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.
Now On-Demand: Keystone Symposia’s Mitochondria Signaling in Physiology and Disease
If you missed the Keystone Symposia conference Mitochondria Signaling in Physiology and Disease—held February 9–12, 2026 at Keystone Resort in Colorado—you now have a second chance. On Demand registration is open, giving you access to the full main-session program from one of the most significant gatherings in mitochondrial biology in recent years. See: keystonesymposia.org/conferences/conference-listing/meeting/onpage-program/b12026.
What the Meeting Was About
Co-organized by Navdeep S. Chandel, Ph.D. (Northwestern University), and Aleksandra Trifunovic, Ph.D. (University of Cologne), the symposium brought together basic scientists, clinicians, and industry researchers around a single ambitious premise: that mitochondria are not simply the cell’s power generators, but dynamic signaling hubs that coordinate metabolism, stress responses, redox biology, proteostasis, and immune activation across virtually every tissue in the body.
In Their Own Words
Dr. Chandel reflected on what the symposium set out to accomplish and what it achieved:
“The objective was to convene a cross-disciplinary community of basic scientists, clinicians, and industry researchers to redefine mitochondria not merely as bioenergetic organelles, but as dynamic signaling hubs that coordinate metabolism, stress responses, redox biology, proteostasis, and immune activation across tissues. By all measures, the meeting achieved these aims. Sessions were intellectually rigorous and highly interactive, trainees were prominently featured through talks and poster sessions, and discussions frequently extended beyond scheduled programming. Many attendees remarked on the collaborative atmosphere and the breadth of disciplines represented, reflecting a field that is both expanding and increasingly integrated.”
Maulik Patel, Ph.D., Associate Professor, Metabolism and Nutritional Programming, Van Andel Institute, offers succinct summary of the Symposium, underscoring the objectives of the gathering.
“It had been some time since I last attended a mitochondrial meeting, so the Keystone Symposium on Mitochondrial Signaling in Physiology and Disease provided a valuable snapshot of where the field now stands. While the idea of mitochondria as signaling hubs is not new, what was striking is how pervasive and mechanistically defined these roles have become—spanning metabolism, immunity, proteostasis, and aging.
The level of technical sophistication was particularly impressive: researchers can now trace signaling events from a mitochondrial metabolite all the way to specific molecular targets, sometimes down to single-residue modifications, making the conclusions far more rigorous and convincing. The meeting also showcased the extraordinary range of scales at which mitochondria are studied, from atomic-resolution structural work to whole-organism physiology, underscoring just how integrative and exciting mitochondrial biology has become.”
Janine H. Santos, Ph.D., Group Leader, National Institute of Environmental Health Sciences (NIEHS), underscores bridging basic science with translational and clinical work.
The Keystone Symposia meeting “Mitochondria Signaling in Physiology and Disease” stands out for its forward-looking reframing of mitochondria as dynamic, cell-type–specific signaling hubs that actively shape cell fate, adaptation, and disease. This perspective places mitochondrial biology at the center of physiology and pathophysiology, including in aging. The program is especially compelling for its integration of diverse areas of mitochondrial research such as metabolite, mtDNA, and redox signaling alongside stress adaptation and emerging technologies. By bridging basic science with translational and clinical insights, it highlights shared mechanisms and therapeutic opportunities across diseases. Its highly interactive format further fosters learning, cross-disciplinary collaboration, and networking, which are particularly attractive and important for young investigators.
Antonio Enriquez, Ph.D., from the Centro Nacional de Investigaciones Cardiovasculares in Madrid, offered a framing of why this meeting stands apart from other conferences in the field:
“The Keystone Symposia meeting explicitly reframes mitochondria from a ‘powerhouse’ housekeeping role into central signaling hubs capable of being tailored for cell type and physiologically changing conditions, shaping cell fate and disease—bringing together basic, translational, and clinical perspectives in one tightly integrated program. In addition to the scientific sessions, the meeting format was designed to maximize cross-career and cross-sector interactions (e.g., poster sessions, a therapy-focused panel, and a dedicated Career Roundtable), making it particularly strong for generating collaborations and for trainees to get targeted career guidance.”
Lena Pernas, PhD, Associate Professor in the Department of Microbiology, Immunology & Molecular Genetics at UCLA and session chair for the Mitochondria Metabolite Signaling session, highlights broad participation:
“The Keystone Mitochondria Signaling in Physiology and Disease showcased talks from researchers who do not traditionally identify as mitochondrial biologists, which brought fresh conceptual approaches to the field. The meeting also highlighted the power of emerging technologies being applied to mitochondrial questions, opening exciting new experimental possibilities. I also very much enjoyed the panel discussions on therapeutic translation, which underscored the impact of mitochondrial research beyond basic biology.”
Mike Murphy, Ph.D., Program Leader at the MRC Mitochondrial Biology Unit and a panelist on the therapy challenges session, appreciates the scientific breadth:
“Some highlights of the meeting were the expansion of metabolic perspectives and regulatory networks on how mitochondria operate in health and disease. Related to this is the development of multiomic approaches and tools, such as that of Dave Pagliarini, that are empowering this next stage in mitochondrial research. The links of these approaches to understanding pathology and potential therapies were also inspiring.”
David J. Pagliarini, Ph.D., HHMI and BJC Investigator, Hugo F. and Ina C. Urbauer Professor, Washington University Medicine, emphasizes the new tools he was exposed to and the value they bring to the field:
“This Keystone meeting featured cutting-edge tool development (e.g., new mitochondrial sensors and screening modalities), new signaling paradigms (via metabolites and PTMs), unexpected mitochondrial interactions with other organelles and external pathogens, and a beautiful summary of where the field stands in our collective quest for new therapeutics.”
Pol Castellano Escuder, Ph.D., a computational biologist and AI researcher currently at the Duke Molecular Physiology Institute (DMPI) and CTO of https://www.heurekalabs.co/, brings a new AI perspective into the mitochondrial research and clinical community.
“Heureka Labs was thrilled to attend the Keystone Symposium on Mitochondria Signaling in Colorado. It was energizing to see the breadth of pathways being explored and the discoveries coming out of this community, and particularly fascinating to watch how so many threads of modern multi-omics research keep converging. As one researcher put it, ‘all roads lead to the mitochondria eventually.’ Between the new tools, methods, and technologies being shared, it’s a genuinely exciting time to study mitochondria and their role in physiology. What the conference also made clear is that data proliferation and the push toward cross-disciplinary integration are outpacing what traditional approaches can handle.
Larissa Govers, a doctoral candidate in the Lab for Retinal Cell Biology at the University of Zurich gave perhaps the most personal account. She presented her work on the metabolic consequences of chronic hypoxia on mitochondrial function in photoreceptor cells:
“What began as a nerve-wracking solo trip across the pond turned into an experience that strengthened my scientific foundation and expanded my network within the field. I left the meeting feeling energized and deeply motivated to continue to grow as a researcher within this collaborative environment. As an early investigator who is relatively new to the field of mitochondrial signaling, attending a conference by yourself specifically focusing on this topic can be an overwhelming experience. There are countless new people to meet and so much to learn from the experts who have shaped the field. Still, deciding to attend this Keystone meeting to deepen my foundation in mitochondrial research was one of the best decisions I could have made.
Beyond the opportunity to expand my knowledge and generate new research ideas, I was blown away by the open culture within this community. I got to meet a lot of new people, and every person I met was inspiring and motivating in their own way. I was particularly grateful for the leaders in the field, who made time to listen to early investigators, gave us direction in our projects, supported us in our career development, and most importantly encouraged us to become the next generation of scientists who will continue advancing mitochondrial research.”
How to Register for the On-Demand Program
The On Demand recordings cover all main-session presentations from the Grays Peak conference room. On Demand Registration here: https://www.keystonesymposia.org/conferences/conference-listing/meeting/pricing/B12026
At the Fusion “Mitochondria & Cell Fate Transitions: From Stemness to Senescence” in
St. Julian’s, Malta, May 10–13, the organizers are bringing together are bringing together mitochondrial and STEM cell biologists to better understand cell-fate mechanisms.
The conference organizers, Drs. Mireille Khacho (University of Ottawa), Elisa Motori (University of Cologne), and Maria Eugenia Soriano (University of Padova), will bring together a range of researchers from different disciplines to connect mitochondrial dynamics, metabolism, redox signaling, and organelle communication with cell-fate decisions.
“Lots of exciting mitochondrial research is being done, but it tends to exist in silos,” said Dr. Khacho. “We want to break down those silos to get beyond simple correlations and on to a mechanistic understanding. As the title says, we want to cover mitochondria from stemness to senescence.”
The Conference will bring together leaders across mitochondrial biology, stem cell biology, aging, metabolism, and disease to explore how mitochondrial state actively governs cell fate transitions. Rather than treating mitochondria as passive bioenergetic organelles, the meeting centers on their roles as dynamic regulators of signaling, gene expression, immune crosstalk, and cellular identity across contexts ranging from development and regeneration to degeneration and senescence.
The Conference organizers have multiple goals. They hope to establish new conceptual frameworks for mitochondria-driven cell fate control, enable cross-disciplinary collaborations, and identify new therapeutic possibilities.
Arising frontiers and challenges will be featured. These include understanding the causality between mitochondrial remodeling and fate transitions, how mitochondrial diversity shapes distinct signaling trajectories and functional outcomes, how mitochondrial dynamics connects with transcriptional and epigenetic regulation, how mitochondria-driven senescence programs are distinct from classical damage-induced models, and how single-cell and spatial approaches can be integrated to capture mitochondrial function in vivo.
This meeting is specifically designed for investigators and trainees working in mitochondrial biology and dynamics, stem cell biology and regeneration, aging, senescence, and cell stress responses, cancer cell plasticity and immune–metabolic crosstalk, systems biology, metabolomics, and advanced imaging.
“The conference will be highly interactive plenty of early-career investigators and time for discussion,” said Dr. Khacho. “We hope to see you in Malta.”
For more information and to review the program and confirmed speakers, please visit the Fusion Conference webpage: https://fusion-conferences.com/conference/197.
Questions for the organizers:
MitoWorld: The Conference title (i.e., From Stemness to Senescence) covers a lot of ground. How did you pick the topics and speakers to bring this all together?
Organizers: The title was chosen to reflect both a biological continuum and a physiological trajectory, from normal stemness and regenerative capacity to pathological states, such as dysfunction, degeneration, and senescence. We deliberately selected topics and speakers that sit at key transition points, where cells change identity, competence, or trajectory, because these are moments when mitochondria their roles extending far beyond energy provision to encompass signaling, adaptation, and cell fate determination. Speakers were chosen for both scientific excellence and conceptual complementarity, bringing together perspectives from stem cell biology, aging, cancer, immunity, and neurobiology to create dialogue across traditionally separate fields.
MitoWorld: You have some outstanding goals for the Conference (e.g., “establish new conceptual frameworks for mitochondria-driven cell fate control”). What was the process to arrive at these, and will anyone attempt to synthesize any conclusions from the discussions?
Organizers: The goals emerged from ongoing discussions among the us three co-organizers, where a recurring challenge was the lack of shared frameworks linking mitochondrial changes to cell fate decisions. When FUSION announced the opportunity to propose a new conference topic, it felt like the right moment—a signal, almost—to turn our ongoing informal discussions into a collective effort. Rather than imposing predefined models, we designed the conference to allow concepts to evolve through discussion. We are planning moderated discussion sessions and thematic synthesis moments, and we intend to explore a post-conference summary or perspective to capture key insights, open questions, and future directions.
MitoWorld: Stem cells are a powerful tool, but also a subject in their own right. I understand you have a special connection to STEM cells and mitochondria. How do you hope the conference will be able to differentiate and yet combine these two goals?
Organizers: Stem cells offer a unique lens through which to study plasticity, commitment, and loss of regenerative potential, processes in which mitochondria play an instructive role. The conference does not treat stem cells as a niche topic, nor mitochondria as background machinery. Instead, stem cells are used as a conceptual framework to ask broader questions about how mitochondrial state encodes fate decisions, questions that extend naturally to aging tissues, cancer, and immune cells.
MitoWorld: Mitochondria research has had some controversies, one of which is the split between specific research findings or facts and adding more directly to basic scientific understanding. Do you anticipate that this Conference will provide an opportunity to re-set that balance?
Organizers: Yes. Many translational efforts in mitochondrial biology have been limited by incomplete mechanistic understanding, and we see real value in tightening that connection. This conference emphasizes mechanism-driven biology while remaining grounded in physiological and disease-relevant contexts. By bringing together basic scientists and translational researchers in a highly interactive format, we aim to foster a more integrated approach in which rigorous discovery and meaningful application inform one another.
MitoWorld: What specific provisions have you made to ensure that trainees will have quality time with the more experienced researchers? And in the future is there a way to make these events more accessible and affordable for them?
Organizers: We’ve been fortunate to build on the FUSION format, which inherently supports trainee engagement through its small size, shared meals, and extended discussion periods. This naturally creates space where early career researchers can interact meaningfully with more senior scientists. We further prioritized trainees through short talks selected from abstracts, dedicated poster sessions, “meet the poster presenters” session and informal networking opportunities. We have also worked diligently to secure funds, in the form of travel awards, for trainees and early career researchers.
MitoWorld: This Conference promises to be an outstanding event. What plans do you have to sustain the momentum?
Organizers: We’re pleased that the ambition and enthusiasm we’ve invested in this conference concept are immediately recognizable. We view this conference as the foundation of an ongoing scientific effort rather than a one-time event. Our intention is to establish Mitochondria & Cell Fate Transitions as a recurring meeting held every other year, creating continuity and an evolving forum for the field. Between meetings, we aim to sustain momentum through continued engagement via platforms such as MitoWorld. This structure allows ideas, debates, and emerging frameworks to mature over time while keeping the community connected and forward-looking.
Conference Organizers:
Mireille Khacho (University of Ottawa) investigates how physiological changes in mitochondrial dynamics and metabolism regulate stem cell fate, function, and regeneration. Her work focuses on mitochondrial-dependent metabolite and redox signaling in physiological contexts, and how disruption of these pathways drives neuromuscular diseases, aging and mitochondria-driven senescence.
Elisa Motori (University of Cologne) investigates how cell type–specific mitochondrial and metabolic programs shape brain health and disease vulnerability, revealing energy-driven mechanisms that govern development, resilience, and neurodegeneration.
Maria Eugenia Soriano (University of Padova) investigates how mitochondrial structure and dynamics are transcriptionally regulated to shape cellular metabolism. Using physiological and disease-relevant models, her work integrates mitochondrial biology, metabolic regulation, and gene expression to uncover how alterations in mitochondrial organization drive metabolic rewiring in cancer and other pathologies.
Get ready for the Cell, Multifaceted Mitochondria Symposium, this year in Glasgow, Scottland, June 21–23.
Like its five biennial predecessors, the Glasgow gathering features the hallmark of the Multifaceted Mitochondria Symposia—a broad and deep array of mitochondrial topics and talks, covering a number of areas of inquiring, including mitochondrial biochemistry and bioenergetics, mitochondria homeostasis and stress response, mitochondrial dynamics and transfer, mitochondrial communication, mitochondria in metabolism, and mitochondria in inflammation and disease. The 2026 event is organized by Isha Jain, Arc Institute and Gladstone/UCF and Thomas Langer, Max Planck Institute for the Biology of Ageing.
Keynotes
Keynote include Judy Hirst, University of Cambridge, and Jared Rutter, University of Utah.
Hirst is a British chemist and mitochondrial biologist at the University of Cambridge, where she is Director of the MRC Mitochondrial Biology Unit and Professor of Biological Chemistry. She leads research into the structure and mechanisms of mitochondrial respiratory enzymes, particularly respiratory complex I, using biochemical and structural methods to understand energy conversion. Hirst is a Fellow of the Royal Society and Fellow of the Academy of Medical Sciences, recognized for her contributions to mitochondrial biology.
Rutter is Distinguished Professor of Biochemistry and holds the Dee Glen and Ida Smith Endowed Chair for Cancer Research at the University of Utah where he has been on the faculty in the Department of Biochemistry since 2003. In 2015, Dr. Rutter was appointed as an Investigator of the Howard Hughes Medical Institute. The Rutter laboratory has identified the functions of several previously uncharacterized mitochondrial proteins, including the discovery of the long-sought mitochondrial pyruvate carrier.
History
The Cell Symposia series on Multifaceted Mitochondria, inaugurated in 2015 in Chicago, has charted the dynamic evolution of mitochondrial research over the past decade. The inaugural meeting focused on foundational themes, such as mitochondrial metabolism and bioenergetics, signaling pathways, mitochondrial dynamics, mitophagy, and quality control. The meeting brought together leaders exploring both basic mitochondrial functions and their intersections with disease, setting a strong mechanistic foundation for the field.
Since then, the symposium has progressively broadened its scope to capture the expanding complexity of mitochondrial biology. By 2022, Jodi Nunnari was the keynote, and the program integrated emerging topics, including mitochondrial communication with other organelles and immune signaling, mitochondrial proteostasis, and the role of mitochondria in inflammation and cancer metabolism. In 2024, several of the www.MitoWorld.org Scientific Advisory Board featured a MitoWorld Initiative. The latest 2026 program anticipates an even wider lens, framing mitochondria as central metabolic and signaling hubs influencing organismal homeostasis, aging, and multi-system diseases. This evolution reflects not only scientific advances but also a growing recognition of mitochondria as versatile regulators and therapeutic targets, a narrative underscored by recurring contributions from influential researchers.
Symposium organizers
Salvatore Fabbiano, Editor-in-Chief, Cell Metabolism, received his PhD in Physiology at the University of Salamanca, where he studied signaling pathways involved in cardiometabolic diseases. He then moved to the University of Geneva to work on host-microbiota homeostasis. He joined Cell Press in 2018.
Shawnna Buttery, Editor-in-Chief, Cell Reports, whose training in the laboratory was in cell biology, studying the cytoskeleton in nematodes as a graduate student at Florida State University and as a postdoc at Dana-Faber Cancer Institute. She has been with Elsevier/Cell Press since 2012.
Thomas Langer, academic co-organizer, who since 2018, has been Director at the Max Planck Institute for the Biology of Ageing in Cologne, focusing on the analysis of mitochondrial proteostasis and its regulation in ageing and age-associated diseases. Langer earned his PhD from the LMU Munich working on chaperone-mediated protein folding and was a researcher at the Memorial Sloan Kettering Cancer Center in New York and professor at the University of Cologne, where he studied the role of mitochondrial protein quality control in neurodegeneration.
Isha Jain, academic co-organizer, associate investigator at the Gladstone Institutes, as well as an assistant professor at UC San Francisco. Jain received her undergraduate degree in chemical and physical biology from Harvard University. There, she worked in the lab of Erin O’Shea on bacterial chromosome segregation. Subsequently, she joined the Harvard-MIT Program in health sciences and technology. She earned a PhD in computer science and systems biology and worked in the labs of Vamsi Mootha and Warren Zapol, where she made the discovery that hypoxia could serve as a therapy for mitochondrial disorders.
MitoWorld Interview
MitoWorld: What makes our Multifaceted Mitochondria meeting unique?
Fabbiano: The mitochondria field is extremely diverse, with researchers working on this organelle from signaling, structural, and bioenergetic perspectives and investigating how they affect cellular, tissue and whole-body homeostasis. This variety of angles is then put in the context of communicable and non-communicable diseases, spanning from the response to infections to metabolic and autoimmune disorders, cancer and aging.
Buttery: Multifaceted Mitochondria stands out because it embraces the full diversity of mitochondrial biology. It offers a comprehensive, top-to-bottom perspective on mitochondria, while bringing together a diverse group of scientists from across the field. This conference strikes a great balance of fresh perspectives and established expertise.
Jain: Because the symposium is intentionally small and highly interactive, you don’t just hear about exciting science; you immediately start brainstorming with the people behind it. That intimacy accelerates collaborations and often launches entirely new directions.
MitoWorld: Is there a risk of being too inclusive, with too many subjects? On the other hand, the field is still emerging. How do you strike a balance?
Fabbiano: The natural risk of such a broad field is thus the breaking down into silos and overspecialization, with each subfield narrowing down their perspective on the individual questions they are answering. Our vision and mission with this meeting are instead to go in the opposite direction, and we make it clear starting from the title: mitochondrial research is multifaceted, and should be appreciated as such to truly push the field forward. What makes us unique is our ongoing mission of strengthening the ties of a diverse community to create new channels of communication, new forms of collaboration, and develop ideas throughout a conference that welcomes both established leaders and emerging voices in the field.
Jain: Multifaceted Mitochondria is the rare meeting where every dimension of mitochondrial biology comes together—from metabolism and genetics to disease and therapy. It’s a unique opportunity to see the whole field at once and spark ideas that wouldn’t emerge in siloed settings.
MitoWorld: For the Glasgow symposium, what did you concentrate on. How did you determine the strands and the array of speakers? What do you hope people come away with?
Langer: It was of utmost importance to us to develop a program that only allows leading experts to discuss their most recent discoveries but also offers plenty of opportunities for young scientists to present their work and interact with other scientists in the field. We hope that the attendees will experience a vibrant and interactive scientific community and will leave with new tools, ideas and collaborators to further push forward the mitochondrial field.
Jain: Mitochondrial biology is advancing at an incredible pace, and this meeting is built to capture that momentum. We want participants to leave with new tools, new collaborators, and a clear sense of the frontier we’re all pushing toward.MitoWorld: What do you find exciting and challenging about organizing a Multifaceted Mitochondria Symposium, given the complexity of the fast-growing field and its many facets?
Langer: It is an exciting possibility and fun to bring together scientists working on different aspects of mitochondrial biology in a small and interactive setting to exchange their discoveries and ideas for new research directions. If I must mention something challenging, then that it is to select speakers among the many excellent scientists to build a program that covers the many aspects of mitochondrial biology and that allows us to identify synergies as a basis for future collaborations.
MitoWorld: It is refreshing to have a leading journal, in this case Cell Metabolism, take on a whole field-in-the making. It sounds like the journal has a hands-on approach with its communities.
Fabbiano: One point that makes us unique is the editorial involvement at these conferences, not only in the organization but in our very presence and engagement with the community. We appreciate that publishing can be a complex experience, and part of our mission with these conferences is also the direct contact with the community to address misconceptions and pain points around peer review and scientific publishing
MitoWorld: Given that approach, how do you interact with the research community in the journal and for a symposia, such as the Multifaceted Symposium?
Buttery: Our meetings are organized by and for the readers, authors, and reviewers that make our journals possible. They reflect the latest directions of the field, address controversies, and are curated in content and size to ensure that everyone from a young graduate student to a tenured professor learn something new and go back to their project with renewed enthusiasm and passion. That is definitely the case for us editors, too.
Important Deadlines:
Abstract submission deadline: February 13, 2026
Early registration deadline: April 10, 2026
Long associated only with energy and somewhat ignored, mitochondria are now recognized as key components in development and disease. On December 12, nearly 550 researchers met in person and virtually at Columbia University to assess the accomplishments and future directions of the Mitochondrial Stress, Brain Imaging, and Epigenetics—MiSBIE study. The study (Kelly et al. 2024) sought to understand the role of mitochondria and energy in mind-body processes and mitochondrial diseases. The “mother paper” (Kelly et al.), as they call it, also spawned other papers.
Symposium organizer Martin Picard (professor of behavioral medicine, Columbia) began by describing the holistic approach to the study. “We want to understand you as a person,” they emphasized to each study participant, as they welcomed them for the 2-day protocol in Manhattan.
Humans can be studied at various levels, including the molecular, cellular, tissue and organ, individual, and populations. The study sought to elucidate the interconnections of these levels through the lens of energy. More specifically, the MiSBIE team focused on the interactions of the immune system, mitochondria, the brain and nervous system, stress hormones, cognition, and behavior. Picard emphasized the importance of working as a team by noting the adage, “If you want to go quickly, go alone. If you want to go far, go together.” The discussions that followed featured several of his research group who contributed to the study.
Brain Mitochondria: The Energetic Landscape
In parallel with integrating mitochondrial energetics with psychobiology, the team developed the first mitochondrial map of the brain (Mosharov et al., 2025), a process led and described by Michel Thiebaut de Schotten (director of research, NeuroCampus of the University of Bordeaux). To link cognitive neuroscience and cell biology, they divided a frozen human coronal hemisphere section into 703 cubes or voxels (3 × 3 × 3 mm). Then, they defined the mitochondrial phenotypes (e.g., oxidative phosphorylation (OxPhos) enzyme activities, mitochondrial (mt)DNA and volume density, and mitochondria-specific respiratory capacity) in each voxel. The map revealed different characteristics for each region of the brain. If validated, the MitoBrainMap v1.0 of mitochondrial phenotypes might eventually allow exploration of the energetic landscape of normal brain function and correlations with standard neuroimaging methods—by magnetic resonance imaging (MRI).
“If this works, it would really be game changing,” said Picard. “You beam energy at the brain with a big magnet, then capture energy coming out of the brain, and somehow that tells you something about the biology of mitochondria. Amazing if this works.”
Building on the MiSBIE neuroimaging dataset, Tor Wager, PhD (professor of neuroscience, Dartmouth) and postdoctoral fellow Ke Bo examined behavioral and cognitive tasks through an energy-focused lens. One of their goals was to identify useful brain neurologic signatures associated with mitochondrial disorders. The molecules GDF15 and FGF21 show the strongest differences between individuals with mitochondrial disorders and controls. Wager used fMRI imaging to look for patterns in response to different tasks. These include cognitive (working memory, executive function tests), affective (cold pain), and sensory (multisensory with lights and stresses). Some of the correlations to mitochondrial disorders include sensitivity to negative emotions, but not to heat. In summary, the team finds that some brain functions and neural circuits are selectively vulnerable to energy deficits (Bo et al. Biorxiv 2025), consistent with an energy tradeoffs or “triage” model of psychopathology.
Immune Cell Bioenergetics
The group then wanted to examine the bioenergetics of immune cells. Jack Devine described how they stratified the phenotypes (or mitotypes) of immune cells. He used a new method developed by Anna Monzel, called mitotyping. Using principal component analysis, hierarchical clustering, and downstream analysis, they analyzed single immune cells from 164 people (ages 26–84). The MiSBIE team found that different types of immune cells have distinct patterns of activity (e.g., OxPhos, glycolysis) and aging.
To measure the bioenergetics of those cells from individuals with mitochondrial disorders, the group used extracellular flux analysis (Seahorse). Anna Monzel explained the process in beautiful details. The MiSBIE team isolated blood cells—monocytes, lymphocytes, neutrophils, platelets—from fasting individuals. For each cell type, they then measured their oxygen consumption and extracellular acidification rates to estimate OxPhos and glycolytic activities, using drugs that block specific enzymes in the mitochondria. OxPhos capacity was reduced in some cell types (not all) in people with mitochondrial disorders, but glycolysis was largely unchanged.
Using a biochemical approach called the mitochondrial respiratory capacity (MRC, formerly the Mitochondrial Health Index, MHI), Cynthis Liu examine mitochondrial biology in the same cells, of the same MiSBIE participants. She then used these data to explore the psychobiological relationships of immune cell mitochondria and mood symptoms, including anxiety and depressive symptoms. The work focused on mitochondrial respiratory chain at complexes I, II and IV, citrate synthase, and mtDNA content. The conclusion was that the maximal energetic capacity of immune cells is largely intact in mitochondrial diseases. Immune mitochondria are thus unlikely to reflect mitochondrial energetics in other tissues, such as the brain, muscles, and other organs.
Health Indicators: Time Perception
The MiSBIE study then focused on the indicators of health for those with mitochondrial disease. Two of these are the perception of time and allostatic load. Darshana Kapri examined the relationship of mitochondria to time perception. Individuals perceive time differently. Some people’s internal clocks run faster or slower than the actual time. Mitochondrial disorders didn’t directly affect time perception (faster or slower) but seemed to affect how potential drivers of time perception, including stress/metabolic hormones, such as norepinephrine, or metabolic rate. The team also discovered potentially meaningful associations between symptoms of burnout and fatigue and time perception, which demand validation in future studies.
Alex Junker then looked at allostatic load—a multi-system metric of physiological dysregulation known to predispose to disease. Allostatic load was higher in people with mitochondrial diseases and strongly correlated with lifetime stress and trauma. So genetics is important, but those with disease might be affected by their lived environment and the psychosocial factors that surround them. This new knowledge could motivate interventions or approaches that can provide additional support for those who have mitochondrial diseases.
Energetics of Stress: Cell-Free Mitochondria
The study also focused on the energetics of stress. Natalia Bobba-Alves described how the group developed a stress reactivity protocol and the effects of mitochondrial disorders. That protocol, which included eight concurrent blood and saliva collection timepoints over a 2-hour period, was used to study several stress mediators. The main stressor was a 5-minute speech task where participants had to give a speech in front of a white coat-wearing intimidating evaluators, while being (mock) videotaped.
David Shire explained their work on cell-free mtDNA in saliva and blood and stress. Levels of cell-free mtDNA are elevated in patients with cancer, heart disease, and inflammation. Higher levels of cf-mtDNA were detected in saliva than in serum or plasma from the same person. Stress caused a nearly 10-fold elevation in saliva cf-mtDNA within 10 minutes on average.
Mangesh Kurade presented results on FGF21 levels after the same stressor. The levels are significantly elevated in people with mitochondrial disorders. They decrease from morning to afternoon, and tend to be higher in people with higher body fat and in older people. Mental stress decreased plasma FGF21 in most control individuals, whereas it caused a robust increase in people with mitochondrial disorders—a remarkable divergence.
Caroline Trumpff looked at whether mental stress altered the mitochondrial disease biomarker GDF15. This molecule is the most robust available marker of mitochondrial disorders and energetic stress. The MiSBIE team found that psychological stress alone is sufficient to causes GDF15 levels to rise, both in blood and in saliva. This new discovery links mental and energetic stress, suggesting that both might converge on mitochondria and reductive stress, the key trigger for GDF15 release.
Future Directions: Hypermetabolism and mtDNA Instability
Evan Shaulson covered an ambitious follow up study: the Mitochondrial Daily Energy Expenditure (MDEE) study. Individuals with OxPhos defects often have fatigue and a short lifespan—on average reduced by 3-4 decades. Evan Shaulson described in vitro experiments from Gabriel Sturm on patient-derived fibroblasts, where subjecting cells to conditions that disrupted OxPhos doubled cellular energy expenditures. This state of hypermetabolism was associated with mtDNA instability, activation of the integrated stress response, and secretion of age-related cytokines and metabokines.
In the new MDEE study (manuscript in preparation), additional experiments were conducted with volunteers who spent a day in a small room while their metabolic rates, activity levels, and other psychobiological parameters were carefully and continuously measured. Half of the volunteers had a mitochondrial disease, and the other half were healthy controls—as in MiSBIE. For a further 8 days, MDEE participants lived their normal lives. The study found that like the fibroblast experiments, individuals living with OxPhos defects experience hypermetabolism. Thus, in both isolated cells and people, mitochondria with defects result in hypermetabolism and reduced lifespan, the connection between which remains to be better understood. This may relate, as the team proposes, to energy constraints that force deleterious tradeoffs where stress-related processes compete with health and healing-promoting processes.
Martin Picard summed up the symposium by focusing on a major gap in knowledge: “Healing is a set of dynamic, energetic processes by which an organism moves towards optimal function. Healing involves growth and development, recovery from injury, and adaptation that increase coherence and efficiency across the organism. Although healing is most likely the key driver of health, and the basis for not getting sick in the first place, we don’t have a science of this. We need a science of healing,” he said, pointing to their work around the science of health, and a new initiative to be unveiled in the coming year.
“Rational, scientific ways to harness the healing process would likely lead to new treatments and interventions that help optimize mitochondrial energy transformation. That would likely then contribute to more coherent and efficient psychobiological processes, freeing up energy to fuel the healing process and sustain health across the lifespan.”
The MiSBIE Symposium concluded with a reception that celebrated the scientific success of the NIH-funded study, supported by Baszucki Group. “MiSBIE sets the table for a new phase in the evolution of health sciences. Understanding psychobiological processes at an energetic level provides a foundation to develop a true science of healing: Healing Science,” said Picard. “There is a lot to be excited about. And we need everyone on board, not just scientists, to come along and join the movement.”
References
Kelly C, Trumpff C, Acosta C, Assuras S, Baker J, Basarrate S, Behnke A, Bo K, Bobba-Alves N, Champagne FA, Conklin Q, Cross M, De Jager P, Engelstad K, Epel E, Franklin SG, Hirano M, Huang Q, Junker A, Juster R-P, Kapri D, Kirschbaum C, Kurade M, Lauriola V, Li S, Liu CC, Liu G, McEwen B, McGill MA, McIntyre K, Monzel AS, Michelson J, Prather AA, Puterman E, Rosales XQ, Shapiro PA, Ghire D, Slavich GM, Sloan RP, Smith JLM, Spann M, Spicer J, Sturm G, Tepler S, Thiebaut de Schotten M, Wager TD, Picard M, The MiSBIE Study Group (2024) A platform to map the mind–mitochondria connection and the hallmarks of psychobiology: The MiSBIE study. Trends in Endocrinology & Metabolism (10): 884–901.
Mosharov EV, Rosenberg AM, Monzel AS, Osto CA, Stiles L, Rosoklija GB, Dwork AJ, Bindra S, Junker A, Zhang Y, Fujita M, Mariani MB, Bakalian M, Sulzer D, De Jager PL, Menon V, Shirihai OS, Mann JJ, Underwood M, Boldrini M, Thiebaut de Schotten M, Picard M (2025) A human brain map of mitochondrial respiratory capacity and diversity. Nature 641: 749–758.
Sturm G, Karan KR, Monzel AS, Santhanam B, Taivassalo T, Bris C, Ware SA, Cross M, Towheed A, Higgins-Chen A, McManus MJ, Cardenas A, Lin J, Epel ES, Rahman S, Vissing J, Grassi B, Levine M, Horvath S, Haller RG, Lenaers G, Wallace DC, St-Onge M-P, Tavazoie S, Procaccio V, Kaufman BA, Seifert EL, Hirano M, Picard M (2023) OxPhos defects cause hypermetabolism and reduce lifespan in cells and in patients with mitochondrial diseases. Communications Biology 6(1): 22.
https://www.nature.com/articles/s42003-022-04303-x.pdf
A Divided Community
In a September 2025 Viewpoint published in Nature Metabolism entitled “Mitochondria Transfer,” the editors noted, “. . . the topic continues to be met with skepticism.” As a result, the journal asked nine mitochondrial biologists to share their personal views on intercellular mitochondria transfer. There was little new here.
Their responses amounted to yes, no, and maybe. Many questions loom for otherwise promising results. What are the mechanisms and consequences of this process? If mitochondria do move between cells endogenously, when they arrive in another cell, do they resume their normal functions? Does the transfer of a relatively small number of mitochondria have the power to rescue a cell that is under bioenergetic stress?
At MitoWorld, we know most of the Viewpoint respondents, and we know the gulf between them. By kicking off debate, Nature Metabolism has started a process that we hope can mature from rhetoric to a more evidence-based picture of the efficacy of mitochondrial transfer and transplantation. Across the globe, investigations are underway in both categories. Given the limited mechanistic understanding of this process, it is surprising that mitochondrial transplantation is now a not uncommon medical intervention and remains a tantalizing subject of research and development in a variety of biotech companies.
First Step: Nomenclature
In all of this, there is a blurring of terminology. In January, Jon Brestoff and Keshav Singh, et al. published “Recommendations for mitochondria transfer and transplantation nomenclature and characterization,” also in Nature Metabolism. What is clear in their paper’s title is the notion of i) transfer being endogenous, part of an intrinsic biological mechanism and ii) transplantation, the act of deliberately introducing mitochondria into organs, tissues, and cells being exogenous. Over 30 researchers participated in what was a laudable effort to explore agreed-upon naming, processes, and explanatory conventions. While the consensus statement and an agreement for an International Committee on Mitochondria Transfer and Transplantation Nomenclature (ICMTTN) represents an important step forward, notable disagreements persist. Foremost among the complications related to mitochondrial transfer and transplantation relates to the unknown fate of any mtDNA harbored by incoming organelles.
Second Step: Conference
MitoWorld found itself in the middle of this controversy when it was asked to help with the first Mitochondrial Transplantation Conference. Held in April at Hofstra University, the event was organized by Northwell Health and led by Lance Becker. It featured a mix of compelling medical intervention talks and video for failing hearts (James McCully), treatment for stroke victims (Melanie Walker), and other resuscitation experiments with animals (Lance Becker). MitoWorld assisted in having endogenous transfer represented (Jonathan Brestoff). In all of this, there was excitement but also apprehension that parents of children and adults with mitochondrial genetic diseases will be given false hope for near-term treatments. Several drug developers were present, as were patient groups. It is likely some form of transplantation organization will emerge from that meeting.
Deeper Dive—Transfer and Transplantation
Given the lack of evidence-based dialogue, MitoWorld reached out to the Viewpoint respondents who are actively doing work in both categories. Yasemin Sancak, The Sancak Lab, University of Washington Pharmacology, and Rubén Quintana-Cabrera, Neurometabolism and Mitochondrial Dynamics Lab, Instituto Cajal, CSIC responded to MitoWorld.
MitoWorld: Why do you think there is such a controversy about mitochondria transfer and transplant?
Sancak: Transfer of mitochondria between cells is shown in different organisms and systems, and although this is relatively novel finding, it is widely accepted in the field. However, mitochondria transplantation attracts skepticism. In my opinion, the controversy stems from the expectation that, for mitochondrial transplantation to work as intended, the transplanted mitochondria should successfully incorporate into the host tissue in large numbers and maybe survive there for a long time, integrate into the donor tissue, and restore mitochondrial function and tissue health. Currently, the evidence of this happening is limited, and mechanisms of mitochondrial entry and survival are not well understood. But we also cannot ignore the exciting data that show the utility of mitochondrial transplantation in the clinic. Until we understand the molecular details and mechanisms of this process, the controversy is likely to continue. The field needs more preclinical and clinical research to understand mechanisms of therapeutic benefit and to establish clinical guidelines.
Quintana-Cabrera: These are quite novel concepts, now widely accepted by the scientific community after solid data in different cells and tissues. My perception is that both general and even specialized audiences are mostly focused on the incorporation of healthy mitochondria from neighboring cells or tissues to enhance mitochondrial activity in the compromised recipient cell. However, we should not overlook the transfer of damaged mitochondria, which may also benefit a cell by enabling their elimination through surrogate degradation in neighboring cells. Regarding transplants, the apparent controversy mainly concerns the injection of isolated mitochondria. Transplants using donor cells, such as mesenchymal stem cells or mitochondria encapsulated in vesicles or artificial membranes are viewed as able to better withstand the extracellular environment and the journey through the body to the target tissue. However, those advocating for transplants of isolated mitochondria need to standardize the approaches and to clarify how mitochondria survive outside the cell, influence inflammation, and integrate into recipient cells, or if they can take over native mitochondrial function in the long term.
MitoWorld: What may convince you that transfer happens naturally and/or that transplantation has effects?
Sancak: Many animal and cell culture studies show that mitochondrial transfer happens naturally, and this process is likely to serve different functions. Mitochondrial transplantation research in a pre-clinical setting mostly shows positive outcomes, but the long-term benefits of mitochondrial transplantation are not addressed. A small number of human studies show clinical benefit, but these are mostly feasibility and safety studies that were conducted with a small number of patients. One promising common finding from human studies so far is that mitochondrial transplantation does not seem to have any adverse effects and is generally considered to be safe. I think this is very promising and should open the door to bigger clinical trials. Ultimately, well-controlled clinical trials are needed to determine if mitochondrial transplantation will work for a disease of interest and what long term effects will be.
Quintana-Cabrera: A growing body of evidence demonstrates the natural occurrence of different types of transfer, mediated by tunneling nanotubes, microvesicles, or naked mitochondria, across various tissues and both in physiology and pathology. This is leading the scientific community to accept mitochondrial transfer as a naturally occurring event.
Of course, this is still a young field, and existing gaps need to be addressed by thoroughly evaluating the various dimensions of mitochondrial transfer. For example, further progress is needed in the assessment of intercellular communication mechanisms, such as tunneling nanotubes, which contribute to mitochondrial transfer but are technically challenging to study in vivo. Transplantation can produce meaningful effects, at least in the short term, depending on the delivery method, dosage, and source of mitochondria. Additional manipulations may enhance mitochondrial integration, modulate immune responses, or improve targeting to the appropriate tissue. However, it remains essential to understand how transplanted mitochondria interact with a much larger population of resident ones and to characterize both the short- and long-term effects of transplantation. This knowledge will help determine which strategies are truly beneficial. Such benefits may arise from whole mitochondria, their components, or even from transient cellular responses triggered by the presence of exogenous mitochondria.
MitoWorld: What do you say to those who contend that transplantation, at best, is a reaction to the presence of transplanted mitochondria, not that transplanted mitochondria are functionally integrated into recipient cells?
Sancak: This is an important question that highlights the significance of understanding what happens at the molecular level once the external mitochondria are delivered to the recipient cells. Most animal experiments show that the transplanted mitochondria must be functional to provide a positive outcome in the recipient cells. This suggests that the recipient cells’ reaction to presence of transplanted mitochondria is not the whole story, and transplanted mitochondria function is important. I think it is more likely that both mechanisms will play a role, and depending on the disease, transplantation method, and recipient cell, one mechanism may play a more prominent role than the other.
Quintana: This is a critical question that indeed needs clarification. Are transplanted mitochondria directly restoring function, or are they instead exerting indirect effects that still benefit the recipient cell or tissue? The latter could involve activation of stress-response pathways that partially restore homeostasis. Again, the source or method to deliver mitochondria may be key to what response is engaged, and the functional integration of mitochondria may not always be necessary to explain beneficial outcomes. Depending on the kind of transfer, whole mitochondria, or at least mitochondrial DNA, may escape degradation and integrate into the acceptor cell. Even in this scenario, we still need to assess whether and how their contribution reconfigures the native mitochondrial content, and what other events may occur in parallel.
MitoWorld: What does your research from actual cases tell you about what the transplanted mitochondria are actually doing?
Sancak: The transplantation studies I was involved in were focused on safety, and no clinical outcomes other than safety were monitored rigorously. What I can say is that mitochondrial transplantation appears safe in every system tested, which makes it more appealing to pursue as a potential therapeutic intervention. We still need to systematically investigate which mitochondrial functions are the most important.
Quintana: We observe spontaneous mitochondrial transfer in the nervous system, particularly at neuron-glia connections, in both healthy tissue and in pathological contexts, such as glioblastoma. The latter represents another dimension of transfer, where cancer-neural connectivity and mitochondrial exchange are emerging as key factors in cancer progression. We see that, in physiological contexts, transfer occurs spontaneously and is regulated by specific molecular players involved in intercellular communication and dynamics. Notably, we observe that different ways of transfer or mitochondrial acquisition serve to reconfigure the mitochondrial signature and metabolism in the nervous system and glioblastomas, with the potential to modulate their physiology and offer new venues for therapeutic interventions.
Recommendation
Having been involved in this topic for some time, MitoWorld has discussed a simple step toward moving from debate to a methodology to review what is being discovered in mitochondrial transfer (endogenous) and what is being performed in mitochondrial transplantation (exogenous). Here are the suggestions and more are welcome from the community.
- Establish a working group to track developments
As Brestoff, Keshav, et al. did with nomenclature, MitoWorld suggests the establishment of an agreed-upon tracking system for transfer and transplantation activity. This could be a formal registry, an inventory, or catalog. It will include common terminology and naming of activity, methods, collection, evidence, results, conclusions, and recommendations. We are asking a number of researchers to help in this process.
- AI review of literature and associated data
MitoWorld has a relationship with Heureka Labs, developed in part by mitochondrial and metabolic researcher and AI specialist Matthew Hirschey, PhD (Duke University School of Medicine). Heureka will develop an initial approach to use AI to index past research for categories of activity and to develop data standards for analyzing and synthesizing data and processes.
- Basic science and the phenomenology of mitochondria
There is still much to learn about our endosymbionts, the mitochondria, along with their DNA, and the complex mitonuclear system. Mitochondria have suffered years of obscurity in many forms of research and medicine. They have been typecast as the powerhouse of the cell. mtDNA is just beginning to be a larger topic, with the first conference on the subject having been held this summer in Nashville, Mechanisms of Mitochondrial DNA Mutation and Repair. We would like to see the still poorly understood mechanisms of mitochondrial biology become more central to funding agencies around the world, as it is increasingly apparent that mitochondria, as the hubs of metabolism, are central to the health of our cells.
A collective effort across the mitochondrial research and clinical communities has sought to play down the “powerhouse of the cell” phrase as the sole description of mitochondria and, instead, to elevate the amazing multiplicity of mitochondrial functions. Top among those functions is mitochondrial signaling. The leaders in the signaling field will be gathering at the Keystone “Mitochondria Signaling in Physiology and Disease Symposium,” Feb 09–12, 2026, at the Keystone Resort, Keystone, Colorado in the U.S, whose keynote speaker is Anu Suomalainen Wartiovaara, University of Helsinki, presenting “Lessons Learned from Patients with Mitochondria Mutations for Physiology and Diseases.” [Conference Flyer]
Scientific organizers, Navdeep Chandel, Northwestern University Feinberg School of Medicine, and Aleksandra Trifunovic (video), Institute for Mitochondrial Diseases and Aging, University of Cologne, among the most published on the topic, have brought together a very strong group of international speakers to present findings and stimulate dialog. Among them is José Antonio (Tonio) Enríquez, Professor and Group Leader of the “Functional Genetics of the Oxidative Phosphorylation System (GENOXPHOS)” Laboratory at the Spanish National Center for Cardiovascular Research (CNIC) in Madrid, Spain.
Because of Tonio’s expertise in mitochondrial bioenergetics, oxidative phosphorylation (OXPHOS) and mitochondrial signaling and communication, MitoWorld asked him to answer a few questions about mitochondrial signaling and its significance to build the platform for understanding mitochondria more completely.
MitoWorld: What is the significance of this conference in terms of content, collaborations and the field of mitochondrial signaling?
Enríquez: This Keystone conference represents a pivotal moment in mitochondrial research, marking the formal recognition of mitochondria as central signaling hubs rather than mere energy factories. The conference, organized by Navdeep Chandel and Aleksandra Trifunovic, brings together field leaders who have fundamentally reshaped our understanding of mitochondrial biology over the past 25 years.
MitoWorld: Why is the conference important to do you individually? Can you introduce your area that relates to signaling?
Enríquez: My research area directly relates to signaling through the study of metabolic channeling and respiratory supercomplex assembly. These structures are not merely efficient ATP production units. They represent sophisticated signaling platforms that regulate ROS production, metabolite flux, and cellular stress responses. The spatial organization of respiratory complexes influences how electrons flow through the chain, affecting both energy production and generation of signaling molecules, such as superoxide and hydrogen peroxide. Furthermore, my work on aging mechanisms connects directly to mitochondrial retrograde signaling pathways that communicate cellular stress to the nucleus, triggering adaptive responses or, when dysregulated, contributing to age-related pathologies.
MitoWorld: It seems that “signaling” always must be added to any mitochondrial discussion to get beyond the APT/powerhouse conversations. Talk about how we should see mitochondria and mtDNA as part of the signaling functions in cells with the nucleus and beyond.
Enríquez: The persistent need to add “signaling” to mitochondrial discussions reflects decades of reductionist thinking that portrayed mitochondria solely as cellular powerhouses. This ATP-centric view, while historically important, has become a conceptual limitation that obscures the true complexity of mitochondrial function. Mitochondria and mtDNA function as integrated signaling networks with multiple mechanisms.
- Metabolite signaling: Mitochondria produce signaling metabolites (e.g., α-ketoglutarate, succinate, acetyl-CoA, and citrate) that directly regulate nuclear gene expression through epigenetic modifications. These metabolites serve as cofactors for chromatin-modifying enzymes, linking mitochondrial metabolism to nuclear transcriptional programs.
- ROS as signal transducers: Rather than just being toxic byproducts, mitochondrial ROS function as essential signaling molecules that activate stress-responsive pathways, regulate hypoxia responses, and control cellular fate decisions. The spatial and temporal regulation of ROS production allows mitochondria to communicate specific information about cellular energetic and redox status.
- Retrograde signaling pathways: Mitochondria communicate their functional status to the nucleus through calcium-calcineurin signaling, AMPK activation, and transcription factor regulation. These pathways allow cellular adaptation to mitochondrial dysfunction and coordinate nuclear gene expression with mitochondrial needs.
- mtDNA as an inflammatory signal: Cytoplasmic release of mitochondrial DNA activates innate immune pathways through cGAS-STING signaling, linking mitochondrial damage to inflammatory responses. This represents a fundamental immune surveillance mechanism that monitors mitochondrial integrity.
MitoWorld: List and discuss the various types of signaling and the ones you personally are interested in.
Enríquez: The diversity of mitochondrial signaling mechanisms reflects the evolutionary origin and cellular integration of these organelles.
- Metabolite-mediated signaling: This includes one-carbon metabolism products (SAM, formate), TCA cycle intermediates (α-KG, succinate, fumarate), and lipid signaling molecules (cardiolipin, ceramide). These metabolites regulate epigenetic modifications, transcriptional programs, and enzymatic activities throughout the cell.
- ROS Signaling: Different mitochondrial sites produce distinct ROS species with specific signaling functions. Complexes I and III generate superoxide with different submitochondrial localizations, affecting cytoplasmic versus matrix signaling pathways. H₂O₂ serves as a diffusible signaling molecule that modifies cysteine residues on target proteins.
- Calcium signaling: Mitochondria function as calcium buffers and signal processors, with calcium uptake and release coordinating with cellular calcium oscillations to regulate gene expression, enzyme activities, and cellular excitability.
- Mitokine secretion: Mitochondrial stress triggers the release of signaling proteins, such as FGF21, GDF15, MOTS-c, and Humanin, that act in autocrine, paracrine, and endocrine manners to coordinate tissue responses. These represent a new class of stress-responsive hormones.
- Intercellular mitochondria or mitochondrial components transfer: Direct transfer of mitochondria or mitochondrial components between cells represents a mechanism for intercellular signaling that can modify recipient cell function.
- Epigenetic regulation: Mitochondrial function directly influences nuclear chromatin structure through metabolite availability, NAD+/NADH ratios, and histone modification enzyme activities. This creates a direct link between mitochondrial metabolism and gene expression programs.
Personally, I am most interested in ROS signaling mechanisms and metabolite-mediated epigenetic regulation, as these directly relate to my research on respiratory complex assembly and aging mechanisms.
MitoWorld: If we are to re-define mitochondria how important is signaling and what might the inclusive definition include?
Enríquez: Signaling is critically important because it represents the mechanism by which mitochondria integrate their traditional functions with cellular and organismal physiology. Without signaling, mitochondria would be isolated organelles incapable of coordinating their activities with cellular needs or communicating their status to other cellular compartments. The new paradigm recognizes mitochondria as “cellular command centers” that process information, make decisions, and coordinate responses rather than simply executing metabolic programs
MitoWorld: For newcomers to the field, what would you tell them in terms of the importance of signaling in general and mitochondrial signaling in particular?
Enríquez: For students and PhD candidates entering the field, I would emphasize several key points.
- Understanding signaling as fundamental biology: Every cellular process, from development to disease, involves signaling networks. Students should approach mitochondria as integrated systems rather than isolated organelles.
- Interdisciplinary perspective is essential: Modern mitochondrial research requires integration of biochemistry, cell biology, physiology, bioinformatics, and clinical medicine. Students should develop broad competencies and collaborative skills to address complex mitochondrial questions.
- Technical diversity: The field requires expertise in diverse methodologies—from single-cell analyses and live imaging to omics approaches and animal models. Students should gain experience with multiple technical approaches to study mitochondrial function.
- Clinical relevance: Mitochondrial signaling dysfunction underlies numerous diseases, including cancer, neurodegeneration, metabolic disorders, and aging. Understanding the translational potential of basic research enhances both scientific impact and career opportunities.
Students must understand that signaling represents the mechanism by which mitochondria exert their biological effects beyond energy production. Dysregulated signaling, not simply energy deficiency, underlies most mitochondrial contributions to disease pathology.
We invite you to read our new article, “Welcome to the Mitoverse,” featured in the October 2025 issue of STEM Magazine—a widely read online publication reaching K–12 STEM teachers, college instructors, and faculty across the United States and beyond.
We’re thrilled to bring the world of mitochondria to a broader educational audience as part of www.MitoWorld.org’s mission to expand understanding of cellular dynamics, the mitochondrial genome, and the crucial mito-nuclear axis.
Why We Wrote “Welcome to the Mitoverse”
As we developed the article—written as an FAQ on MitoWorld—we realized how few straightforward, accurate, and well-referenced explanations exist for what mitochondria really are: their origins, their roles in health and disease, and their central place in modern biology and medicine.
We also recognized a deeper challenge. While genetics and the microbiome have each had their revolutions, the mitochondrial revolution is only beginning. Raising awareness must start early—in schools—where students’ natural curiosity can be fostered with accurate, up-to-date narratives about how life works.
Help Us Build a Mito-STEM Curriculum
This publication represents an opportunity to start a new effort we call MITO-STEM— partnerships connecting K–12 teachers, college instructors, and mitochondrial researchers. Our hope is to engage educators who want to introduce students to the remarkable world of mitochondria: their dynamic structure, their unique DNA, and their continuous dialogue with the nucleus and the rest of the cell.
In most biology classrooms, cells are still depicted as static spheres with a few scattered mitochondria—an image that bears little resemblance to reality. Yet understanding how mitochondria actually function, and how they dynamically coordinate and communicate with the nucleus, is essential to understanding life itself.
If you are interested in participating, please contact info@mitoworld.org
Mainstreaming Mitochondria
At MitoWorld, our mission is to mainstream mitochondria—to make their importance visible in both public understanding and medical research. Greater awareness will help drive funding for conditions ranging from rare mitochondrial diseases at birth to neurodegenerative disorders in later life.
By connecting scientists and educators through MITO-STEM, we hope to reshape how biology is taught and understood—inspiring students to see the living cell as a vibrant, interconnected system and mitochondria as its central players.
We invite teachers, researchers, and institutions to join us in this effort. Read “Welcome to the Mitoverse” in STEM Magazine’s October 2025 issue, and explore how you can get involved at www.MitoWorld.org.
www.MitoWorld.org is committed to raising public, professional and patient community awareness globally about mitochondria science, diseases, dysfunction and health. As a central resource, MitoWorld strives to share advances in mitochondrial research and clinical practice.
Guided by a senior scientific advisory board (SAB) comprising leading mitochondrial researcher and clinician-researchers and several mitochondrial medicine clinicians (Medical Advisors).
MitoWorld’s mostly volunteer Team includes three postdoc level gifted young investigators, a senior editor and writer, talented web developer and long-time patient and industry relations expert.
Together, this team with the advisory boards’ guidance produces, collects, and publishers external resources on the site and then internally produces a constant stream of high-quality original media.
- MitoBlog. We post on the latest research papers, profile mitochondrial researchers and clinicians, portray mitochondria labs globally, and report on major conferences.
- MitoCast. We conduct video interviews and accumulate information from leading researchers and clinicians.
- MitoNews. We post articles from outside sources and feature mitochondria newsfeeds from PubMed, Nature Portfolio, PRNewswire and Google on our homepage.
- Mito Events. Posting upcoming conferences and symposia and, in many cases, providing special coverage of the upcoming events through media partnerships with the conference companies and academic organizers.
- “Beyond the Disease”. In partnership with the United Mitochondrial Disease Foundation (UMDF.org), we compile a monthly set of papers to be published in their newsletter.
The core information resources on the site include a directory of leading mitochondrial researchers, academic institutions, patient organizations and clinical centers (LINK).
We are a participatory, community building nonprofit organizations. We invite inquiries, participants, and we are always looking for collaborators, supporters and funders. Feel free to reach out and help us build the “Mitochondrial Revolution” (Contact)
MitoWorld™ is a project of the California-based national R & D human capital and STEM nonprofit, National Laboratory for Education Transformation, NLET.
When Gordon Freedman, NLET’s founder and former journalist, discovered he had several mitochondrial disorders, NLET launched MitoWorld to help get the word out about the emerging potential of mitochondrial research to help across the health and disease spectrums.