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.
MitoWorld.org and MITOS Global have announced a new partnership with Heureka Labs, an AI-driven discovery platform with roots at Duke University, aimed at fundamentally expanding the analytical and discovery capacity of the global mitochondrial research community.
The collaboration brings together MitoWorld’s role as an organizing and convening force in mitochondrial science with Heureka’s advanced agentic research infrastructure, designed to support hypothesis generation, multi-omic analysis, and translational insight at scale.
“The mitochondrial research community has extraordinary biological insight, but it has largely lacked access to modern, integrated computational discovery systems,” said Gordon Freedman, Founder and President of the National Laboratory for Education Transformation (NLET), the nonprofit organization that operates MitoWorld and MITOS Global. “This partnership gives mitochondrial researchers discovery, analysis, and hypothesis-generation capabilities that have not previously existed in this field.”
Addressing Fragmentation in Mitochondrial Science
Mitochondria sit at the center of energy production, cellular signaling, metabolism, immunity, aging, and disease. Yet mitochondrial research remains highly fragmented across institutions, disease areas, and data silos. MitoWorld and MITOS Global were created specifically to address this fragmentation, building shared infrastructure for collaboration, translation, and synthesis across the field.
The addition of Heureka Labs introduces a powerful computational layer to that mission.
“This partnership represents exactly the kind of transformative collaboration we envisioned when building the Heureka platform,” said Dr. Matthew Hirschey, Professor at Duke University, Director of the Duke Center for Computational Thinking, and co-founder of Heureka Labs. “By combining MitoWorld’s deep domain expertise in mitochondrial research with our advanced computational capabilities, we’re not just organizing existing knowledge. We’re creating a powerful engine for scientific discovery that can accelerate breakthrough research in this emerging field.”
Augmenting, Not Replacing, Experimental Science
Through the partnership, MITOS Global researchers will gain access to Heureka’s agent-based research environment, which integrates scientific literature, biological databases, and computational analysis into a unified workflow. The platform is designed to augment and catalyze existing scientific processes—allowing researchers to explore complex hypothesis spaces, test data-driven connections, and identify promising directions before committing time and resources in the laboratory.
The partners emphasize that experimental science remains central to discovery. Computational exploration is used to guide, refine, and strengthen laboratory investigation and not substitute for it.
Heureka Labs has already been adopted by biotechnology companies, universities, and research institutes across the United States, Europe, and Asia. The MITOS Global partnership represents a focused application of this platform to one of the most biologically and clinically significant domains in modern science.
This builds on parallel efforts that leveraged Heureka’s data models to successfully uncover unexpected interactions across genes and pathways, leading to recently published discoveries relating to cancer research.
What This Means for Researchers
For mitochondrial researchers, the partnership provides access to consolidated multi-omic datasets, automated and reproducible bioinformatics workflows, and same-day analytical capabilities that previously required weeks or months of effort. The platform supports tasks ranging from transcriptomic and metabolomic analysis to pathway mapping, target prioritization, and biological interpretation, all within a unified research environment.
Importantly, the system is designed to serve laboratories with varying levels of computational expertise. Advanced users can directly engage with analytical pipelines and annotated code, and labs with limited bioinformatics capacity can interact through guided workflows and plain-language prompts. This flexibility reduces dependence on external contract research organizations and overburdened core facilities, lowering costs while expanding access to high-quality computational analysis.
Beyond efficiency gains, the partnership enables a qualitative shift in how mitochondrial research is conducted. By centralizing data in the MITOS environment and enabling real-time insight sharing across institutions, the platform supports collective learning rather than isolated discovery. As new findings are generated within MITOS Global projects, they enrich a growing knowledge base that strengthens future analyses and uncovers previously hidden biological relationships.
Heureka’s platform also supports downstream translational activities, including grant development, manuscript drafting, and review preparation, ensuring that insights generated through computational exploration can be efficiently communicated and validated. This integrated approach improves research quality while reducing administrative and analytical bottlenecks.
Initial Joint Project: A Mitochondria-Cancer Atlas
As part of the partnership, MitoWorld.org and Heureka Labs also announced an initial early-stage project to develop a Mitochondria-Cancer Atlas. This effort is designed to catalog the diverse ways cancers adapt, reprogram, and exchange mitochondria to support tumor growth, survival, and therapeutic resistance. The project will apply advanced computational analysis to one of cancer biology’s most complex and rapidly expanding frontiers: mitochondrial plasticity in cancer, with the goal of sharing insights across the broader mitochondrial and medical communities.
“Cancer provides the best living laboratory for the range of behaviors and manipulations that can happen to mitochondria in a living context,” said Alexander Sercel, PhD, MitoWorld’s Director of Scientific Affairs. “Cataloging these in a comprehensive way should lead to deeper levels of understanding of the basic science of mitochondria.”
Partnership Structure
The primary agreement for this partnership is between Heureka Labs and the National Laboratory for Education Transformation (NLET), the parent nonprofit organization that operates both MitoWorld and MITOS Global.
Information: Heureka Labs
In a recent paper in Nature Metabolism, an international research group, used a new multi-gene approach to pathway mapping to identify complex II as a central regulator of de novo purine biosynthesis and a promising therapeutic target for acute myeloid leukemia.
Understanding genetic pathways is important in biology and medicine. However, complex diseases, such as cancer, might involve interactions between different pathways that are not immediately obvious. While much work has been done in understanding how individual genes interact, less is known about how multi-gene pathways interact.
Now a team, led by Matthew Hirschey and Kris Wood of Duke University and Alexandre Puissant of the Saint-Louis Research Institute/Hospital, INSERM in Paris, have developed a tool that can look for interactions between pathways. Specifically, they developed novel computational methods to examine genetic pathways involved in acute myeloid leukemia.
Interestingly, they discovered an unexpected link between complex II and purine metabolism with glutamate as a key intermediate. This observation implicates complex II as a potential therapeutic target. AML patients with higher complex II expression have worse survival rates.
These findings clearly demonstrate the power of data-driven tools for identifying critical interactions between genetic pathways. They also show the value this approach for finding possible new therapeutic strategies.
A conversation with Dr. Hirschey
MitoWorld: Congratulations on taking this next step in systems biology. Have you received any feedback from others in the field about it?
Hirschey: Thank you. The response has been very positive, particularly from colleagues working on cancer metabolism. Many have noted that our pathway-level approach fills a gap; while gene-gene coessentiality has been powerful, the emergent properties of pathways working together were being missed. Several groups have already started using our web tool at datadrivenhypothesis.org to explore their own systems of interest.
MitoWorld: Your work yielded surprising connections for glutamate and complex II. Do you have any other systems in mind to look at with this new tool?
Hirschey: Absolutely. Our analysis revealed Complex II has additional unique pathway connections that other ETC complexes don’t share. Beyond nucleotide metabolism, we saw strong links to amino acid pathways, particularly aspartate and glutamine metabolism. We’re interested in exploring how other TCA cycle enzymes might have similar “moonlighting” functions. Recent work from other groups on OGDH and fumarate hydratase suggests this is a rich area.
MitoWorld: You note several reasons that complex II is a possible therapeutic target in AML. Do you have any plans to follow up this line of research?
Hirschey: Yes, we’re actively pursuing this. Our data showing that Complex II inhibition sensitizes AML cells to venetoclax are particularly exciting given venetoclax resistance is a major clinical problem. We’re working on in vivo pharmacological studies and exploring synergistic strategies.
MitoWorld: Complex II may indeed be a target for AML and some other cancer. Can you speculate on whether it might be for a broader range of cancers?
Hirschey: Our pan-cancer analysis suggests caution here. High SDHB expression significantly increases mortality risk in only two cancer types, with AML being one. This contrasts sharply with pheochromocytoma and renal cancers, where Complex II acts as a tumor suppressor. So this isn’t a “one-size-fits-all” target. That said, our data point to broader vulnerability in hematolymphoid malignancies, where B-ALL, DLBCL, and anaplastic large cell lymphoma all showed Complex II dependency.
MitoWorld: In your discussion, you mention the increasing number of non-canonical functions of the mitochondria that have been found in recent years. Can you speculate on others that might be awaiting discovery?
Hirschey: I think we’re just scratching the surface. The TCA cycle has traditionally been viewed as an energy-producing pathway, but it’s clearly a biosynthetic hub with sensing functions. The finding that both FH deficiency and SDH inhibition suppress purine synthesis through metabolite accumulation suggests mitochondria may act as metabolic sensors, detecting imbalances through substrate buildup. I suspect we’ll find more examples where TCA intermediates serve as signaling molecules regulating distant pathways.
MitoWorld: We are obviously interested in mitochondria, but do you have any plans to examine pathways not involved with mitochondria?
Hirschey: Our pathway coessentiality tool is agnostic and can examine any gene set provided. We’ve already looked at transcription factor targets and cell-type signatures beyond metabolism. I’m particularly interested in how metabolic pathways connect to epigenetic regulation, given the known links between TCA metabolites, such as succinate and α-ketoglutarate to chromatin-modifying enzymes. The tool is publicly available, so we hope others will explore non-mitochondrial systems as well.
Reference
Stewart AE, Zachman DK, Castellano-Escuder P, Kelly LM, Zolyomi B, Aiduk MDI, Delaney CD, Lock IC, Bosc C, Bradley J, Killarney ST, Stuart JD, Grimsrud PA, Ilkayeva OR, Newgard CB, Chandel NS, Puissant A, Wood KC, Hirschey MD (2025) Pathway coessentiality mapping reveals complex II is required for de novo purine biosynthesis in acute myeloid leukaemia. Nat Metab 7: 2474–2488 (2025). https://doi.org/10.1038/s42255-025-01410-x.
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
2025 was a strong year for www.MitoWorld.org. As an information, publishing, and community web hub devoted to mainstreaming mitochondria, mtDNA, and the mitonuclear system as core to physiology, medicine, health, and translational research, we now have positive user reactions and acceptance across the research, clinical, and patient worlds. Thank you to our visitors, readers, and followers on social media for this.
MitoWorld is a largely volunteer organization that succeeds due to the incredible support of our Scientific Advisory Board (SAB) and the efforts of Alex Sercel, PhD (MitoWorld Director of Scientific Affairs and cofounder), Gary Howard, PhD, (MitoWorld Editor-Writer), Dane Wolf, PhD (MitoWorld Microscopist, Writer), Kyrie Wilson, PhD (MitoWorld Director of Scientific Communications) and Zach Kirshner for his never-ending creativity in designing and managing the MitoWorld website.
We hope we are providing a constant drumbeat of attention for the emerging and ever more popular field of mitochondrial medicine and research, sharing key insights within the research, medical, and patient communities, and playing a unique role in advocating for deeper basic science for all things mitochondrial and mitonuclear.
As the publisher of MitoWorld and the founder of the parent nonprofit, www.NLET.org/biomed, my introduction, as a nonscientist, to mitochondria was first as a patient with a non-mutational mitochondrial dysfunction. This led me directly and personally into the vast and complex terra incognita of mitochondrial cellular biology, endosymbiosis, mtDNA, and its relationship to the nucleus. Having worked in big-science reporting and outreach in astrophysics and cosmology, I found biology more complicated, with less theory and a smaller emphasis on building basic science.
Report for 2025
MitoWorld launched in the spring of 2023 after early contact with Mike Murphy (Cambridge) and Phillip West (then Texas A&M Hospital, now the Jackson Laboratory), which led to support from Navdeep Chandel (Northwestern) and Anu Wartiovaara (University of Helsinki), resulting in the formation of our SAB with the support of Douglas Wallace (CHOP) and others.
www.MitoWorld.org (web hub, communications, and media) and www.MITOS.Global (collaboration network structure) are sub-parts of the California-based research and development human capital and STEM nonprofit National Laboratory for Education Transformation, www.NLET.org, founded in 2011 and based in Oakland, CA.
1. MitoWorld Media
At this stage, MitoWorld’s primary activity is publishing five or more MitoBlog posts every month reviewing top papers in the field, covering leading conferences, and occasionally producing long-form MitoCast podcasts.
MitoBlog Posts: 55 posts in 2025 in four categories: Mitochondrial Frontiers, From the Field, Profiles, Events. Examples: First Mito Drug Approval, Mitochondria In Space, José Antonio Enríquez Profile (CNIC, Madrid), Motherboard of the Cell (Scientific American), mtDNA FASBE Conference
MitoCast Podcasts: Conducted by Danny Levine of the www.LevineMediaGroup.com these include Douglas Wallace (CHOP), Navdeep Chandel (Northwestern), Craig Thompson (Memorial Sloan Kettering), Chris Mason (Weill Cornell) with Afshin Beheshti (U Pittsburgh) “Is Life in Space Possible.”
UMDF-MitoWorld “Beyond the Disease”: Each month MitoWorld provides the United Mitochondrial Disease Foundation, www.UMDF.org, a set of blogs and podcasts for their monthly newsletter.
What Mito Media Needs: MitoWorld, primarily a volunteer organization, is seeking volunteers or stipend-supported contributors to help expand Mito Media—curating research papers into collections, managing social media, curating articles, videos, and programs. Writers are also welcome.
Contact: info@mitoworld.org
2. MitoWorld Directories
MitoWorld provides two primary sets of registries or directories for “Patients and Clinics” and “Research and Industry.” These directories were created, based on my experience and that of many others, in trying to find resources, contacts, and pathways to understand and follow the research community, clinical options, and mitochondrial science more broadly.
We have only begun this work. In 2026, we aim to grow these directories and use AI to identify mitochondrial researchers and build comprehensive databases across clinics, patient organizations, research groups, industry, and funding entities.
What Mito Directories Needs:
MitoWorld seeks volunteer or stipend-supported coordinators to help secure funding and support to build out these registries, implement structured databases, and deliver deep search and discovery capabilities for the mitochondrial community. MitoWorld has an AI partnership that can assist with this work.
See: https://www.heurekalabs.co/
3. Introducing MITOS Global (Mitochondria, Informatics, Translation, Outreach, Science)
www.NLET.org/biomed, the nonprofit parent of MitoWorld, recognized that MitoWorld serves as an information, communication, and outreach hub, but it does not itself conduct research. MitoWorld exists to support, connect, and amplify the mitochondrial research, clinical, and patient communities.
Two key realities emerged:
- Funding is limited and fragmented, preventing sustained, coordinated investigation across labs and disciplines.
- There is insufficient time and infrastructure for collaborative, systems-level research integrating biology, computation, and data science.
MitoWorld repeatedly heard from researchers about the need for coordinated, multi-investigator efforts addressing foundational mitochondrial questions.
www.MITOS.Global was organized to meet this need, with leadership including Patrick Chinnery, MD, PhD (University of Cambridge, MRC-UKRI), Anu Suomalainen Wartiovaara, MD, PhD (University of Helsinki), Phillip West, PhD (The Jackson Laboratory), and Jared Rutter, PhD (University of Utah).
The parent nonprofit, www.NLET.org, has over 14 years of experience managing large-scale, multi-institutional collaborations supported by federal agencies and philanthropic organizations.
Currently, two collaborative, multi-PI projects are active within MITOS Global, with two more in development.
Human Mitochondrial Metabolic Drive and Ecological Consequences
Activity: Letter of Interest, Simons Collaboration in Ecology and Evolution, Simons Foundation
Principal and Co-Principal Investigators:
Florencia Camus, University College London
Iain Johnston, University of Bergen
Nick Jones, Imperial College London
Kevin McCann, University of Guelph
Dan Mishmar, Ben-Gurion University of the Negev
Joel Sharbrough, University of California, Santa Barbara
Gordon Freedman, National Laboratory for Education Transformation (Applicant/Lead)
Ken Sorey, National Laboratory for Education Transformation (Project Personnel)
Mitochondrial Intercellular Mobility: Standards, Methods, and Validity
Activity: Concept Letter Submission, ARIA Precision Mitochondria, Advanced Research and Invention Agency (UK)
Note: The ARIA category MITOS Global submission is on hold until initial research begins. However, the core MITOS team continues to advance mobility protocols.
Principal and Co-Principal Investigators:
Phillip West, PhD, The Jackson Laboratory
Rajarshi Mukherjee, FRCS, PhD, University of Liverpool
Martin Picard, PhD, Columbia University
Kostas Tokatlidis, PhD, University of Glasgow
Stephen P. Burr, PhD, University of Cambridge
Cristiane Benincá, PhD, UCLA
Matthew Hirschey, PhD, Duke University
Internal Team:
Alexander J. Sercel, PhD – Director of Scientific Affairs, www.MitoWorld.org
Colwyn Headley, PhD – Stanford University
Gavin McStay, PhD – Liverpool John Moores University
Dane M. Wolf, PhD – www.MitoWorld.org
Kyrie Wilson, PhD – Medical College of South Carolina
Yasemin Sancak, PhD – University of Washington
4. External Education Outreach
October 2025: STEM Magazine, “Welcome to Mitoverse,” by Dane Wolf, PhD, and Gordon Freedman. An in-depth introduction to mitochondria in a major STEM education publication reaching over 500,000 readers.
5. MitoWorld Conference Support
MitoWorld supports mitochondrial conferences as a media sponsor, typically exchanging coverage and promotion for participation. MitoWorld also submits posters describing its mission to expand awareness of mitochondrial science and engage future scientists.
- January 13–16, 2025 | Keystone Symposia: Mitochondrial Biology in Health and Disease | NTUH International Convention Center, Taipei, TPE, Taiwan. Scientific Organizers: Lena Pernas, Anne N Murphy, and Johan Auwerx. MitoWorld LinkedIn Post.
- March 23-28, 2025 | Gordon Research Conference: Mitochondria Metabolism and Signaling, Ventura, CA: Organizers: Giovanni Manfredi, Chair; Janine H Santos, Co-Chair; Maria Eugenia Soriano, Vice Chair; Jared P Rutter, Co-Vice Chair. MitoWorld Support Logo. MitoWorld Poster.
- April 27-29, 2025 | Northwell Health & Feinstein Institute: Mitochondrial Transplantation and Next Generation Therapeutics Conference, Hofstra University. Organizer: Lance Becker. MitoWorld was a co-organizer. MitoWorld Poster.
- June 1-5, 2025 | FASEB: Mechanisms of Mitochondrial DNA Mutation and Repair, Nashville, TN. Organizers: Primary Organizer, Patrick Chinnery; Organizers, Michal Minczuk, Agnel Sfeir. MitoWorld, Essential Sponsor. MitoWorld Poster. MitoBlog Post. MitoWorld LinkedIn Post.
- June 18-20, 2025 | The UMDF Mitochondrial Medicine for Scientists and Clinicians Mitochondrial Medicine 2025, Clinical & Scientific Program 2025. St. Louis, MO. Organizer: Jonathan Brestoff. MitoWorld Poster. MitoBlog Post. MitoWorld LinkedIn Post.
- July 14-15, 2025 | Van Andel Institute, Science on the Grand. MitoWorld was a sponsor, STEM educators.
- December 12, 2025 | Columbia University, Mitochondria PsychoBiology Lab: Mitochondrial Stress, Brain Imaging, and Epigenetics Symposium, Columbia University, NY: Organizer Martin Picard. MitoBlog Post. MitoWorld LinkedIn Post.
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
Recently, a multi-institute research team led by Yosuke Togashi reported on a study that showed that cancer cells transfer mitochondria with mutant DNA and inhibitory molecules to immune cells to reduce the antitumor response. This previously unknown mechanism also shows that cancer cells with mutated mitochondrial (mt) DNA indicate a poor prognosis for certain patients.
Cancers use many strategies to avoid immune surveillance. Among those are the acquisition of mitochondria from T cells that infiltrate the tumor. Those mitochondria enhance the cancer cells energy production. But the transfer of mitochondria also works in the other direction. Mitochondria with mutations from the cancer cells are transferred to the immune cells. Those defective organelles degrade the antitumor response. Thus, the metabolic reprogramming resulting from the bidirectional exchange of mitochondria creates an environment that encourages tumor growth.
The Togashi research team sought to determine the mechanisms that promote that exchange. They examined clinical samples of immune cells for mtDNA mutations from the cancer cells. They found similar mutations in mtDNA in the immune cells. In most cases, mitochondria with mutated mtDNA are destroyed by mitophagy. However, the team identified proteins that attach to the mitochondria with mutated mtDNA and are transferred with them to the immune cells. One of these was the mitophagy-inhibiting protein USP30. Those recipient immune cells then failed to undergo mitophagy. In addition, the T cells with the mutant mitochondria became senescent.
This work has valuable clinical implications. Finding of mutant mtDNA in the cancer cells indicates that immune checkpoint inhibitors may be less effective in patients with melanoma and non-small-cell lung cancer.
A conversation with Dr. Togashi
MitoWorld: What directions do you foresee your research taking to advance this work?
Togashi: Our next steps are to clarify the mechanistic basis of mitochondrial replacement in addition to just transfer, the key molecules on donor and recipient cells, and the tumor microenvironmental conditions that promote it. We will then expand the work across additional cancer types and other recipient cell populations (beyond T cells) to build a broader map of who transfers mitochondria to whom and with what functional consequences. We are also interested in whether similar mitochondrial transfer in non-cancer diseases, such as chronic inflammation disease. In parallel, we will determine how transfer intersects with mitochondrial dynamics (fusion-fission, mitophagy, and quality control) that may determine whether transferred mitochondria persist. Ultimately, we aim to translate these findings into biomarkers that predict therapy response and therapeutic strategies that restore mitochondrial quality control to improve immunotherapy efficacy.
MitoWorld: Do you have any thoughts on the mechanism by which the immune cells receiving the mutated mtDNA become senescent?
Togashi: We think senescence is likely driven by a combination of mitochondrial dysfunction and stress signaling. Mutant mitochondria can impair respiratory capacity and elevate reactive oxygen species, which may trigger DNA-damage responses and activate pathways, such as p53–p21 and/or p16. Importantly, if mitophagy is suppressed, these damaged organelles may persist, making the dysfunction more durable.
MitoWorld: As you noted, mitochondria might be mediated by various mechanisms. Do you have a favorite candidate for this process?
Togashi: Several mechanisms could plausibly mediate mitochondrial transfer, including tunneling nanotubes, extracellular vesicles, and direct cell-cell contact-dependent processes. From our observations so far, a leading candidate is tunneling nanotubes and/or EVs. At the same time, we have the impression that the dominant route may differ, depending on the cell type and context. So these mechanisms are not mutually exclusive and may operate in parallel in different tumor microenvironments.
MitoWorld: Your work here and that of others have provided good evidence for the concept of mitochondrial transfer. However, some researchers have been slow to warm to this idea. Can you speculate on why there has been this reluctance to accept this?
Togashi: I think the hesitation is understandable. Demonstrating mitochondrial transfer convincingly in vivo is technically challenging: mitochondria are abundant, dynamic, and easy to mis-attribute due to imaging limitations, labeling artifacts, or contamination during cell isolation. In addition, the field has long emphasized mitochondria as strictly cell-autonomous organelles, so the conceptual shift takes time. In our case, we view the evidence as particularly strong because we can identify transferred mitochondria by shared genetic mutations in both clinical specimens and in vivo models, providing an orthogonal line of support beyond imaging alone. As methods improve, particularly lineage tracing, spatial approaches, and rigorous controls, I expect the evidence base will continue to strengthen and the community will converge.
MitoWorld: Do you have any speculation on how your findings might be translated to clinical applications?
Togashi: We see a few translational opportunities. First, tumor mtDNA mutation profiles could serve as biomarkers to stratify patients who are less likely to benefit from immune checkpoint inhibitors and, thus, help to guide treatment selection. Second, therapeutically targeting the transfer process or restoring mitochondrial quality control in recipient immune cells may help to preserve anti-tumor immunity. Third, these insights may inform combination strategies (e.g., pairing immunotherapy with mitochondria-targeted agents), thereby converting non-responders into responders.
MitoWorld: How did you become interested in mitochondria?
Togashi: My original training is in pulmonary medicine and thoracic oncology. From there, I became increasingly interested in cancer immunology, and during my postdoctoral period, I worked primarily on regulatory T cells. I was already aware of the accumulating evidence that mitochondrial dysfunction is an important feature of exhausted T cells, but when I was preparing to start my own laboratory, I was searching for an original research direction. Around that time, I learned about the phenomenon of mitochondrial transfer, and it immediately struck me as a fascinating and potentially transformative concept for understanding tumor-immune interactions. That was the starting point that led me to pursue this line of work.
Reference
Ikeda H, Kawase K, Nishi T, Watanabe T, Takenaga K, Inozume T, Ishino T, Aki S, Lin J, Kawashima S, Nagasaki J, Ueda Y, Suzuki S, Makinoshima H, Itami M, Nakamura Y, Tatsumi Y, Suenaga Y, Morinaga T, Honobe-Tabuchi A, Ohnuma T, Kawamura T, Umeda Y, Nakamura Y, Togashi Y (2025) Immune evasion through mitochondrial transfer in the tumour microenvironment. Nature 638: 225-236.
A paper in Nature Cancer by a multi-institute research team, led by Michael Cangkrama and Sabine Werner at the ETH Zurich, describes how cancer cells use the transfer of mitochondria to highjack fibroblasts to support the cancer. The study also implicates a protein as critical for the transfer that may be useful in novel therapeutic strategies.
The transfer of mitochondria from various cell types into cancer cells has been reported to enhance cancer cell proliferation, motility and more. Fibroblasts associated with tumors are known to adopt certain characteristics, and they frequently support cancer development. The Cangkrama-Werner team sought to determine if the transfer of mitochondria might work in the opposite direction. In other words, do cancer cells transfer mitochondria to the fibroblasts?
To answer this question, the team examined cancer cells and fibroblasts in co-cultures and xenograft tumors. Intriguingly, mitochondria were transferred to the fibroblasts where they caused changes in the metabolism of the recipient cells. The fibroblasts began to express markers associated with cancer-associated fibroblasts and to release secreted soluble and extracellular matrix proteins that support tumor growth. The team also found that the transfer of mitochondria depends on the mitochondrial trafficking protein MIRO2. Without MIRO2, the transfer and the other changes failed. These findings are consistent with the overexpression of MIRO2 at the leading edge of epithelial skin cancers and other malignancies. Finally, they found that the mitochondria are transferred through thin membranous structures called tunneling nanotubes.
This study demonstrates that mitochondrial transfer from cancer cells to fibroblasts is a key regulator of CAF differentiation. The findings also implicate MIRO2 and mitochondrial transfer as potential targets for strategies to treat cancers.
A conversation with Drs. Cangkrama and Werner
MitoWorld: Can you give us an idea of what studies you might do to advance the findings presented here?
Werner: There are several open issues, including the signals that induce the transfer, the genes and proteins that promote the transfer and the targets of the transferred mitochondria, which induce the pro-tumorigenic phenotype in fibroblasts.
MitoWorld: You showed that oxidative phosphorylation is the main activity that is influenced by the mitochondrial transfers. Can you speculate on how that process translates into the changes in gene expression in the fibroblasts? Might there be other mitochondrial activities involved in activating the interferon-response genes?
Werner: Oxidative phosphorylation is highly relevant in this context, but it is probably not the only relevant factor. Oxidative phosphorylation results in the production of various metabolites, which are likely to regulate transcription factors that control gene expression in fibroblasts. We found that the interferon-response genes are not regulated by transferred mitochondria, but likely by transfer of other molecules from cancer cells to fibroblasts in co-cultures, which remain to be identified.
MitoWorld: The transfer of mitochondria from cell to cell has been somewhat controversial. Can you comment on the seeming reluctance of some researchers to embrace this concept?
Werner: Many results were obtained with MitoTracker, which is known to be leaky. Several studies did not include appropriate controls to address this problem, which might have contributed to skepticism about mitochondrial transfer. The concept was also unexpected when first proposed. Even when transfer occurs, it is difficult to predict and appears to depend on specific conditions, such as cellular stress or high metabolic demand, further fueling doubts about its physiological relevance. However, many exciting and well-controlled studies have recently been published, which show the relevance of mitochondrial transfer under various conditions. This makes mitochondrial transfer a promising area of research, with the potential to uncover new mechanisms of intercellular communication and to develop innovative therapeutic strategies.
MitoWorld: Can you speculate how your findings might translate to therapies for cancer?
Werner: There is a long way from this discovery to a cancer drug. Nevertheless, our work suggests that inhibition of mitochondrial transfer (e.g., by blocking MIRO2 or other proteins important for the transfer) could be a novel approach for cancer treatment. In addition, identification of the relevant targets of the mitochondrial transfer in recipient fibroblasts could provide new therapeutic opportunities.
MitoWorld: How did you first become interested in mitochondria?
Werner: Several previous studies of our laboratory revealed the important role of mitochondria in the pro-tumorigenic cancer-associated fibroblast phenotype. This raised our interest in these exciting organelles.
Reference
Cangkrama M, Liu H, Wu X, Yates J, Whipman J, Gäbelein CG, Matsushita M, Ferrarese L, Sander S, Castro-Giner F, Asawa S, Sznurkowska MK, Kopf M, Dengjel J, Boeva V, Aceto N, Vorholt JA, Werner S (2025) MIRO2-mediated mitochondrial transfer from cancer cells induces cancer-associated fibroblast differentiation. Nature Cancer 6: 1714–1733.
Recently, a multi-institute team led by Thomas Langer, PhD, at the Max-Planck-Institute for Biology of Ageing examined the effects on ribonucleotide incorporation into mitochondrial (mt)DNA on inflammation. Published in Nature, the study found that increased incorporation of ribonucleotides into mtDNA during replication resulted in the release of mtDNA fragments into the cytosol and an increase in inflammation.
Mitochondria are now recognized as far more than just producers of ATP. They have many critical activities, and disruption of those functions is associated with inflammation, cell death, and disease. Dr. Langer´s team previously showed that disturbances in the nucleotide metabolism result in the release of mtDNA into the cytosol and, like pathogenic DNA, the mtDNA elicits an inflammatory response by the cell. Now they found that this is caused by an increased incorporation of ribonucleotides into mtDNA. The incorporation of ribonucleotides is a problem for mitochondria because they lack the enzyme that removes those molecules from DNA.
More specifically, they looked at mice that lacked MGME1, a mitochondrial exonuclease that maintains mtDNA, and observed increased ribonucleotide incorporation into mtDNA. Similarly, cells lacking the mitochondrial protease YME1L or senescent cells that have decreased deoxynucleotide levels accumulate ribonucleotides in their mtDNA. As a result, mtDNA leaks into the cytosol, and induces an inflammatory senescence-associated secretory phenotype, which can be reduced by adding deoxyribonucleosides.
Based on these findings, they conclude that throwing nucleotide metabolism out of balance leads to incorporation of ribonucleotides into mtDNA and age- and mtDNA-dependent inflammatory responses and SASP in senescence. The study results provide clues to several diseases, such as renal failure, systemic lupus erythematosus, cancers, and neurodegenerative diseases
A Conversation with Dr. Langer
MitoWorld: What are the likely next steps to continue this research?
Langer: This work can be taken in many different directions. Since we observe the incorporation of ribonucleotides into mtDNA in aged tissues and in senescent cells, it will be of interest to better understand the relevance of this phenomenon for the increased chronic inflammation with age. Which cells are predominantly affected and vulnerable to metabolic disturbances inducing mtDNA-dependent inflammation? From a mechanistic angle, we would like to understand better how replication stress ultimately lead to the release of mtDNA into the cytosol.
MitoWorld: Detection of double-stranded DNAs in the cytosol is a key feature of the innate immune system, but the leaking mtDNA fragments in senescent cells seems to be an “oversight” of evolution. Is this another example of the problems we face with living longer now?
Langer: The accumulation of ribonucleotides in mtDNA in aged tissues may indeed suggest that this problem worsens with age and, in this sense, it may contribute to problems associated with long life. However, we should keep in mind that mtDNA-driven inflammation is not necessarily always bad, as it was shown previously in models for mitochondrial disease that low rates of mtDNA release can prime cells and tissues to better respond to viral inflammation.
MitoWorld: Your finding that mtDNA fragments accumulate in senescent cells is intriguing, especially given that so many diseases of aging (especially neurodegenerative disease) feature inflammation. Could you expand on that idea?
Langer: A cell-cycle arrest and inhibition of nuclear DNA replication is a hallmark of senescent cells that therefore reduce the synthesis of deoxynucleotides, the building blocks of DNA. However, mtDNA replication still occurs in senescent cells (i.e., in the presence of low deoxynucleotide levels). This leads to increased ribonucleotide incorporation into mtDNA and inflammatory SASP. Indeed, this response is detrimental in many diseases settings, stimulating intense efforts to identify senolytics to selectively remove senescent cells from tissues. Our findings suggest that rebalancing the nucleotide metabolism helps to suppress the SASP, which therefore might represent an alternative approach for the treatment of at least some aging associated diseases.
MitoWorld: Can you speculate on how your findings might be translated into potential treatments beyond simply treating the inflammation?
Langer: Although it remains speculative at this point, it is an attractive possibility to use deoxynucleoside therapy to restore the nucleotide balance and to alleviate inflammation in autoimmune diseases or in ageing. Just recently, the FDA has approved a nucleoside therapy for thymidine kinase 2 deficiency, a rare mitochondrial disorder affecting children.
MitoWorld: How did you come to be interested in mitochondria in the first place?
Langer: Mitochondria are in many ways fascinating organelles. They are dynamic and very heterogeneous in different cells and tissues, reflecting their diverse functions. I originally studied protein folding and turnover in bacteria and then got interested in mitochondrial proteins and only realized with time that these processes often drive adaptative responses of mitochondria that are so important to understand their role in aging and disease. The fascination never stops!
Reference
Bahat A, Milenkovic D, Cors E, Barnett M, Niftullayev S, Katsalifis A, Schwill M, Kirschner P, MacVicar T, Giavalisco P, Jenninger L, Clausen AR, Paupe V, Prudent J, Larsson N-J, Rogg M, Schell C, Muylaert O, Larsson E, Nolte H, Falkenberg M, Langer L (2025) Ribonucleotide incorporation into mitochondrial DNA drives inflammation. Nature 24: 1-9.
Unlike the nuclear genome, which contains genes from both parents, the mitochondrial genome is inherited only from the mother. This presents a problem since mitochondrial DNA (mtDNA) is prone to mutations that can accumulate over generations and threaten species survival. To avoid this, two still poorly understood mechanisms have been selected for in evolution to counteract the accumulation of harmful mtDNA mutations: the bottleneck, whereby only a small number of mtDNA molecules is passed on to the next generation and purifying selection, a mechanism that prevents mtDNA molecules with severe mutations from being transmitted.
A recent study published in Science Advances sought to better understand how these two mechanisms cooperate to ensure healthy mitochondria in offspring. The research was led by Professor Nils-Göran Larsson, MD, PhD, and performed at the Department of Medical Biochemistry and Biophysics at Karolinska Institutet, Sweden. Dr Laura Kremer, first author of the study is currently an independent researcher at University of Göttingen and was conducting the research as a postdoc at Karolinska Institutet.
To explore the role of the bottleneck and purifying selection in the transmission of mutant mtDNA, the team produced mouse models with random mtDNA mutations along with alleles that modulated mtDNA levels or decreased autophagy.
They found that tightening the bottleneck, by decreasing the amount of mtDNA in the mother, resulted in greater variability in the levels of mtDNA mutations between individuals but reduced the overall mutational burden. Vice versa, decreasing autophagy weakened the selection, allowing more mutant mtDNA molecules to be passed on to the offspring leading to an increased mutation burden.
This study yielded novel insight by showing that the two mechanisms directly interact. Learning how cells protect the mitochondrial genome is valuable not only from an evolutionary perspective but also has medical relevance. Mutations in mtDNA are associated with many human diseases, including mitochondrial disorders, cancer, neurodegeneration, and ageing.
A conversation with Dr. Larsson
MitoWorld: You have a prolific laboratory, and this paper represents a great deal of work. Perhaps the work in this paper has progressed since its publication. Could you summarize the direction of any newer work?
Larsson: Since the publication, one direction we have undertaken involves the development of new mouse models that allows us to track different type of mtDNA variants and understand whether there are differences in the selective mechanisms that limit their transmission.
MitoWorld: At first glance, a reader might assume that increasing heteroplasmy would lead to more mtDNA mutations being transmitted. Can you simplify that concept?
Larsson: It may seem intuitive that higher levels of mutant mtDNA would facilitate mutation transmission, but our study shows that purifying selection is more efficient if mutation levels increase. A tighter bottleneck increases the heteroplasmy variance between individuals, but it also allows selection to act more efficiently. In other words, harmful variants can be identified and purged more effectively when individual mutations are present at higher levels.
MitoWorld: Can you expand on what triggers autophagy? It’s interesting that the one protein Bcl2l13 attaches mitochondria with a high HF ratio to the autophagosome.
Larsson: Autophagy is triggered by several cellular stress signals, nutrient limitation, energy imbalance, or structural damage to the organelles. In the germline, we think the process is tuned specifically to identify dysfunctional mitochondria. Bcl2l13 appears to act as a recognition factor, marking mitochondria with a high proportion of mutant genomes for degradation. This selective role is still only partly understood, but it suggests a remarkable level of specificity during mtDNA transmission.
MitoWorld: The conservation of aspects of these mechanisms across most metazoa is interesting. Most eukaryotes feature maternal inheritance of mitochondria. These mechanisms must have evolved very early in evolution. Any speculation?
Larsson: Yes, these systems likely arose very early. Once organisms started relying on oxidative phosphorylation, mutations in the mitochondrial genome became a genuine threat to fitness. Mechanisms such as bottlenecks and selective degradation would have been strongly favored by evolution. Their conservation suggests they were effective solutions and have remained largely unchanged across hundreds of millions of years.
MitoWorld: Your extensive work on mitochondria has covered many topics, including cancer, inflammation, obesity, and much more. Is the central role of mitochondria in all these areas a function of energy production or are there other activities involved?
Larsson: Energy production is certainly fundamental, but mitochondria do far more. They influence signaling pathways, metabolite synthesis, innate immunity, and cell death. Their dysfunction sends ripple effects through many biological systems, so it is not surprising that mitochondrial defects appear across diverse diseases. Understanding mtDNA inheritance is one aspect of a much broader picture of mitochondrial biology.
MitoWorld: Can you imagine how your findings might be translated into clinical treatments? Will your lab be following up on that possibility?
Larsson: We are cautious about translating findings prematurely, but the work does suggest conceptual avenues. If we can identify the key factors that guide purifying selection, it may eventually be possible to enhance this process in patients carrying pathogenic mtDNA variants. Our immediate focus remains on basic mechanisms, but we collaborate closely with clinical groups, and we certainly see therapeutic potential in the long term.
MitoWorld: In you brief bio on the MitoWorld website, you stated that you became interested in mitochondrial DNA in diseases during your PhD training. Since then, you have contributed significantly to the understanding of mitochondria. Could you comment on your thoughts on these organelles today?
Larsson: My appreciation for mitochondria has only deepened over the years. They are extraordinarily dynamic organelles, genetically, metabolically, and evolutionarily. What continues to inspire me is how much remains unknown. Every time we think we understand a pathway, we find additional complexity. That curiosity is what keeps our field vibrant, and I believe mitochondria will continue to surprise us for many years to come.
Reference
Kremer LS, Golder Z, Barton-Owen T, Papadea P, Koolmeister C, Chinnery PF, Larsson NG (2025) The bottleneck for maternal transmission of mtDNA is linked to purifying selection by autophagy. Science Advances 11(46): eaea4660.