied by a breakdown of mitochondrial architecture, closely linked to the loss of the MICOS complex. We observed coordinated declines in MIC60, CHCHD3, CHCHD6, MIC10, MIC13, and OPA1—proteins that help maintain cristae and inner membrane organization. The key distinction from previous reports in our study is that this architectural maintenance system appears to deteriorate systematically during kidney aging.
These changes were associated with cristae disorganization, altered mitochondrial networks, oxidative stress, calcium dysregulation, fibrosis, and metabolic remodeling. Mechanistically, we propose that MICOS loss destabilizes cristae, reducing electron transport efficiency and promoting reactive oxygen species production. This may create a feed-forward cycle of mitochondrial damage. The key conceptual leap and contribution is that age-related loss of MICOS-dependent mitochondrial architecture may be a central organizing feature that links cristae disruption, mitochondrial remodeling, oxidative stress, metabolic dysfunction, and altered organelle communication in the aging kidney.
We also observed age-associated changes in mitochondria–endoplasmic reticulum contacts; the novelty here is not simply cristae disruption, but the suggestion that age-related architectural decline may influence communication between organelles.
MitoWorld: How do alterations in cristae architecture contribute to oxidative stress and mitochondrial dysfunction during aging?
Hinton et. al.: Some of the most transformative discoveries in biology emerged from the realization that structure can be a mechanism rather than merely a consequence of function. The double-helical architecture of DNA explained heredity, the quaternary structure of hemoglobin revealed cooperative oxygen transport, the organization of the sarcomere uncovered the basis of muscle contraction, and the intricate architecture of the ribosome illuminated the process of protein synthesis. In each case, biological form provided the missing causal link between molecular organization and physiological outcome.
Emerging research suggests that mitochondrial cristae follow this same pattern. Rather than treating age-associated changes in cristae morphology as a passive hallmark of mitochondrial decline, we seek to address whether alterations in cristae architecture can themselves drive functional deterioration, for example, in altered electron transport, oxidative stress, and impaired cellular and organ physiology.
Cristae organize the respiratory machinery required for oxidative phosphorylation. In aged kidneys, we observed reduced cristae volume, surface area, and integrity, accompanied by decreased MICOS expression. Disruption of cristae architecture likely impairs electron transport efficiency, increases electron leakage and reactive oxygen species production, and promotes oxidative damage. Because cristae also regulate respiratory supercomplex assembly, calcium homeostasis, and organelle communication, their deterioration may contribute broadly to mitochondrial and cellular dysfunction during aging.
MitoWorld: What advantages did 3D electron microscopy provide compared with traditional two-dimensional approaches?
Hinton et. al.: At its core, this question asks what level of observation is necessary to reveal the biological organization of aging mitochondria. A two-dimensional image can tell us what an individual mitochondrion looks like, but aging is unlikely to be an isolated organelle phenomenon. We wanted to understand how mitochondrial networks are organized throughout a tissue and how those relationships change with age. Three-dimensional electron microscopy allowed us to observe mitochondria in their native architectural context, revealing that aging may involve a loss of network organization and organelle connectivity, rather than simply damage to individual mitochondria. 3D EM allows aging to be studied as a network-level architectural process rather than as isolated mitochondrial snapshots.
Using serial block-face scanning electron microscopy, we reconstructed mitochondrial networks throughout kidney tissue. This allowed us to quantify volume, surface area, connectivity, branching, network organization, and spatial relationships with nearby organelles. A major advantage was that 3D imaging revealed network remodeling and connectivity loss that were not apparent from isolated 2D views. It also allowed us to examine how mitochondria are positioned relative to the endoplasmic reticulum, supporting our interest in the mitochondrial connectome.
MitoWorld: Do you believe MICOS proteins represent viable therapeutic targets for age-related kidney dysfunction?
Hinton et. al.: One way to think about this question is not simply whether MICOS proteins can be targeted therapeutically, but whether preserving mitochondrial architecture can preserve tissue function during aging. MICOS proteins sit at the intersection of structure and function, organizing cristae architecture, inner membrane integrity, respiratory supercomplex assembly, calcium handling, and interactions with proteins such as OPA1. This makes them particularly attractive because they may act upstream of many aging-associated processes rather than regulating a single pathway.
In our study, MICOS decline was associated with cristae deterioration, oxidative stress, metabolic remodeling, fibrosis, and kidney dysfunction. However, the critical unanswered question is whether restoring MICOS function can reverse existing pathology or merely slow its progression. Ultimately, the therapeutic promise of MICOS depends on whether mitochondrial architecture is a driver of aging or simply a marker of it.
MitoWorld: What are the most important unanswered questions regarding MICOS biology in aging tissues?
Hinton et. al.: Perhaps the most important unanswered question is not why a particular MICOS protein declines with age, but whether biological architecture itself represents a fundamental layer of aging biology. We have spent decades cataloging age-related changes in genes, proteins, and metabolites, yet cells are also highly organized spatial systems.
The emerging challenge is to determine whether aging reflects a gradual loss of this organization and whether restoring architectural integrity can restore function. Addressing that question will require us to move beyond studying individual organelles and toward understanding the cellular connectome—the network of interactions that links mitochondria with the ER, lysosomes, lipid droplets, and other compartments. In that sense, the future of the field may be less about mitochondria themselves and more about how cellular architecture is maintained across the lifespan.
Looking ahead, we believe the most exciting aspect of this work is not what it answers, but what it leaves unanswered. In our opinion, the following questions will be particularly important in the years ahead, as they address the fundamental relationship between mitochondrial architecture, cellular organization, and aging.
- What drives the age-dependent decline of the MICOS complex?
- Can restoration of MICOS reverse age-associated dysfunction?
- How does MICOS shape communication between mitochondria and the rest of the cell?
MitoWorld: What are the major limitations of the study?
Hinton et. al.: Every study ultimately comes down to the difference between what we can observe and what we can conclude. Scientific progress often occurs in two stages: first, identifying a pattern, and then proving that the pattern is causal. This study provides strong evidence that MICOS decline and architectural remodeling accompany kidney aging, but the ultimate test will be determining whether restoring that architecture can meaningfully alter the aging process itself.
Reference: