A multi-institute research team, led by Arupratan Das, sought to find possible drugs to treat glaucoma. Using a high throughput mitochondrial screen in retinal ganglion cells (RGCs), they identified the 5-HT1A antagonist WAY-100635 (WAY) as an intriguing candidate. The paper was published in a recent issue of the journal Communications Medicine.
Early metabolic dysfunctions in RGCs have been implicated in glaucoma. Moreover, mitochondrial abnormalities cause degeneration of RGCs and have been implicated in mitochondrial optic neuropathies (MON), such as Leber hereditary optic neuropathy (LHON) and dominant optic atrophy (DOA).
Unfortunately, there is no approved therapy for preserving vision in this disorder. The Das research team set out to solve this problem. They used a live-cell mitochondrial screen in human embryonic stem cell-derived retinal ganglion cells. They identified the 5-HT1A antagonist WAY-100635 (WAY) as a candidate. WAY restored mitochondrial fitness, inhibited excitotoxicity, and enhanced aerobic glycolysis. It also preserved visual acuity and stopped glaucoma progression of the disease in mouse models of glaucoma mice. Importantly, WAY has already been approved for other indications, and not surprisingly, it showed no toxicity in the models used in this study.
The findings of this study are significant. No approved therapy is currently available for treating glaucoma. Here, the authors identified WAY as an intriguing possible treatment for this debilitating disorder. The results will give new hope to patients with glaucoma and other mitochondrial optic disorders.
A Statement of Significance from Dr. Das:
Glaucoma causes irreversible blindness by damaging retinal ganglion cells (RGCs), the neurons that carry visual information from the eye to the brain. Today’s treatments mainly lower eye pressure, yet many patients still lose vision because no approved therapy directly protects these neurons or preserves the retina-to-brain visual circuit. In this study, we used a live-cell screen in human stem cell–derived RGCs to identify a small molecule that strengthens cell’s energy producing unit mitochondria and protects these neurons. We show that it boosts key survival signaling, restores mitochondrial function, and preserves visual pathway activity in animal models. A major translational advantage is that this compound has already been used in human brain-imaging clinical studies, providing an existing safety foundation that could accelerate development of a first-in-class neuroprotective add-on therapy for glaucoma and potentially other optic nerve diseases.
A Conversation with Dr. Das:
MitoWorld: What are your plans to continue this line of research?
Dr. Das: This publication is the starting point for a much broader research program. Next, we want to determine which retinal ganglion cell (RGC) subtypes are protected; because different RGC classes support distinct visual functions (light/dark sensitivity, motion detection, and image-forming vs. non–image-forming vision). In parallel, we will deepen the molecular mechanism in human stem cell-derived RGCs by mapping the full downstream signaling network triggered by 5-HT1A antagonism, how cyclic adenosine monophosphate (cAMP) dynamics, PGC-1α–linked mitochondrial biogenesis, and mitochondria independent signaling converge to prevent degeneration. We will also define the metabolic reprogramming in the native retina, asking how the treatment reshapes energy use across compartments (RGC soma vs. long axons in the optic nerve), and whether this involves coupling mitochondria to aerobic glycolysis to sustain axonal structure and transport. Finally, we will test whether protection is purely RGC-autonomous or also involves neighboring retinal neurons, glia, and immune cells, and we will rigorously distinguish axon preservation from true axon regrowth with longitudinal tracing and optic-nerve profiling.
MitoWorld: Can you expand on the mechanisms for how WAY seems to protect the RGCs?
Dr. Das: In our study, we show that WAY acts by antagonizing the 5-HT1A G-protein–coupled receptor (GPCR), which reversibly elevates cyclic adenosine monophosphate (cAMP) in retinal ganglion cells. cAMP is a central second messenger that coordinates multiple neuroprotective programs, and in our system, it restores mitochondrial health in part by transiently activating PGC-1α–dependent mitochondrial biogenesis. Improving mitochondrial fitness showed two key consequences: it reduced the metabolic “workload” per mitochondrion (lowering stress while sustaining energy supply), and it supported a protective metabolic state that couples mitochondria with aerobic glycolysis. That glycolytic program is not just an ATP backup; it supplies building blocks needed for protein and lipid synthesis that help RGCs survive and maintain long-distance axonal structure and function.
MitoWorld: Your study was predicated on finding possible therapies for glaucoma. Do you have plans to take WAY into clinical trials?
Dr. Das: Yes, we are actively planning an FDA-enabling path and are serious about advancing WAY toward a first-in-human trial. Our next goal is to generate a complete Good Laboratory Practice (GLP) preclinical toxicology and pharmacokinetic data package using GLP-manufactured WAY, including dose-ranging, safety margins, and exposure–response relationships in a higher model (for example, canine), to support an Investigational New Drug (IND) application and a Phase I clinical trial. In parallel, we are optimizing drug formulation and delivery to maximize bioavailability and real-world usability, prioritizing an oral regimen and a long-acting depot option (for example, poly(lactic-co-glycolic acid) (PLGA) slow-release packaging for intramuscular administration) that could be practical across different patient age groups. We are also actively seeking funding to execute these critical translational studies because we believe this program represents a real opportunity to deliver a neuroprotective therapy for glaucoma, and potentially other optic neuropathies, where current treatment options remain limited to pressure management.
MitoWorld: You note that these findings might benefit studies of other neurodegenerative diseases. Can you elaborate on how that might work?
Dr. Das: The reason we believe these findings can extend beyond glaucoma is that WAY targets a core, convergent stress pathway that many neurodegenerative conditions share -loss of metabolic resilience, and mitochondrial stress. We are already testing this directly in traumatic brain injury (TBI) models and are seeing strong, reproducible early signals: TBI triggers progressive degeneration of retinal ganglion cells and robust immune activation in injured brain regions, whereas following injury WAY treatment preserves retinal ganglion cell survival, markedly reduces neuroinflammatory responses in the lesion, and is associated with improved visual function (including visual acuity) and reduced anxiety-like behavior. We are currently completing the remaining validation experiments and preparing this dataset for submission, with the broader goal of defining where this mechanism provides the greater therapeutic leverage across optic neuropathies and related brain-injury conditions.
MitoWorld: You mention that, in some glaucoma models, intraocular pressure disrupts mitochondrial function. Do you have any idea of how that happens?
Dr. Das: Yes. In glaucoma, high eye pressure puts the greatest strain on the point where retinal ganglion cell axons leave the eye, the optic nerve head. These axons are still unmyelinated there and they make a sharp turn as they enter the nerve, which makes this region mechanically and energetically demanding. Under pressure stress, axonal transport slows down, so mitochondria and other cargo can pile up in the optic nerve head. Because unmyelinated axons already rely heavily on mitochondria for energy, this added crowding and stress can increase harmful mitochondrial byproducts and damage the mitochondria, making the retinal ganglion cells more vulnerable over time.
MitoWorld: Are you surprised by the rapidly growing recognition of the importance of mitochondria in human disease?
Dr. Das: I’m not surprised. Life ultimately runs on energy, and mitochondria sit at the center of how cells make and manage that energy. Across many diseases, we now see mitochondrial metabolism and quality control become disrupted; sometimes as an early contributor and sometimes as a downstream consequence. Either way, if we learn how to restore mitochondrial fitness in a cell- and disease-specific manner, we can open new therapeutic options by addressing root vulnerabilities or by buffering the harmful cascades that follow.
Reference
Dutta S, Surma ML, Chen J, Anbarasu K, Meng J, Want N, Das A (2026) The 5-HT1A receptor antagonist WAY-100635 maleate promotes retinal ganglion cell differentiation and protects the retino-visual circuits. Commun Med 6: 254.
A screen of iPS cells recently identified sildenafil as a potential treatment for Leigh syndrome (LS). Moreover, further testing of the drug showed marked improvement in animal models and human patients. The results of the study, led by Alessandro Prigione, were published in Cell.
LS is a severe mitochondrial disease that affects neurological development and muscles and results in death. It is caused by mutations in over 100 genes in either the nuclear or mitochondrial genomes. There are no treatments. Moreover, the lack of model systems has been a major obstacle to understanding LS.
The Prigione research team set out to change this. They used iPS cells from LS patients to generate neural precursor cells (NPCs). Those cells have an MT-ATP6 variant with abnormal mitochondrial membrane potential that can be exploited in screens. They screened 5,632 approved compounds and identified sildenafil as a possible candidate.
Sildenafil has been implicated in the treatment of multiple disorders. It is widely studied and beneficial in a wide range of conditions, including pulmonary arterial hypertension in children. In this study, it relieved disease symptoms, promoted neuronal outgrowth, normalized calcium homeostasis in human and animal models of LS and in six patients treated on individual basis.
The findings in this study demonstrated the value of screenings in iPS cell models and also identified sildenafil as a potential therapy for mitochondrial diseases. Dr. Prigione recently published a separate study that complements this one. That study in Nature Communications is the subject of a separate blog.
A Statement of Significance from Dr. Prigione:
LS is currently untreatable. The most frequent causes are variants in the mitochondrial gene MT-ATP6. Since it is difficult to engineer mitochondrial DNA (the famous genetic scissor CRISPR does not work for the mitochondrial DNA), it has been difficult to study this disease. Using patient-derived neural cells, we could screen drugs directly in the cell type affected by the disease. We identified sildenafil as a promising drug. We performed several validations using 3D organoid models and also animal models of LS due to nuclear genetic variants. Since sildenafil can be safely used in children with pulmonary arterial hypertension, we could treat children with LS on off-label individual basis. Sildenafil improved motor and developmental function and lowered the risk of metabolic crises, which can be detrimental in affected individuals. A double-blind placebo-controlled trial is now being set up to start in October 2026.
A Conversation with Dr. Prigione and Dr. Annika Zink, first author of the study in Cell
MitoWorld: You have developed a new method for repurposing existing drugs. Do you have plans for continuing this line of research?
Dr. Zink: Definitely. We are currently using iPS models in 2D and 3D to study additional treatments for LS and other rare disorders. The bottleneck is finding a reliable disease phenotype in these models. Once this is identified, we can use the models as drug discovery platform. In fact, in an AFM-funded project, we are employing our iPS platform not only for repurposable drugs but also to assess complementary strategies based on gene therapy.
Dr. Prigione: We have a new consortium called SynLeigh that starts in June 2026 and is funded by the European rare disease program ERDERA. In this project, we are looking at potential synergy of sildenafil with other repurposable drugs to find improved therapeutic options. We are also investigating the impact of sildenafil on different variants causing LS and in the context of other mitochondrial disorders.
MitoWorld: Do you think the iPS cells could be used in other tissues and diseases?
Dr. Zink: Yes. This is the strength of this model. iPS cells can be easily differentiated into different cell types and tissues in both 2D and 3D. Patient-specific iPS models make it possible to study tissue-specific disease mechanisms and also provide a powerful platform for disease modeling and drug discovery. In fact, in our study in Cell, we used cardiac cells generated from LS patient iPS cells to exclude potential cardiotoxicity of sildenafil.
Dr. Prigione: In our laboratory, we are using iPS cells to generate different types of brain organoids (e.g., cortex, cerebellum, midbrain). These studies may help us to understand which areas of the brain can be more strongly impacted by disease features. In this way, we may discover underlying mechanisms that could be targeted for therapies.
MitoWorld: Sildenafil has shown promise in a surprising number of different disorders. Can you speculate on why that is so? Is it due to its connection to calcium and mitochondria or simply vasodilation?
Dr. Prigione: This is exciting. Previous works suggested that sildenafil may be beneficial also in Alzheimer’s disease or Huntington’s disease. We like to think that it has to do with the central role of mitochondria in several disease processes. If sildenafil can improve mitochondrial calcium and increases the delivery of oxygen to tissues, it may provide support in those conditions that could benefit from additional energy. Surprisingly, lower oxygen has also been found beneficial in LS. Perhaps then the modulation of oxygen is really crucial, and additional work should focus on understanding this aspect.
MitoWorld: Are you interested in taking sildenafil into clinical trials for the mitochondrial diseases?
Dr. Prigione: Yes, we are currently setting up a randomized double-blind placebo-controlled trial with sildenafil in individuals with LS carrying MT-ATP6 variants. We should start recruiting patients in October 2026. We designed the trial in concert with the European Medicines Agency (EMA). To achieve a sufficient patient number, the trial will be conducted in Germany, The Netherlands, France, Italy, and Spain. We welcome patients coming from additional countries if their conditions allow them to travel to one of the trial sites.
Unfortunately, no pharma showed any interest in financial supporting this. The trial is entirely supported by third-party funding, primarily through the Horizon consortium SIMPATHIC (www.simpathic.eu). In fact, we are searching for additional funds to cover greater expenses due to the larger number of patients requested by EMA. We would be grateful if anyone would like to reach out for suggestions on how to raise additional funds. For patient families interested in the trial, please write to this email address: Simpathic.aig@radboudumc.nl
MitoWorld: We asked you about your interest in mitochondria in another blog. Interest has grown in mitochondria in various diseases. What is your sense of where all this research is going?
Dr. Prigione: Mitochondria are increasingly recognized in aging and several disease processes and also as treatment targets. Improving mitochondrial function may be seen in the future as a central goal for several therapeutics and as a general strategy to maintain health and prevent deterioration. Transplantation of mitochondria may also represent an innovative approach beyond compounds and gene therapy applications. As rare disease researchers, we hope that this renewed interest in mitochondria in more common conditions would lead to increased treatment options for children affected by primary mitochondrial diseases.
References
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.
https://www.cell.com/cell/fulltext/S0092-8674(26)00173-X
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.
“There is a lot we can learn from putting together the mitochondria and cancer research fields, from a better understanding of basic biological processes to identifying metabolic vulnerabilities with clinical potential. I am particularly looking forward to seeing how the Mitochondria-Cancer Atlas Working Group will provide a higher resolution into mitochondrial function across cancer types and how it can be leveraged therapeutically.” Salvatore Fabbiano, PhD, Editor-in-Chief, Cell Metabolism
Cancer cells lead a harsh existence. To support their growth, they need large amounts of energy, but their environment involves hypoxia, metabolic competition, and nutrient scarcity. Interestingly, they manipulate that environment and particularly their mitochondria to mitigate those challenges.
Cancer presents a unique opportunity to understand how tumors manipulate mitochondria and to ask what those lessons mean both for the cancer community and mitochondrial biology. A commentary in Cell Metabolism by Thomas MacVicar, Laura Greaves, Payam Gammage, and Steven Tait of Cancer Research UK Scotland Institute, Kelsey Fisher-Wellman of Wake Forest University and MitoWorld’s Gordon Freedman expands on this insightful observation. The intersection of these two research fields has informed studies of metabolic reprogramming, mitochondrial genetics, and regulation of cell death.
The metabolic reprogramming of mitochondria is critical to cancer cells. For example, the accumulation of oncometabolites due to mutations drive cancers in distinct cell types. One of the more intriguing aspects of mitochondria is their ability to migrate from cell to cell to enhance tumor metabolism or to weaken immune cell defenses. As more is learned about changes in mitochondrial metabolism, the challenge becomes of how to translate these advances into possible new biomarkers and therapeutic strategies for the treatment of various cancers.
Mitochondria have their own small genome, and mutations in mitochondrial DNA (mtDNA) are widespread across tumor types but non-random. While the role of these mutations in cancer is not clear, mutation burden, heteroplasmy, copy number, and other factors may be involved. Normal age-related mutations seem to accumulate in tumors, and some others may be subject to selective pressures during tumor evolution. These features of mtDNA may have potential as biomarkers and therapeutic targets, and in turn, advances in cancer biology will elucidate principles of mitochondrial genetics.
Although mitochondria are best known for producing cellular energy, they also have a significant role in programmed cell death. In apoptosis, the mitochondrial outer membrane becomes permeable and release proteins that activate caspases. Tumors can circumvent this cascade of activities. Yet, this very weakness suggests a possible therapy by inhibiting caspases and encouraging anti-tumor immunity.
In the last few years, scientists and physicians have come to realize that mitochondria do so much more than simply transform cellular energy. They have fundamental roles in a wide variety of human diseases, such as cancer. However, the activities of cancer cells provide a means to study mitochondria and, in turn, elucidate the biology of cancer. This strategy might be particularly helpful in “threading the needle” to kill cancer cells while leaving normal cells untouched. The metabolic reprogramming, mtDNA mutations, or openings in programmed cell death offer new possibilities for treatments. One hopeful development by the authors and others has been the establishment of the Mitochondria-Cancer Atlas Working Group. They hope to use modern molecular methods to define quantitative measurements of mitochondrial physiology and apply those findings to cancer biology and treatments. Although cancer is the initial focus, those same processes will eventually be applied to the many other diseases associated with mitochondria.
“Mitochondria are intimately involved in so many aspects of our health,” said Gordon Freedman. “Our goal here is to leverage our knowledge of cancer and mitochondria to improve human health.”
A Conversation with the Authors.
MitoWorld: The Cell Press Symposium on “Multifaceted Mitochondria” will emphasize the close relationship between cancers and mitochondria. What are you looking forward to from that meeting?
MacVicar: The roundtable session dedicated to mitochondria in cancer will be a nice opportunity to discuss new ideas for characterizing mitochondrial signatures in tumors and identifying disease-specific metabolic vulnerabilities.
Greaves: I am particularly looking forward to the round-table discussion. It will be exciting to hear different perspectives from researchers working in cancer, mitochondrial disease, and basic mitochondrial research, and to explore where these fields overlap.
Fisher-Wellman: The conference will bring together experts in mitochondrial biology across multiple disciplines. This kind of interdisciplinary environment is often the best catalyst for new ideas and impactful collaborations.
MitoWorld: Your commentary describes three general areas of intersection between mitochondria and cancers. Is there one area that you think will yield patient benefit sooner than the others?
MacVicar: Metabolic reprogramming, mitochondrial genetics and cell death signaling are interconnected. Unveiling the interactions between these mechanisms will improve our chances of targeting mitochondria effectively in future cancer treatments.
Fisher-Wellman: Because all therapies must achieve a therapeutic window, I am bullish on leveraging the intrinsic biology of tumor cells to drive cancer-type–specific targeting. The success of CLPP activators is a strong example. Once specificity was achieved (CLPP is highly expressed in the indicated cancers relative to most all other tissues of the body), durable responses can follow.
Greaves: I think mitochondrial signaling and its role in cancer therapy resistance may be the fastest route to patient benefit. While targeting cancer metabolism is an attractive approach, I think we need to be cautious, given the potential for toxicity in healthy tissues. Understanding how mitochondrial function influences treatment response in specific cancer contexts may offer more selective ways to improve existing therapies and ultimately benefit patients.
MitoWorld: What has surprised you the most in your studies of cancer and mitochondria?
MacVicar: Coming from a background of studying mitochondria in cultured cell lines, I continue to be amazed by the metabolic crosstalk between cancer cells, immune cells and stromal cells within primary and metastatic tumor microenvironments.
Fisher-Wellman: The remarkable specialization that exists within and across cancers. They are certainly not all organized the same, and this creates a massive opportunity.
Greaves: What has struck me most is the extent of tissue specificity in mitochondrial function across cancers. While not entirely surprising given my background in ageing and mitochondrial disease, it has important implications for therapeutic development.
MitoWorld: Although mitochondrial exchanges between cells was controversial just a few years ago, it now seems to be real. Can you elaborate on how that feature might be leveraged in cancer biology?
Fisher-Wellman: Understanding how these transfer events reshape cancer cell biology and the surrounding immune microenvironment is an exciting area of exploration.
MitoWorld: Can you describe the work of the Mitochondria-Cancer Atlas Working Group and what you hope it will achieve?
Fisher-Wellman: Early efforts to target mitochondria in cancer were heavily skewed toward core energy transduction pathways that are ubiquitous across tissues. While this approach has not translated into clear clinical benefit, it has been informative. The key lesson is that mitochondria themselves are not drug targets per se; rather, the tissue- and context-specific biology encoded within them is actionable. The goal of the Atlas is to systematically define this specialized biology across cancer types, with the aim of enabling truly cancer-specific mitochondrial targeting strategies.
Greaves: I hope that by mapping mitochondrial biology across different cancers, we can gain a better understanding of tissue-specific mitochondrial dependencies and uncover new opportunities for therapy.
Freedman: MitoWorld became interested in cancer and mitochondria to help put definition around the mitochondria transfer question that is debated in the mitochondrial research community. It seemed that cancer provided an incredible long-term laboratory for what can be done to and with mitochondria. Once we examined this, it seemed an atlas of mitochondrial variation by cancer and tumor state would be useful, and we met up with Fisher-Wellman to organize a working group.
MitoWorld: What is your sense of how other researchers and clinicians are picking up on the association of mitochondria with cancer and other diseases?
Freedman: MitoWorld posted a MitoBlog about the mitochondria transfer session, Mitochondrial Transfer Networks in Cancer Progression, at this year’s American Association of Cancer Research. This was one of the first mitochondria sessions at a major cancer conference, and there was standing room only.
Fisher-Wellman: The idea that organelle biology is central to many aspects of cancer cell function is becoming hard to ignore. That said, it is still underappreciated just how different mitochondria are in their intrinsic biology. Mapping this specialization is critical for scaling mitochondrial-targeted therapies that can meaningfully translate to the clinic.
This will be great to learn more about at the MitoWorld roundtable session!
Reference
MacVicar T, Greaves LC, Gammage PA, Tait SWG, Fisher-Wellman KH, Freedman G (2026) Cancer as a window into mitochondrial biology. Cell Metabolism. In press.
A Report from the Mitochondria Panel at SynBioBeta conference in San Jose, CA, May 7, 2026
For the first time in the conference’s fourteen-year history — SynBioBeta draws up to 1,500 founders, investors, Fortune 500 executives, scientists, and government program managers annually — mitochondria had its own dedicated session in the Longevity Track. The session was titled “Mitochondrial Transplantation and Genome Editing: Engineering the Metabolic Engine of Complex Life.” It filled the room and ran long.
Why Mitochondria, and Why Now?
Before the panel opened, it’s worth establishing what the conversation was actually about — because most people in the room had been told since high school that mitochondria are the powerhouse of the cell, and stopped there.
Mitochondria sit at the intersection of aging, metabolic disease, neurodegeneration, cancer, and cellular resilience. The science has been building slowly for decades, largely outside the mainstream of medicine, research and health. For those who understand the intricacy of the mitochondria, its mtDNA, its interactions with the nucleus and its evolutionary symbiosis that formed life as we know it, a question has loomed – can we manipulate mitochondria for improvements in therapy, quality of life and longevity?
Across the landscape of cancer and tumors, the complex involvement of mitochondria are coming into focus: mitochondria in cancer ecology run a range of dynamics, re-programmability, with high overall plasticity. Their form, function, and behavior have been seen in cancers and tumors to be dramatically differentiated by tissue, organ, and cancer. An added layer is that mitochondria have their own DNA, mtDNA, separate from the cell’s nuclear DNA. This raises the question: Can mitochondria be transferred between cells, and resume function? Can they be edited? Or engineered? And nature itself already performs an extraordinary range of mitochondrial configurations across the physiology — which is precisely what makes them such compelling engineering targets – or “platforms.”
A Government Steps In
Mitochondria are difficult to manipulate with drugs and equally challenging to edit their tiny genomes dedicated to making ATP and powering a range of signaling and clean-up or cell death roles. This has made the funding landscape difficult, but also promising. In the U.S., surprisingly little attention is paid to this deep partner in life, disease and death. However, the opposite is true in the U.K, a committed outlier, that has recognized in national health policy, and now innovation funding that mitochondria could lead to a revolution akin to nuclear genomics fifty years ago.
Ryan Olf, a Californian by birth, holds one of the most unusual jobs in science right now: Programme Director of ARIA’s Precision Mitochondria Programme. ARIA is the UK’s DARPA-inspired breakthrough research agency — built explicitly to fund the kind of high-risk, high-reward science that conventional grant-making cannot reach. The fact that an agency like ARIA has placed a major bet on mitochondrial engineering is itself data.
Panelists
Ryan Olf — “My main job is maximizing ARIA’s chances of success and their potential translational impact, in the UK and beyond. We’re just about to kick off the research — teams chosen, contracts being finalized — and there isn’t much I currently needed from the SynBioBeta community to hit our programme’s immediate technical goals. But panels like this one can really move the needle on the long-term impact of our work.”
The mechanism he described is compounding: more people appreciating the role of mitochondria means more people working with them, which means more people possibly using and further developing the tools ARIA is building, which increases the odds those tools get used for what Ryan calls “history-defining breakthroughs — cures for neurodegenerative disease or some cancers among them.”
For a synthetic biology audience, he framed it even more directly:
“Mitochondria are potentially model organisms sitting at the heart of life’s complexity. With the tools we’re developing, they could be the perfect chassis for bridging the most powerful instruments of synthetic biology — sensor-actuator circuits and robust programmability — into eukaryotic cells.”
ARIA’s funding choices will be disclosed within two months.
Crossing a Threshold
Maximilian Sichrovsky — Science & Technology Lead for ARIA’s Precision Mitochondria programme, and a biochemist whose own Cambridge PhD focused on mitochondrial membrane transport — was watching the room as much as the stage. What he saw was engagement.
“The scientific case for ignoring difficult problems in mitochondrial biology is becoming increasingly hard to ignore. I think the field is slowly crossing a threshold where the tools to intervene are actually catching up with rising ambitions. What struck me most about the session was how engaged people were — also afterwards, asking me questions and making connections to their own work.”
He was candid about what ARIA’s model is trying to do that the existing ecosystem cannot:
“Most of the mitochondria work being done right now is either deep in academia or scattered across early-stage biotechs. What the ARIA programme is trying to do — coordinate across those silos, set ambitious technical targets, and de-risk the space at a programme level — is a model that doesn’t have many precedents in biotech.
What he found inspiring wasn’t just the established scientists in the room. “Having younger students in the crowd excited about bioenergetics is really inspiring,” he said.
From the Clinic and the Clinic-to-Be
Dr. Colwyn “Coco” Headley works at Stanford’s Cardiovascular Institute, where his mitochondrial transplantation research has drawn support from two institutions that don’t usually fund the same science: NASA NIAC and the American Heart Association. His work sits at what he calls the gap — the distance between bold concepts and the rigorous preclinical validation needed before anything reaches a patient.
“The growing interest from across synthetic biology, cell therapy, aging, and translational medicine signals that the field is moving quickly from an emerging concept into a serious platform for therapeutic innovation. More sustained investment will be needed to bridge the gap between bold concepts, rigorous preclinical validation, and eventual clinical translation.”
He was equally clear about the public education challenge:
“It will be important to re-educate and update the public on the far-reaching impact of mitochondrial health — not only within individual cells, but collectively across tissues, organs, and whole-body systems. The systemic story is what will ultimately drive the clinical and investment momentum this field needs.”
Building on “the Platform”
Mariëlle van Kooten came to the session from inside the startup that is trying to do the engineering work in real time. She co-founded Powerhouse Biology out of a Stanford postdoc and a PhD in Synthetic Systems Biology at ETH Zurich — where her doctoral work contributed to international efforts to build a synthetic cell. Her company is developing precision protein and peptide therapeutics targeting mitochondrial dysfunction, with a mission she describes plainly: reboot the human powerplant. Advisors include Ron Davis of the Stanford Genome Technology Center, Seth Shipman at the Gladstone Institutes, and Pat Sharp, co-founder at Gate Bioscience.
On what makes mitochondria a genuine engineering platform — not just a research subject:
“Mitochondria carry their own heritable genome, are safely enclosed by a double membrane, share conserved biology with well-studied prokaryotes, and as a defined subsystem within the cell they’re feasibly computable. It’s a combination unique among organelles.”
On what has changed to make the moment viable:
“Mitochondria were always a compelling engineering target. What’s changed is that the computational tools now match the dimensionality their biology demands — and the biological tools can validate real candidates. Repair is where Powerhouse starts; the unmet need is immediate and the validation is clearest. But the platform is built to push toward enhanced resilience and durability over the longer arc.”
The Room After the Session
After the formal panel ended, people stayed. That’s usually an indicator that something landed.
Justin Cooper is a tenth grader at Lick-Wilmerding High School in San Francisco, at SynBioBeta because he’s interested in bio entrepreneurship. He called the mitochondria session his favorite workshop of the conference.
“I learned the fundamental differences between mitochondria and nuclear DNA — mitochondrial DNA being passed from the mother — as well as the nuances and severe difficulty of attempting to edit it. I see great potential in the bioengineering of mitochondria in cancer research and human performance. Building a virtual mitochondrial model would be a key step in the creation of full virtual cell models. Techniques such as using phage-derived enzymes could hold promise in precisely editing mitochondrial DNA.”
His next step: researching how engineering mitochondrial DNA might be used to prevent cancer — specifically targeting cancer mitochondria to prevent their function. A tenth grader, leaving with a research agenda.
Devashree Hemant Agarwal, an undergraduate research assistant in the Bioinformatics Lab at San Jose State University, was also there — and her reflections on what drew her to the session.
“I was just curious about seeing the newest research and progression on mitochondria. The panel discussion was very informative, and had professionals from the industry, academia, and start-ups; so, we got to listen to different perspectives on a very concentrated area of research. It was my first time listening to a panel focused on mitochondrial and gene editing research, and I got to learn a lot of new things!
Dr. Laura Hix Glickman, Co-Founder and CEO of Adjuvia Therapeutics, was also in the room. A cancer immunologist and serial biotech entrepreneur with over 25 years of experience, she co-invented one of the first synthetic astaxanthin derivatives and has spent years studying the role of mitochondria in oxidative stress, inflammation, and cancer. Adjuvia is developing ATI-105 — an oral small molecule nanoparticle formulation targeting mitochondrial dysfunction — for Friedreich’s Ataxia and Leigh Syndrome, with planned clinical trials at CHOP initiating later this year.
On what drew her to the session:
“I was thrilled that there even was a panel focused on mitochondria — it’s about time. I truly believe this is the beginning of a new era, and to learn about the new ways and new tools scientists are using to better understand mitochondrial biology was very exciting.”
On the U.S. government’s relative silence on mito-tech:
“These are difficult days for US research, and we are ceding ground to the rest of the world across all of our research and development agencies due to the unprecedented pullback in government funding. But we will learn what we can from our friends overseas while we wait out this administration, and I know now we have many dedicated scientists who are undaunted in their quest to unlock the secrets of mitochondrial biology.”
What This Moment Means
The SynBioBeta session was not a single event. It was a signal.
For the first time, the Bay Area’s defining synthetic biology conference made room for mitochondrial bioengineering as a serious platform technology — not a curiosity, not a footnote, but a session in the Longevity Track alongside gene editing, synthetic proteins, and AI-driven drug discovery. In the room: a UK government program director running a DARPA-equivalent mitochondria initiative. A startup founder building the first mitochondria-targeted therapeutics for childhood rare diseases. A Stanford researcher funded by NASA and the American Heart Association. A tenth grader leaving with a cancer research agenda. An undergraduate bioinformatics researcher whose questions reflected exactly the next generation the field needs.
Mitochondrial bioengineering is not a future possibility. It is happening now — in California labs, in UK government programs, in a new generation of startups whose founders see in mitochondria what an earlier generation saw in mRNA: a platform capable of addressing an enormous range of human disease and aging.
The conversation is open. We, at www.MitoWorld.org, hope to start a Mito-Bioengineering working group, meet-ups and webinars.
Contact: Info@MitoWorld.org | www.MitoWorld.org
Mitochondria house metabolic pathways that support cell growth, survival, function and identity. Mutations in mitochondrial metabolic enzymes are drivers of many mitochondrial diseases, but different diseases arise when certain metabolic functions are disrupted, and the cell types affected are often poorly understood. In recent work published in Cell and Molecular Cell, a research team at Memorial Sloan Kettering Cancer Center, led by Abigail Xie, Julia Brunner and Lydia Finley shed light on when cells use different metabolic pathways within mitochondria and what essential functions are supported by mitochondrial metabolic networks.
The researchers focused on two related metabolic pathways that are required for importing nutrients into mitochondria and converting them into molecules that cells need to function. The tricarboxylic acid (TCA) cycle harnesses reducing equivalents from nutrients to fuel energy production in the electron transport chain (ETC), and the malate-aspartate shuttle transfers reducing equivalents from the cytosol to mitochondria for deposition onto the ETC. Despite the central role of these pathways within cellular metabolism, mammalian cells display surprising heterogeneity in whether, and how, they use these pathways. For example, some reactions of the TCA cycle can run in reverse or be skipped by exporting intermediates that are converted in the cytosol. The authors, therefore, set out to investigate the factors and contexts that dictate how the TCA cycle and related pathways are assembled in mammalian cells.
Reporting in Cell, co-first authors Xie and Brunner sought to determine what makes cells use the complete set of reactions that make up the “canonical” TCA cycle. They found that increasing cellular nutrient consumption by supplying cells with TCA cycle substrate pyruvate increased the production of citrate, the metabolite formed in the first step of the TCA cycle. Enhancing citrate production led to increased forward flux through the TCA cycle and induced dependence on enzyme aconitase 2, the TCA cycle enzyme that that breaks down citrate. To determine if aconitase 2 is also essential to break down citrate in vivo, they generated a mouse model of whole body, inducible aconitase 2 deficiency. Here, they discovered the kidney to be exquisitely sensitive to aconitase 2 loss. Notably, the kidney is unique for its ability to uptake and catabolize circulating citrate. The authors showed that cell autonomous citrate uptake is sufficient to induce reliance on aconitase 2 in cultured cells. Collectively, these results indicate that a major function of the TCA cycle is to remove citrate from mitochondria. This work demonstrates that apart from its known roles in nutrient breakdown and provision of metabolic intermediates, the TCA cycle is also important for metabolite clearance.
In the second study, the authors described how pathways that feed into the TCA cycle are differentially utilized depending on cell state. For cell metabolism to continually function, reducing equivalents generated in the cytosol must be transferred to mitochondria, where they can be safely deposited on the ETC. Reciprocally, oxidized intermediates generated within mitochondria must be delivered to the cytosol where they can be used to fuel biosynthetic pathways. One pathway, the malate-aspartate shuttle, fulfills both needs by transferring reduced nutrients (the TCA cycle intermediate malate) to mitochondria in exchange for aspartate. Mitochondrial production of aspartate is an essential function of the ETC in cultured cells. Here, the authors showed that the ability of aspartate to participate in the malate-aspartate shuttle and transfer reducing equivalents back into mitochondria depends on the relative balance between aspartate supply and demand within cells. Increasing or decreasing cytosolic aspartate levels with bacterial enzymes allowed cells to increase or decrease flux through the malate-aspartate shuttle, respectively. In turn, changing malate-aspartate shuttle flux changed how cells use metabolic pathways that depend on clearing reducing equivalents from the cytosol. Specifically, the ability to oxidize glucose required increased malate-aspartate flux. Accordingly, whereas proliferating cells with high aspartate demand had limited malate-aspartate shuttle flux and reduced glucose oxidation, differentiated cells with lower aspartate demand exhibited higher malate-aspartate shuttle flux that was sufficient to enable increased glucose oxidation—a metabolic hallmark of differentiated cells.
These findings illustrate how metabolic networks adopt different configurations depending on environmental context and cell state. Understanding when, and why, metabolic components become essential for different tissues and contexts will ultimately provide insight into the etiology of metabolic disease and nominate new approaches to target metabolism to manipulate cell states in cancer and other diseases.
A Statement of Significance from Dr. Lydia Finley
Mitochondria play critical roles converting nutrients into the molecules that cells need to function, but which metabolic pathways are used and which outputs are essential for cells are highly context-specific. For example, mutations in mitochondrial enzymes result in highly tissue-specific pathologies, indicating that different tissues—different cell types or cell states—have unique requirements for outputs of individual enzymes. In two papers, Brunner, Xie, and colleagues add to our understanding of how mitochondrial metabolic pathways are wired in to meet the demands of different cell contexts. In one study, they show that some cells depend on the TCA cycle not just to support energy production or anabolic synthesis but also to prevent metabolite accumulation within mitochondria. In another study, they show that as progenitor cells differentiate, they fully engage the malate-aspartate shuttle—an electron shuttle that enables cells to oxidize glucose within mitochondria. Together, these studies show how metabolic programs are wired to meet unique demands of different cell states. These studies support the argument that further identifying when and why metabolic enzymes are required will provide critical insight into how mitochondria support cell fitness and why mutations in mitochondrial genes lead to human disease.
A Conversation with Dr. Lydia Finely:
MitoWorld: How did you become interested in studying mitochondria? What interests you about them?
Dr. Finley: I became interested in metabolism as an undergraduate when I first learned that muscles can continually switch fuels to meet metabolic demands during exercise. This adaptability fascinated me, and I ended up working in a mitochondrial bioenergetics lab studying how mitochondria select different fuels to use during exercise and recovery from exercise. This adaptability fascinates me to this day: mitochondria are constantly sensing and responding to their surroundings and providing information about their decisions to the rest of the cell. They are like a little brain within a cell, taking in information and coordinating cellular responses.
MitoWorld: You mention that the kidney is uniquely sensitive to ACO2 deletion in the TCA cycle. Is that simply because it has to process so much citrate to remove it from circulation, or do you think there may be other reasons for this?
Dr. Finley: Likely many factors contribute to the importance of ACO2 in the kidney. We focused on the role of citrate uptake and showed that citrate uptake is sufficient to induce ACO2 dependence in non-kidney cells. That doesn’t rule out other functions of ACO2 in the kidney. Notably, the kidney proximal tubule cells, which displayed pathological abnormalities following ACO2 loss, are considered to be some of the most energy-demanding cells in the body. It will be interesting for future studies to determine whether this energy requirement contributes to ACO2 dependence in the kidney and, potentially, other organs.
MitoWorld: Other than the kidney, are there other types of cells or disease contexts that have unique characteristics or sensitivities when it comes to the TCA cycle? What does this tell you about them?
Dr. Finley: This is a major open question. Patients with ACO2 mutations often manifest with retinal phenotypes, suggesting that this cell type may have high reliance on ACO2. In cultured cancer cells, ACO2 is one of the most variably essential metabolic genes, meaning that some cells don’t care much about ACO2, while others do. What underlies this variability is a major question for us moving forward.
MitoWorld: The metabolic hallmark of differentiated cells with regard to the malate-aspartate shuttle is very interesting. Is this generally true of all types of differentiated cells, or are there some cell types that behave differently? Are there disease contexts where this changes, such as in cancer?
Dr. Finley: This is a great question. We’ve tested a few contexts where the transition from proliferative, progenitor to differentiated states shows this characteristic metabolic switch. How generalizable this switch is remains to be determined. Likely, some differentiated tissues will have specific metabolic requirements that push them to an alternate metabolic state. Continuing to identify how changes in cell state reorganize metabolism and which metabolic programs are required for certain cell states is a major area for future work.
MitoWorld: How might these pathways be targeted to treat disease, as you suggest in the conclusion? Through pharmaceuticals, through diet, other?
Dr. Finley: To know how to treat disease, we need to know why the disease arises. In many cases, mitochondrial diseases driven by the same genetic mutation affect different tissues (and even different people) differently. Why some tissues care more than others about specific mutations isn’t always clear. This variable dependence suggests that metabolic enzymes are required to meet needs that are specific to some tissues. If we can understand what these needs are—which metabolic outputs support essential functions in different tissues—we can better understand why pathologies emerge and, then, hopefully identify strategies to help tissues meet their specific needs and overturn these pathologies.
MitoWorld: What are the next steps for this research? What questions are you still trying to answer and why are they important?
Dr. Finley: We found that citrate accumulation within mitochondria activates a stress response known as the integrated stress response, which turns on genes that helps cells adapt to stress or other environmental changes. We are working to understand how mitochondrial citrate, or consequences of citrate accumulation within mitochondria, turn on a cytoplasmic stress response. We hope these studies will provide new insight into how changes within mitochondria are communicated throughout the cell to help cells adapt and respond to changes in mitochondrial activity.
MitoWorld: Anything else you think the audience should know?
Dr. Finley: Metabolism is not one-size-fits-all. It highly, highly variable, and there is a lot left to learn about cell metabolism!
References:
Abigail Xie, Julia S Brunner, Sangita Chakraborty, Angela M Montero, Anna E Bridgeman, Katrina I Paras, Ruobing Cui, Maider Fagoaga-Eugui, Monika Komza, Paige K Arnold, Benjamin T Jackson, Santiago Noriega Madrazo, Mohamed I Atmane, Sebastian E Carrasco, Lydia W S Finley (2026) Citrate clearance is a major function of aconitase 2 in the canonical TCA cycle. Cell 189(9):2684-2699.e21.
https://pubmed.ncbi.nlm.nih.gov/41763199/
Julia S Brunner, Anna E Bridgeman, Benjamin T Jackson, Sangita Chakraborty, Maider Fagoaga-Eugui, Katrina I Paras, Abigail Xie, Paige K Arnold, Julia Losner , Lydia W S Finley (2026) Aspartate availability drives differential engagement of the malate-aspartate shuttle. Mol Cell. Mar 5;86(5):954-967.e7.
“What was striking was not simply that mitochondrial transfer was being discussed, but how many different cancer systems it appeared to connect. Across all three talks, mitochondria were presented less as isolated organelles and more as mobile biological assets shaping metastasis, immune exhaustion, therapeutic resistance, and even tumor innervation. You could feel the field beginning to connect previously separate observations into a larger systems-level framework.”
— Alex Sercel, Co-Founder, MitoWorld.org
For decades, mitochondria occupied an uneasy place in cancer research. Everyone knew they mattered. They appeared in discussions of metabolism, apoptosis, oxidative stress, and cellular energetics. But they rarely occupied center stage at major oncology meetings. The mitochondrion was often treated as background infrastructure — essential, certainly, but secondary to the “real” drivers of cancer biology.
Something changed at the American Association for Cancer Research (AACR) Annual Meeting 2026 in San Diego.
For the first time in the history of the AACR Annual Meeting, mitochondrial transfer in cancer was given its own dedicated symposium. That may sound procedural to outsiders, but to researchers working at the intersection of mitochondria, metabolism, immunology, and cancer, it represented something much larger: institutional recognition that mitochondrial dynamics are no longer peripheral to oncology. They are becoming central to it.
The symposium, “Mitochondrial Transfer Networks in Cancer Progression,” brought together three researchers approaching the field from distinct but converging directions:
- Yosuke Togashi, Okayama University
- Simon Grelet, University of South Alabama / Mitchell Cancer Institute
- Luca Gattinoni, University of Regensburg / Leibniz Institute for Immunotherapy (LIT)
Collectively, the presentations argued something profound: mitochondrial transfer is not a niche biological curiosity. It is emerging as a fundamental mode of intercellular communication in cancer biology — one that tumors exploit, immune systems respond to, and future therapies may intentionally manipulate.
After the session, MitoWorld.org reached out to all three panelists with a series of questions about the field, the symposium, and where mitochondrial cancer biology may be headed next. What emerged from those conversations was not just enthusiasm, but the unmistakable sense that an entire area of science is crystallizing in real time.
A Field Arrives
When asked what made the AACR symposium so important, all three researchers independently focused on the same point: this was a first.
“This was, to my knowledge, the first time mitochondrial transfer in cancer had been given its own dedicated special session at AACR,” explained Simon Grelet. “The room was charged with enthusiasm and curiosity.”
Yosuke Togashi emphasized the scale of interest from the oncology community itself:
“The sheer volume of questions indicated a significant surge in interest regarding how mitochondrial dynamics influence oncology.”
For Luca Gattinoni, the significance was not merely that the session existed, but how it was framed.
“The three talks together made an argument that no single one of us could have made alone: that mitochondrial transfer is not a niche phenomenon but a fundamental mode of intercellular communication that tumors exploit and that we can potentially exploit back.”
That framing matters.
Cancer biology has increasingly become the biology of systems: tumor microenvironments, immune interactions, stromal signaling, metabolism, and cellular networking. What mitochondrial transfer research suggests is that mitochondria themselves may function as active biological currency moving between cells — influencing survival, adaptation, immune suppression, metastasis, and therapeutic resistance.
From “Power Plants” to Networks
One of the strongest themes emerging from the symposium was that the classical textbook view of mitochondria is rapidly collapsing.
For generations, mitochondria were taught primarily as intracellular energy factories — isolated organelles generating ATP inside sealed cellular boundaries.
That view now appears incomplete.
“The field is moving away from the traditional view of the mitochondrion as an isolated ‘power plant’ enclosed within a cell,” said Yosuke Togashi. “Instead, we are beginning to understand it as a dynamic component of a larger networking system.”
That conceptual shift may ultimately prove as important as any individual experiment.
Mitochondria are increasingly being understood not simply as metabolic engines, but as signaling entities, stress sensors, inflammatory regulators, and now potentially mobile intercellular participants capable of moving between cells and altering biological outcomes.
Simon Grelet noted how rapidly evidence for mitochondrial transfer has accumulated across multiple dimensions of cancer biology:
“It is proving to touch multiple dimensions of cancer biology: how tumor cells acquire metabolic advantages, how they interact with their microenvironment, how they evade treatment, and more.”
Meanwhile, Luca Gattinoni highlighted how evidence is arriving simultaneously from very different domains:
“Nerve-tumor interactions shaping metastasis, tumor cells offloading dysfunctional mitochondria to suppress immune responses, stromal cells using the same mechanism to sustain T cell fitness.”
“The same biological currency,” he added, “deployed in radically different contexts.”
The Room Itself Told the Story
Scientific meetings often reveal the future of a field less through formal presentations than through hallway conversations afterward.
By all accounts, that happened here.
Yosuke Togashi was struck not only by the engagement during the session, but by what happened after it ended:
“The technical nature of the follow-up questions showed that researchers are already thinking about how to integrate these concepts into their own models.”
Luca Gattinoni described something rarer still:
“The conversation that emerged felt like the field thinking out loud in real time.”
That may ultimately be the most important signal of all.
Not simply that mitochondrial transfer research is growing, but that cancer researchers working in metastasis, immunotherapy, stromal biology, metabolism, and genomics are beginning to realize they are asking overlapping questions about the same underlying system.
The Next Frontier: mtDNA and the Mitonuclear System
If mitochondrial transfer itself is emerging as a major area, the next wave may center on mtDNA and the mitonuclear system.
The mitochondrial genome remains one of the least fully integrated components of modern cancer biology. Heteroplasmy, mutation dynamics, mitochondrial-nuclear coordination, and intercellular mitochondrial inheritance remain only partially understood.
Yosuke Togashi believes advancing sequencing technologies will rapidly change that.
“While the complexities of mutation patterns and heteroplasmy remain largely mysterious, advancing sequencing technologies will soon make this a focal point of cancer genomics.”
Luca Gattinoni sees the mitonuclear axis becoming its own frontier:
“We now have enough mechanistic footing to ask harder questions about directionality, selectivity, and what it truly means for a cell to absorb another cell’s mitochondria and their DNA.”
And perhaps most intriguingly, he believes the future will move beyond observation:
“The ambition should grow: not just observing transfer, but engineering it with intent.”
That single sentence hints at where this field could eventually lead: mitochondrial engineering, mitochondrial immunotherapy, and perhaps entirely new therapeutic architectures built around manipulating cellular energy and signaling systems directly.
A New Scientific Convergence
Historically, mitochondrial biologists and cancer researchers often existed in adjacent but separate scientific cultures. That separation may now be ending.
Simon Grelet noted that mitochondrial biology appeared across multiple AACR tracks far beyond this single symposium.
Meanwhile, Yosuke Togashi offered perhaps the most insightful observation of the entire discussion:
“The most vital ‘transfer’ occurring right now isn’t just between cells, but between disciplines.”
That may ultimately define this moment.
Cancer biology, immunology, mitochondrial medicine, metabolism, genomics, and systems biology are beginning to converge around a shared realization: mitochondria are not passive background organelles. They are dynamic participants in disease.
AACR 2026 may be remembered as one of the first moments when that convergence became visible at scale.
And if the energy in San Diego was any indication, this is only the beginning.
In a recent study by Dr. Ana Andreazza of The University of Toronto, a team of researchers generated 3D brain organoids from patient blood cells to study how cells from patients with bipolar disorder differed from those without. Culturing these brain organoids from 3 normal controls and 3 patients with bipolar disorder (BD), they find significant metabolic and immune differences that impact neuronal function. The study published in Translational Psychiatry points to mitochondria as key players in this complex psychiatric condition.
Comparing BD-derived brain organoids to normal controls, Andreazza finds many abnormalities. While their structure, organization and cell types are normal (consisting of neurons and astrocytes), their metabolic function is impaired. Deficits in ATP within these cells can be traced back to dysfunctional mitochondria, which exhibit altered morphology and weaker membrane potentials. BD brain organoids have small, rounded mitochondria, indicative of immature organelles experiencing oxidative stress and fragmentation. Indeed, these mitochondria show deficits in membrane potential and polarization, which are essential to generate ATP. As a result, these cells are not able to keep up with the high energy demands of neurons in the brain, leading to misfiring and hyperactive neural networks that are a hallmark of BD. This energy deficit also impairs neurogenesis, with BD brain organoids containing fewer cells than controls.
Not only do dysfunctional mitochondria impact brain function via energy deficits, but they also drive a neuroinflammatory cascade that further damages neurons. When mitochondria are stressed they release reactive oxygen species (ROS) and mitochondrial DNA (mtDNA) into the cell, both of which are elevated in the BD brain organoids compared to controls. These molecules trigger innate inflammatory pathways, including inflammasome activation, that drive neuroinflammation and pathology in a self-reinforcing cycle. These impacts are observed in neurons and astrocytes, supporting cells that promote neuronal health but can perpetuate inflammatory damage when dysregulated.
Many of Andreazza’s findings in brain organoids parallel observations in patients with BD. For example, high ROS and mtDNA are associated with symptom severity in patients. As such, she attempts to correct some of these abnormalities with molecules that block inflammasome activation. Applying the inflammasome inhibitor MCC950 normalizes inflammasome activity in BD brain organoids and also reduces mtDNA release, indicating a reduction in mitochondrial stress. However, phase II studies of MCC950 for the treatment of autoinflammatory and autoimmune disorders suggest it may cause liver toxicity, so Andreazza also tested a new compound: Bioactive Flavonoid Extract (BFE), which has antioxidant, anti-inflammatory and neuroprotective effects via partial inflammasome inhibition. While inflammasome inhibition was not as strong with BFE, it did reduce mtDNA release to a similar extent. There may be opportunities for elevating the dose or combining it with other treatments to achieve greater impacts.
Altogether Andreazza’s study deconstructs molecular and cellular mechanisms at the intersection of metabolic and immune dysregulation in bipolar disorder. With the novel patient-derived 3D brain organoid model, she aims to bridge the gap between molecular pathology and clinical interventions.
Statement of Significance from Dr. Andreazza:
This study provides a patient-derived, human brain model that links mitochondrial dysfunction, inflammasome activation, and abnormal neuronal activity in bipolar disorder. Led by first author Dana El Soufi El Sabbagh, our team generated cerebral organoids from induced pluripotent stem cells derived from individuals with bipolar disorder and matched controls. The bipolar disorder organoids showed reduced ATP production, altered mitochondrial morphology and membrane potential, increased release of reactive oxygen species and cell-free mitochondrial DNA, and heightened NLRP3 inflammasome sensitivity, accompanied by hyperactive neuronal firing. Importantly, pharmacological inhibition of NLRP3 and a bioactive flavonoid extract partially restored cellular homeostasis, supporting the mitochondria-inflammasome axis as a tractable therapeutic pathway. This work was made possible through a close partnership with Australian collaborators at Deakin University, IMPACT and Barwon Health, who enabled patient recruitment and sample preparation. We are especially grateful to the patients and controls whose participation made this research possible.
A Conversation with Dr. Andreazza:
MitoWorld: Do you have an idea or theory on how mitochondrial dysfunction may play a role in the flip between manic and depressive episodes in bipolar disorder? Are the mitochondria acting differently in these different circumstances?
Dr. Adreazza: Our study did not directly compare cells from manic versus depressive states, so I would be cautious about assigning a specific mitochondrial profile to each episode. What we can say is that mitochondria sit at the centre of processes that are highly relevant to mood-state transitions: ATP production, calcium buffering, oxidative stress, inflammatory signalling, and neuronal excitability. One working model is that an intrinsic mitochondrial vulnerability reduces the energetic flexibility of neurons and astrocytes. During periods of high demand, such as sleep disruption, psychosocial stress, or systemic inflammation, cells may compensate by increasing excitability and stress signalling. This could contribute to manic symptoms in some contexts. Over time, the same system may become energetically depleted, inflammatory pathways may remain activated, and neuronal networks may lose resilience, contributing to depressive symptoms. Rather than mitochondria being entirely different organelles in mania and depression, I think their function may shift dynamically across a spectrum of energetic compensation, oxidative stress, and inflammatory burden.
MitoWorld: Bipolar disorder, and many other psychological conditions where mitochondria are implicated, arise during late adolescence and early adulthood. Do you expect this is when the mitochondria start dysfunctioning, or have they been dysfunctioning all along and reach a certain threshold around this time? Why now?
Dr. Adreazza: I suspect that, in many individuals, mitochondrial vulnerability is present before the first clinical episode, but it may not become functionally limiting until the brain reaches a developmental and environmental threshold. Late adolescence and early adulthood are periods of intense synaptic refinement, circuit maturation, hormonal change, circadian instability, increased psychosocial stress, and, for many people, changes in sleep, diet, and substance exposure. All of these factors place substantial demands on mitochondrial metabolism and redox regulation. If mitochondrial reserve capacity is already reduced, the system may tolerate early development but become less able to adapt when neuronal circuits require more precise energy regulation. Our cerebral organoid data support the idea of an intrinsic, patient-derived cellular vulnerability, because the mitochondrial, inflammatory, and electrophysiological phenotypes emerged in vitro. However, clinical illness likely reflects the interaction between this vulnerability and developmental timing, genetic background, medications, lifestyle, immune activation, and environmental exposures.
MitoWorld: The use of therapeutics to target the inflammasome in your study sounds promising… what are the next steps for potential treatments along those lines? Are there other therapies targeting mitochondria directly that have been tried? What are the challenges to this approach?
Dr. Adreazza: The next step is replication and refinement. We need to test a larger and more clinically diverse set of patient-derived organoids, define dose-response and timing effects, and determine whether inflammasome modulation improves not only inflammatory markers, but also mitochondrial function and neuronal activity. MCC950 was useful experimentally because it is a selective NLRP3 inhibitor, but concerns about hepatotoxicity make it less straightforward as a clinical path. This is why compounds such as the bioactive flavonoid extract are interesting: they may provide broader antioxidant and anti-inflammatory effects, although their potency, active components, pharmacokinetics, safety, and ability to reach the brain need careful evaluation. Mitochondria-directed strategies have also been explored in mood disorders, including agents that influence oxidative stress, bioenergetics, and mitochondrial resilience, such as N-acetylcysteine, coenzyme Q10, creatine, and the mitochondrial effects of lithium. The challenge is that mitochondria are essential in every tissue, and bipolar disorder is biologically heterogeneous. We will need biomarkers to identify who has a mitochondria-inflammatory phenotype and to monitor target engagement.
MitoWorld: How did you become interested in the connection between mitochondria and bipolar disorder? Were you surprised to find this integral relationship?
Dr. Adreazza: My interest developed from the observation that bipolar disorder is not only a disorder of mood regulation, but also a disorder associated with systemic metabolic and inflammatory abnormalities. Over many years, studies from our group and others identified oxidative stress, altered mitochondrial enzymes, and cell-free mitochondrial DNA in blood and brain samples from individuals with bipolar disorder. Those findings made mitochondria a compelling biological link between cellular metabolism, immune activation, and neuronal function. I was not surprised that mitochondria were involved, but I was struck by how clearly the organoid model connected these domains. In the same patient-derived system, Dana El Soufi El Sabbagh and the team could observe impaired mitochondrial energetics, increased mitochondrial stress signals, heightened NLRP3 inflammasome sensitivity, and altered neuronal firing. That integration is important because it moves us beyond isolated biomarkers and toward a mechanistic framework for understanding how cellular stress may influence brain circuit function.
MitoWorld: What is next for this research?
Dr. Adreazza: The immediate priority is to expand the cohort and incorporate clinical information that may explain biological heterogeneity, such as illness stage, predominant polarity, medication exposure, metabolic status, inflammatory burden, and treatment response. We also want to improve the organoid platform by adding greater cellular complexity, including microglia and vascular-like components, because immune and metabolic signalling in the brain depends on interactions among multiple cell types. Longitudinal organoid studies will allow us to follow mitochondrial function, inflammasome activity, and neuronal excitability over developmental time. Another important direction is therapeutic screening. Patient-derived organoids can help us test whether targeting the mitochondria-inflammasome axis restores cellular homeostasis and whether responses differ among individuals. Ultimately, our goal is to integrate organoid biology with blood-based biomarkers, such as cell-free mitochondrial DNA and metabolomic profiles, to move toward more precise, mechanism-based interventions for bipolar disorder.
MitoWorld: Anything else you would like the audience to know?
Dr. Adreazza: I would like to emphasize that this work was highly collaborative. Dana El Soufi El Sabbagh, the first author, led the experimental work across iPSC culture, cerebral organoid generation, mitochondrial assays, inflammatory assays, data analysis, interpretation, and manuscript preparation. The project also depended on an international partnership with our Australian colleagues at Deakin University, IMPACT and Barwon Health, whose expertise in clinical phenotyping, patient selection, and sample preparation made the patient-derived model possible. We are deeply grateful to the individuals living with bipolar disorder, as well as the healthy control participants, who contributed samples and trusted us to use them responsibly. Their participation allows us to study disease mechanisms in a human cellular context that would otherwise be inaccessible. I hope the audience sees this study not as a final answer, but as a platform for building more biologically precise and compassionate approaches to understanding and treating bipolar disorder.
Reference:
iPSC-derived cerebral organoids reveal mitochondrial, inflammatory and neuronal vulnerabilities in bipolar disorder. El Soufi El Sabbagh, D., Kolinski Machado, A., Pappis, L., Beroncal, E. L., Ji, D., Nader, G., Ravi Chander, P., Choi, J., Duong, A., Jeong, H., Panizzutti, B., Bortolasci, C. C., Szatmari, A., Carlen, P., Hahn, M., Attisano, L., Berk, M., Walder, K., & Andreazza, A. C. (2025). Translational Psychiatry, 15, Article 303. https://doi.org/10.1038/s41398-025-03529-7
Melanoma cells release abnormal mitochondria into the extracellular compartment. This novel mitochondrial quality-control mechanism points to possible biomarkers for the disease. The results of the study were recently published in a paper in Cancer Letters and led by Francisca Alcayaga-Miranda.
Melanoma cells experience significant levels of oxidative stress. While they depend on glycolysis, they still need mitochondria for other cell functions. Other studies had shown that damaged mitochondria are expelled from a stressed cell. However, it was not known if this process occurred with melanoma cells and how it was accomplished.
The research team sought to clarify this process. Using electron microscopy, they examined mitochondria released from normal and melanoma cells from mice. All cell lines released damaged mitochondria. The differences were found in the amounts of mitochondria released and the routes. The mitochondria were released through a non-vesicular route. Furthermore, the expelled mitochondria lacked cristae and had multiple other indications of loss. Complementary analyses showed that melanoma cells do not degrade mitochondria through canonical mitophagy in conditions of oxidative stress. Instead, melanoma cells upregulate mitochondrial release to the extracellular medium. With this data, the team concluded that the melanoma cells release mitochondria as an alternative mitochondrial quality control mechanism.
Interestingly, the mitochondria expelled from the melanoma cells were detected in the tumor microenvironment and plasma of the mice. The levels of those mitochondria correlated with the tumor burden. In agreement with these findings, more total extracellular mitochondria were also detected in the circulation of melanoma patients, supporting the translational relevance of this phenomenon.
The study revealed a novel mechanism for releasing dysfunctional mitochondria. It also points to new strategies for non-invasive biomarkers and therapies.
A Statement of Significance from Dr. Alcayaga-Miranda:
This study expands the conceptual framework of mitochondrial quality control in cancer by showing that melanoma cells can externalize structurally and functionally altered mitochondria into the tumor microenvironment and circulation. Rather than being confined to intracellular degradation pathways, mitochondrial dysfunction in melanoma may generate extracellular signals that reflect tumor-associated stress, mitochondrial quality-control imbalance, tumor burden, and systemic disease progression. These findings open two important horizons: first, the development of minimally invasive biomarkers based on circulating extracellular mitochondria, and second, the need to define whether tumor-derived mitochondrial material is only a consequence of mitochondrial stress or also an active mediator of immune modulation and metastatic niche formation. Thus, this work provides a foundation for future mechanistic and translational studies aimed at understanding extracellular mitochondria as both measurable indicators and potential functional players in melanoma progression.
A Conversation with Dr. Alcayaga-Miranda:
MitoWorld. This is rich study filled with experimental detail. Can you give us an idea of what you are considering to follow up on this research?
Dr. Alcayaga-Miranda: Our next step is to determine whether extracellular mitochondria released by melanoma cells are merely a consequence of mitochondrial stress or whether they actively contribute to tumor progression. We are particularly interested in understanding how this mitochondrial material interacts with the tumor microenvironment, especially immune cells, and whether circulating extracellular mitochondria can be further developed as minimally invasive indicators of tumor burden and disease progression.
MitoWorld. It is interesting that multiple mechanisms are available to expel mitochondria. Do you have any thoughts on why these exist?
Dr. Alcayaga-Miranda: Cells likely rely on more than one mechanism to eliminate or externalize mitochondria because mitochondrial quality control is highly context-dependent. Depending on the intensity of cellular stress and the capacity of intracellular degradation pathways, damaged mitochondria may either be degraded within the cell or exported through alternative routes. In melanoma, our findings suggest that extracellular mitochondrial release may represent an additional layer of mitochondrial quality control, particularly when mitochondrial stress is sustained or canonical degradation pathways are insufficient.
MitoWorld. You indicate that melanoma release mitochondria into the bloodstream. It is amazing that so many mitochondria are circulating. Do you have any estimates of that or of how long they circulate before being completely eliminated?
Dr. Alcayaga-Miranda: At this stage, we do not yet have precise estimates of how long extracellular mitochondria remain in circulation. This is an important open question. Their persistence is likely influenced by structural integrity, association with vesicular or non-vesicular compartments, recognition by phagocytic cells, and clearance by organs involved in filtering circulating particles. Future kinetic studies will be necessary to define their half-life, clearance routes, and whether these parameters change during tumor progression.
MitoWorld. There have been other reports that mitochondria are transferred from tumor cells to normal cells, such as immune cells. Did you see any evidence of this in your studies?
Dr. Alcayaga-Miranda: In this study, we focused primarily on demonstrating that melanoma cells release dysfunctional mitochondria into the tumor microenvironment and circulation. We did not directly evaluate mitochondrial transfer to immune cells as a central endpoint. However, the detection of tumor-derived mitochondrial material in the tumor microenvironment raises the possibility that these structures may interact with stromal or immune cells. This is one of the directions we are now actively exploring, particularly in relation to how tumor-derived mitochondria may influence antitumor immune function.
MitoWorld. Do you have any plans to pursue the development of biomarkers?
Dr. Alcayaga-Miranda: Yes. One of the translational horizons of this work is to determine whether circulating extracellular mitochondria can be developed as minimally invasive biomarkers. Before clinical implementation, several steps are required, including analytical standardization, rigorous control of pre-analytical variables during blood processing, validation in larger patient cohorts, and comparison with established clinical parameters. Our current data provide a strong rationale for this direction, but biomarker development will require systematic validation.
MitoWorld. We are always interested in what sparked your interest in mitochondria. Can you tell us?
Dr. Alcayaga-Miranda: My interest in mitochondria began with the idea that they are not only intracellular powerhouses, but also dynamic signaling organelles capable of shaping cell behavior and intercellular communication. In cancer, this is particularly fascinating because tumor cells continuously adapt their metabolism under stress. Understanding how mitochondria move beyond the cell may reveal new dimensions of tumor biology and open unexpected translational opportunities.
Reference
Georges-Calderón N, Fuentes C, Hidalgo Y, Grunenwald F, Corrales-Bermúdez J, Figueroa-Valdés AI, Ramirez-Pereira M, Arriagada G, Bustos FJ, Ahumada-Marchant C, Lopez M, Alcayaga-Miranda F (2026) Melanoma cells release dysfunctional mitochondria to the tumor microenvironment and circulation in association with tumor progression. Cancer Letters 647: 218457.
https://www.sciencedirect.com/science/article/pii/S030438352600220X?via%3Dihub
Dysfunctional mitochondria are associated with serious diseases (e.g., neurodegenerative disorders, heart failure), and transplantation of healthy mitochondria to diseased cells has been suggested as a possible therapeutic strategy. Recently, a research team, led by Botond Roska, developed a system for transplanting mitochondria to specific cell types. Their MitoCatch system is an exciting advance in harnessing mitochondria in therapies. The study was published recently in a paper in Nature.
The Roska team sought to identify protein binders that would facilitate the uptake of donor mitochondria by specific target cells. They engineered a series of such binders for their MitoCatch system. Using this system, they showed that the donor mitochondria were internalized into the cytosol and that they behaved as normal mitochondria exhibiting movement, fusion, and fission. In addition, the researchers showed that the mitochondria could be targeted to specific cell types, including retinal, cardiac, endothelial, and immune cells, and neurons. Most importantly, the diseased or damaged cells receiving the donor mitochondria had improved survival and function.
In a relatively short time, mitochondrial transfer has moved from fantasy to reality. The development of MitoCatch now provides a method for targeting specific disease cell types. This exciting advancement brings mitochondrial transfer closer to a therapeutic strategy for serious disease conditions.
A Statement of Significance from Dr. Roska:
Many diseases that involve malfunctioning mitochondria currently have no effective treatment. Transplanting healthy mitochondria into diseased cells has emerged as a promising therapeutic approach, but until now, there has been no reliable way to deliver them to the right cell types in the body. We developed a system called ‘MitoCatch’ that uses protein-based targeting tools to guide healthy mitochondria directly to affected cells. In laboratory experiments with human cells and in live mice, MitoCatch-delivered mitochondria improved the survival of damaged nerve cells. MitoCatch thus offers a new strategy for treating diseases linked to mitochondrial dysfunction by delivering healthy mitochondria precisely where they are needed.
A Conversation with Dr. Roska:
MitoWorld. Your work offers lots of intriguing possibilities. Can you give us an idea of where you are going next to follow up on this paper?
Dr. Roska: We are particularly interested in understanding how long donor mitochondrial DNA can persist in recipient human cells, as this information is important for therapy development. We are also optimizing our bispecific protein binders for specific human applications.
MitoWorld. Your work also has obvious clinical possibilities. Do you plan to exploit those as well?
Dr. Roska: Yes. Our goal is to develop MitoCatch into a therapy. We are in discussions with leading physicians across different medical fields to identify which mitochondrial diseases would be the best fit for the first MitoCatch-based treatments. LHON is among the first candidates.
MitoWorld. We have been following the emergence of mitochondrial transfer for some time. Are you as amazed as we are about how quickly it has been accepted as a fact and as a potential therapy?
Dr. Roska: This is indeed a fascinating field that is moving ahead at lightning speed. There are still sceptics who question the usefulness of mitochondrial transfer as a therapy, but this is healthy in science. The best way to respond to skepticism is to demonstrate the value of mitochondrial transfer in the clinic.
MitoWorld. In the Discussion, you mention that your system, like mitochondria free in the blood, did not elicit an immune response upon transfusions. That’s an interesting observation for your work and evolution. Can you speculate on that?
Dr. Roska: The key question is what these free mitochondria in the blood are doing — whether they are functional or waste products. This is not yet known, and the answer will have important implications for therapy.
MitoWorld. Clearly, mitochondria are the focus of MitoWorld, and we also enjoy hearing what brought researchers to the study of these amazing organelles. Can you tell us how you became interested in mitochondria?
Dr. Roska: About eight years ago I was thinking about the complexities of different therapeutic modalities. Gene therapy introduces one or at most a few genes into the body and so carries very low genetic complexity. Cell therapy, on the other hand, brings all of a cell’s genes into the body and, therefore, operates at extremely high complexity. I wondered whether therapies with an intermediate level of genetic complexity were possible. This led me to think about organelles and mitochondria in particular. At the time, very few papers had been published on mitochondrial transfer, but this has since changed dramatically, and I am very happy to be part of such an exciting and fast-growing field.
Reference
Ayupov T, Moreno-Juan V, Curtoni S, Fratzl A, et al. (2026) Cell-type-targeted mitochondrial transplantation rescues cell degeneration. Nature 15:
Cancer cells need changes to metabolism to supply energy, especially during metastasis. In a recent paper in Cancer Discovery 1, a research team led by Kivanç Birsoy compared the metabolites of normal and breast cancer cells. They found that metastasis of the cancer cells relied on mitochondrial glutathione. This discovery provides insights into the process of metastasis and implicates glutathione as a potential therapeutic target for breast cancer.
The team compared the primary and metastatic breast cancer cells. This metabolomics study revealed accumulation of more mitochondrial glutathione in metastatic cells. Further analysis identified increased expression of SLC25A39. In previous work, the Birsoy group showed that this mitochondrial membrane carrier regulates glutathione transport into mitochondria.2 SLC25A39 is required for metastases, but its loss has no effect on primary tumors. Interestingly, the team found that the stress-induced transcription factor ATF4 could rescue SLC25A39-deficient metastatic cells. This observation links SLC25A39 to activation of ATF4.
This work provides new insights into the processes of metastasis. It defines a new role for glutathione beyond its well-know role antioxidant role. Finally, it suggests that glutathione, SLKC25A39, and ATF4 as possible therapeutic targets for breast cancer.
A Conversation with Dr. Kıvanç Birsov
MitoWorld: What is the next step in continuing your research?
Dr. Birsov: We’ll dissect how mitochondrial glutathione (mtGSH) is required for ATF4 activation. Specifically, we aim to identify the ISR node that senses mtGSH loss (e.g., GCN2 vs. PERK) and map the molecular steps that couple mitochondrial redox to ATF4. In parallel, we’ll define the precise stresses in the lung that drive this dependency using in vivo stress reporters and targeted perturbations. More broadly, our data suggest there are additional “hidden” metabolites that govern metastatic fitness. With our organelle-resolved metabolomics and genetic tools, we’re poised to systematically uncover these metabolites and their transport pathways.
MitoWorld: Can you speculate on the mechanism by which glutathione enhances metastasis? Do you think the effect is felt by making cells lose their connection to other cells or by helping in the actual colonization at a distant site?
Dr. Birsov: It’s a bit more complex. Sean Morrison’s elegant work has shown that glutathione is essential for tumor cell survival in circulation by buffering oxidative stress. Our findings extend this concept but emphasize that the compartmentalized functions of redox metabolites can differ. In our case, mitochondrial glutathione seems to be particularly important during the colonization phase rather than dissemination. We think its role may go beyond antioxidant defense—potentially involving redox-dependent signaling that supports metabolic adaptation and growth at the metastatic site. But this is still an open question and a major focus of our ongoing work.
MitoWorld: Lung and liver are common sites of metastases. Might this connection be generalized for other forms of metastasis or to other organs?
Dr. Birsov: The environments of metastatic sites are vastly different; each imposes unique metabolic stresses and nutrient availabilities. The lung, for instance, is highly oxidative, and the liver can be hypoxic. Because of these differences, I expect distinct metabolic mechanisms to underlie colonization in each organ. Mitochondrial glutathione may be critical in some contexts, but other metabolites and pathways likely take over in different tissues.
MitoWorld: ATF4 seems to be a two-edged sword. It is activated in stress situations, but aids metastasis. Do you have any thoughts about these strange multiple activities?
Dr. Birsov: That’s exactly what makes ATF4 so fascinating. It’s part of the integrated stress response, normally activated to restore homeostasis when cells face nutrient or redox stress. Cancer cells hijack this pathway—what’s meant to be a transient adaptation becomes chronically active, allowing them to survive and grow in hostile environments. In our system, ATF4 activation seems to compensate for the loss of mitochondrial redox balance, effectively turning a stress response into a metastatic advantage. It’s a perfect example of how tumors repurpose normal adaptive programs for malignant ends.
MitoWorld: Do you have any thoughts as to how these findings on glutathione might be translated to a therapy? Might SLC25A39 or ATF4 be a target?
Dr. Birsov: We are actively trying to find small-molecule inhibitors, and we believe this may be helpful for certain cancers. Additionally, we need to know whether there will be off target effects as well.
MitoWorld: How did you become interested in mitochondria in the first place?
Dr. Birsov: We’re fascinated by how mitochondria connect metabolism to disease and cell function. These organelles contain thousands of metabolites, and yet, we still know very little about what most of them do or how their levels are maintained. Our work on mitochondrial transporters provides an entry point to start decoding this complexity, understanding how metabolites move across membranes and how these movements shape cellular behavior.
References
1 Yeh HW, DelGaudio NL, Uygur B, Millet A, Khan A, Unlu G, Xiao M, Timson RC, Li C, Ozcan K, Smith KW, Nascentes Melo LM, Allies G, Basturk O, Sickmann A, Byraktar EC, Possemato R, Tasdogan A, Birsov K (2025) Mitochondrial glutathione import enables breast cancer metastasis via integrated stress response signaling. Cancer Discovery 15: 2437–2449.
doi: 10.1158/2159-8290.CD-24-1556.
2 Wang Y, Yen FS, Zhu XG, et al. (2021) SLC25A39 is necessary for mitochondrial glutathione import in mammalian cells. Nature 599: 136–140.