Do neurons help cancer spread? In a paper published in Nature, a multi-institution research team, led by Simon Grelet at the University of South Alabama, provides strong evidence for a key relationship between cancer cells and neurons. They showed that mitochondria migrate from neurons to cancer cells to increase the metabolism of the cancer cells.
Dr. Grelet’s team focused on the mitochondria in cancer cells. The spread of tumors requires a significant amount of energy, and mitochondria produce energy for the cells. Cancer cells are well-known for adapting their metabolism to fit changing conditions. However, this metabolic plasticity was thought to be due to changes within the tumor cells themselves. For example, they could obtain energy by glycolysis (a less efficient process for producing ATP in the cytoplasm) or by oxidative phosphorylation (a more efficient process in the mitochondria). However, cancer cells also receive outside help in the form of metabolites, growth factors and cytokines from other cells.
Previous experiments had shown that somehow the neurons aid tumor progress, but what really interested the Grelet team was a relatively new concept that mitochondria can move from cell to cell. When neurons were co-cultured with tumor cells, the neurons experience changes to their metabolism. The number of their mitochondria increases, and some are transferred to the tumor cells. How could this work?
The team first looked at a co-culture of an aggressive breast cancer cells and neurons. The neurons underwent a morphological change from globular to tubular structures, which indicated the cancer-induced differentiation of the neurons. Neuronal differentiation is associated with changes of metabolic programming from glycolysis to oxidative phosphorylation. These changes were also associated with the establishment of long neuron protrusions, forming a neural network in the culture in vitro, which reflects the establishment of a nerve-cancer crosstalk and suggests the communication or sharing of biological materials.
Next, the team used fluorescent-labeled mitochondria to show that the mitochondria migrated from neurons to cancer cells. These methods revealed additional insights into the transfers, but they had significant limitations. To overcome those limitations, the team developed MitoTRACER. This system used genetic engineering where the donor cell mitochondria carry a tag protein that, once transferred to the recipient cells, triggers an enzymatic reaction activating the permanent expression of a fluorescent protein. The trick is that, when mitochondria move from the neurons to the cancer cells, the red fluorescence is lost, and a green signal is permanently activated. Thus, it is easy to monitor cells with mitochondria that have migrated into a new cell.
Using this unique approach, the researchers have been able to investigate the fate of the recipient cells during the cancer progression cascade, and by fate mapping of the recipient cells from the primary tumor during metastasis progression in vivo. The researchers noted enrichment of acquired mitochondria in brain metastases that might indicate enhanced metabolic plasticity from those extra mitochondria. Neuronal mitochondria are more metabolically active and might better enable tumor cells to thrive in the brain environment. This approach allowed us to define the role of mitochondrial transfer in the primary tumor environment. This process generates a subset of highly efficient metastasis cells that succeed through the complex stops and that are resilient to the metastatic barriers to ultimately form distant metastases, which is the main driver of cancer-associated mortality.
In summary, this fascinating paper might have significant implications for future cancer therapies, and beyond the cancer context, the mitoTRACER approach could have broader applications in studying cell-cell transfer of mitochondria in health and disease to understand the physiopathological implications of these transfers better.
Discussion with Dr. Grelet
MitoWorld: Your paper brings to mind the work of Judah Folkman who showed that tumors need and encourage the formation of a blood supply to progress. What do you believe the tumor may be getting from the nerve cells?
Interesting comparison. Yes, there are definitely commonalities between cancer angiogenesis and cancer innervation. In fact, cancer can actively “call” neurons to innervate them. In the context of cancer, we recently showed that aggressive subtypes of breast cancer cells can secrete axon guidance molecules, including Semaphorin-4F, to promote cancer innervation. We also found that this increased nerve density is associated with enhanced metastasis (PMID: 34810279).
The role of axon guidance molecules in promoting cancer innervation was demonstrated years ago by Dr. Gustavo Ayala (PMID: 11746267; PMID: 24097862), who pioneered the field of cancer innervation and collaborated with us on this study. Since then, many studies, including our own, have confirmed the contribution of these molecules to cancer innervation and cancer aggressiveness. While increased nerve density is often associated with poor clinical outcomes, the underlying mechanisms have remained poorly understood. This gap in understanding is precisely what motivated us to conduct this study.
MitoWorld: The movement of mitochondria from cell to cell is still controversial. What do you think it will take to solidify the concept?
The idea of intercellular mitochondrial transfer remains controversial, largely due to the lack of robust tools and clear in vivo evidence. To solidify the concept, new rigorous and physiologically relevant approaches are needed. For example, genetic systems, such as our MitoTRACER approach, which allow for precise and conditional signaling of transfer events, open the avenue for lineage-based tracking of transferred cells in vivo. Such models are critical to move the field forward and to convincingly demonstrate that mitochondrial transfer is not merely an artifact, but a biologically meaningful process.
MitoWorld: How do you think the cells signal to each other to initiate the transfer of mitochondria?
A variety of signals could potentially be involved in initiating mitochondrial transfer, but these remain to be better defined. In the context of cancer innervation, axon guidance molecules may contribute; more generally, transfer events may occur as part of a stress or help response, or by hijacking existing physiological communication routes. These signals could include reactive oxygen species, cytokines, or changes in membrane potential or lipid composition. Cancer cells, for instance, can upregulate molecules involved in cell-cell contact to facilitate mitochondrial transfer, as elegantly demonstrated by Watson et al. (PMID: 37169842). Deciphering the molecular language of this intercellular request remains a critical next step for the field.
MitoWorld: These experiments seem to have ramifications for how the nuclear and mitochondrial genomes coordinate their activities. Do you think the communication between the donated mitochondria and the recipient cell also involves the donor genes?
Absolutely, and this is a topic that warrants further investigation. Mitochondrial transfer introduces not only a new metabolic organelle with all its associated machinery, but also foreign mitochondrial DNA into the recipient cell, raising important questions about nuclear–mitochondrial coordination. While the nuclear genome of the recipient cell continues to govern most mitochondrial functions, the donor mitochondria carry their own genome and organelle machinery, which in our case is fine-tuned for neuronal metabolism and may not be fully compatible. This mismatch could influence mitochondrial gene expression, protein stoichiometry, and ultimately, the bioenergetic output. Whether donor mitochondrial DNA or its transcripts actively modulate recipient cell behavior remains an open and fascinating question. Clarifying the extent and mechanisms of this intergenomic crosstalk is essential to fully understand the consequences of mitochondrial transfer.
MitoWorld: You note that more work is needed to determine if the effects of the donated mitochondria are related to metabolic efficiency or simply that there are more of them. Do you have any sense of which it might be?
In the context of neurons, it is likely a combination of both abundance and quality. On one hand, the increase in mitochondrial mass may help support basic energy demands, particularly under stress. On the other hand, the quality and origin of the donated mitochondria, such as their neuronal bioenergetic efficiency, may actively contribute to metabolic reprogramming in the recipient cell. In our system, the integration of neuronal mitochondria appears to enhance not only energy production but also metabolic plasticity, enabling cancer cells to better adapt to new microenvironments. Dissecting the relative roles of mitochondrial abundance versus functional impact will be key to understanding how mitochondrial transfer influences cell fate and behavior.
MitoWorld: Folkman used his findings to suggest that cancers could be treated by preventing angiogenesis, and that is now widely accepted. Do you have any thoughts on how your findings with neurons might be used to develop therapeutic strategies for cancer?
Yes, absolutely, that is the ultimate goal. There are several possible strategies. First, we can target tumor innervation itself, which supports cancer progression. Second, we can aim to block the intercellular transfer of mitochondria, which fuels cancer cell adaptation. Third, and perhaps most compelling, we can selectively target recipient cancer cells that have acquired unique metabolic or phenotypic traits as a result of mitochondrial uptake. These cells may represent a vulnerable subpopulation that could be eliminated through precision therapies. Together, these approaches offer a new framework for tackling cancer’s adaptability.
MitoWorld: You looked at breast cancer and melanoma cells, both highly metastatic cancer types. Is the neuronal connection equally valid in less metastatic cancers?
We also previously reported a link between cancer plasticity and cancer innervation (PMID:37046688). Our findings suggest that more aggressive cancer cells are more likely to establish neuronal connections and engage in mitochondrial transfers. This, in turn, may further amplify their aggressive behavior, creating a vicious cycle. The ability of these cells to co-opt neural signaling and reshape their metabolic and phenotypic programs reflects a high degree of plasticity that likely contributes to disease progression.
MitoWorld: Also your work focused on solid tumors. Is there anything to be learned about blood tumors?
Interesting point. Blood cancers reside in richly innervated niches, such as the bone marrow, where neurons regulate hematopoiesis and immune responses. So, similar mechanisms might shape the behavior of leukemia or lymphoma cells. However, this remains largely unexplored, and adapting lineage-tracing tools, such as MitoTRACER, to hematological models could open exciting new directions in the field.
Reference
Hoover G, Gilbert S, Curley O, Obellianne C, Lin MT, Hixson W, Pierce TW, Andrews JF, Alexeyev MF. Ding Y, Bu P, Behbod F, Medina D, Chang JT, Ayala G, Grelet S (2025) Nerve-to-cancer transfer of mitochondria during cancer metastasis. Nature
Dr. José Antonio Enríquez—known to his lab simply as Toño—leads the Functional Genetics of the Oxidative Phosphorylation System (GenOXPHOS) group at the Spanish National Centre for Cardiovascular Research (CNIC). Using large-scale bioinformatics, his lab investigates many aspects of mitochondria, including how their protein complexes assemble, the pathophysiology of mitochondrial diseases, and even the evolutionary history of mitochondrial proteins.
Toño’s path to mitochondrial science began at the University of Zaragoza, where he completed his PhD. He then moved to California for a postdoc at Caltech before returning to Zaragoza to establish his first lab as a Principal Investigator. About 15 years ago, he moved his lab to CNIC, where he continues to push the boundaries of mitochondrial biology.
When asked what drew him to this field, Toño recalled:
“When I finished my biology degree, I knew I wanted to dedicate my life to science, but my interests were broad. I wasn’t drawn to one specific topic or focused on curing a particular disease. I was more interested in understanding the logical rules behind life itself. During a lab rotation at the University of Zaragoza, I encountered mitochondrial DNA (mtDNA). I was fascinated by the fact that this tiny but essential chromosome lives outside the cell nucleus. The idea of an ‘outsider’ chromosome inside a eukaryotic cell sparked my curiosity, and that’s what brought me to mitochondrial research.”
Known for his passionate and fiercely curious nature, Toño fosters a lab culture that encourages creativity, independence, and open scientific debate. He pushes his lab members to think outside the box—not just in their experiments, but in how they approach problems, question assumptions, and imagine what might be possible. He thrives on “crazy” ideas and welcomes disagreement as a sign of engaged thinking. Weekly lab meetings often begin with him sharing a new paper, a philosophical question, or a hypothesis that came to him out of the blue.
What are the big questions ahead for mitochondrial research?
“Mitochondria continue to surprise us,” says Toño. “From their own unique DNA and divergent genetic code to their roles in apoptosis, signaling, and disease, there’s always something unexpected. The OxPhos system alone is remarkably complex in both structure and function.”
As for what’s coming next?
“I think the most important discoveries may still be ones we don’t expect. But if I had to name specific questions for the coming year, I’d point to three:
- Understanding how sodium (Na⁺) helps build the mitochondrial membrane potential,
- Figuring out how cells maintain different types of specialized mitochondria within a single cytoplasm, and
- Resolving the debate over whether mitochondria can move between cells in a physiologically meaningful way.”
A major breakthrough: SCAF1 and mitochondrial supercomplexes
One of the lab’s most exciting discoveries was identifying the protein SCAF1 (supercomplex assembly factor 1), which enables the physical interaction between two key components of the electron transport chain—complex III and complex IV.
“This was a big step in supporting our ‘plasticity model’ of how the mitochondrial electron transport chain is organized,” says Dr. Enríquez. “We were also excited to show that variations in mtDNA can influence metabolism and healthy aging. And our recent finding that respiration complex I acts as a sodium/hydrogen (Na⁺/H⁺) antiporter revealed that sodium plays a major role in building the mitochondrial membrane potential.”
Meet the GenOXPHOS Team:
The GenOXPHOS lab currently includes around 10 members, each pursuing their own research, but generally, the group can be divided into the following research directions.
Mitochondrial Supercomplexes and Their Role in Health
This team includes three graduate students, each using different strategies to understand how respiratory supercomplexes are assembled and what role they play in health and disease.
Carmen Morales Vidal studies a highly conserved supercomplex made up of respiratory complexes I and III, exploring the importance of this interaction in mammalian cells.
Paula Fernández-Montes Díaz focuses on a family of complex IV protein isoforms, each of which is responsible for a different conformation of complex IV. These variants allow tissues to fine-tune their metabolism based on specific energy needs.
Sara Natalia Jaroszewicz specializes in advanced super-resolution microscopy to visualize these supercomplexes inside intact cells. Until recently, this was only possible using indirect and often disruptive methods.
Heart-Specific Mitochondria
Located in a cardiovascular research center, the lab has a strong focus on heart-specific mitochondrial biology.
Dr. Michaela Veliova, a postdoctoral researcher, studies different subtypes of mitochondria within individual heart cells. She’s investigating how these subtypes form and function and what roles they play in disease.
Dr. Rebeca Acín, a senior scientist, examines the reversal of ATP synthesis, a process where ATP synthase (normally making ATP) starts breaking it down. While this may help with mitochondrial quality control, Rebeca is exploring its connection to disease. She’s also investigating how ATP synthase dimerization (its ability to form pairs) affects this reversal process.
Translational Research: From Discovery to Therapy
This part of the lab focuses on translating basic mitochondrial science into potential therapies.
Dr. Marta Pérez-Hernández Durán, a postdoctoral researcher, is studying a protein kinase called FGR that regulates the activity of mitochondrial complex II. Stress-dependent activation of FGR increases reactive oxygen species (ROS) production and stabilizes HIF1a, ultimately leading to increased release of inflammatory cytokines. Since inflammation is present in numerous heart diseases, Marta is testing whether blocking FGR could be a promising treatment.
Dr. Rebeca Acín is exploring another potential drug target. OMA1, a stress-activated mitochondrial protease can trigger fragmentation of mitochondria. She is examining whether modulating its activity could help prevent mitochondrial damage in disease.
Bioinformatics and Structural Modeling
This line of research seeks to uncover how mitochondrial structures and genetic interactions shape function and dysfunction.
Dr. Jose Luis Cabrera Alarcón, a postdoctoral researcher, studies evolutionary conservation of mitochondrial genes at the population level, with the aim of identifying how genetic incompatibilities between nuclear and mitochondrial genomes might contribute to disease.
Marina Rosa Moreno, a graduate student co-mentored by Dr. Enriquez and José Luis, studies the structural biology of respiratory chain complexes. Using computational modelling and cryo-electron microscopy, she investigates how the respiratory chain complexes assemble and how structural variations may affect energy production and pathology.
The Lab’s Backbone
A great research environment doesn’t just depend on bold ideas. It also relies on the people who keep things running. GenOXPHOS is supported by a dedicated technical team:
Dr. María Concepción Jiménez Gómez, the lab manager, keeps operations smooth and organized.
Eva Raquel Martínez brings deep expertise in histology and molecular biology techniques.
Dr. Raquel Martínez de Mena oversees tissue culture and cell maintenance.
María del Mar Muñoz Hernández, the lab’s mouse technician, specializes in advanced animal procedures critical for the in vivo and translational work.
If our website is MitoWorld, the Mechanisms of Mitochondrial DNA Mutation and Repair conference was the introductory gathering of what could be called “mtDNA World.”
The organizers, Patrick Chinnery (Cambridge), Agnel Sfeir (Sloan Kettering) and Michal Minczuk (Cambridge), emphasized that this conference focused solely on mtDNA is a first of its kind.
“This brand-new conference will focus on understanding how mitochondrial DNA mutations occur in the germ line and somatic tissues with age and how they contribute to common diseases, including neurodegeneration and cancer. The conference will also cover mitochondrial DNA’s molecular and cellular consequences and new approaches to repair and remove mutations.” [conference website]
The global mitochondria conference circuit generally is focused on mitochondria themselves (often in primary mitochondrial disease) in all their complexity with a smaller percentage of presentations on mtDNA itself. In Nashville, June 1–5, about 75 individuals representing labs globally, went deep into a range of heteroplasmy dynamics over lifetimes and in various disease and dysfunction cases. There was a sense of the importance of mtDNA and its relationship with the nuclear DNA as a primary and secondary driver of disease and dysfunction and also as part of the fundamental aging process.
“The result was an interactive meeting that highlighted the current multi-functional nature of mtDNA (beyond its known role in ATP production) and the cutting-edge new techniques and approaches now available to understand how mtDNA genes are expressed, how mtDNA mutations contribute to human physiology and pathology, and how we can now edit mtDNA or otherwise modulate this maternally inherited genome to improve human health,” said Gerry Shadel (Salk Institute).
The conference was very participatory and, since it was held in Nashville, ended with an evening of line dancing.
In the words of some of the organizers and attendees:
Agnel Sfeir, Organizer, Sloan Kettering
The meeting exceeded our expectations in every way. The quality of the science, the level of engagement, and the sense of community were truly exceptional. One of our goals was to create a space that fostered open discussion across disciplines and career stages, and I think we succeeded, which was evident by the engagement of trainees, the quality of their presentations, and the insightful questions they asked.
Dmitry Temiakov, Thomas Jefferson University
The conference’s exclusive focus on mitochondrial DNA was both timely and highly valuable for the scientific community. By concentrating on mtDNA, the meeting brought together researchers across diverse disciplines—from genetics and structural biology to clinical medicine—who might otherwise not engage in direct dialogue. This focused format fostered in-depth discussions on unresolved questions, including the mechanisms underlying mitochondrial diseases, maternal inheritance, and the role of mtDNA in inflammation and aging.
Maria Falkenberg, The Falkenberg Lab, University of Gothenburg
The meeting was a unique and refreshing experience, being the first to focus only on mtDNA. It gave space for interesting discussions that went all the way from basic science to possible new treatments. The talks covered many parts of mtDNA biology, from how it is maintained to how it can be targeted in disease. It was great to see the community come together around a topic that is often included in bigger meetings, but not usually the main focus.
Gerald Shadel, Salk Institute
Our genome comprises nuclear and mitochondrial DNA, both of which are essential for life and contribute to human diseases and aging. The biology and genetics of mtDNA is complex due to it being present in multiple (often thousands) copies/cell and its sequence dynamically changing in our bodies as we age. While there are many meetings on nucleic acids (DNA and RNA), genetics and even mitochondria, rarely is mtDNA a central theme. This FASEB meeting was therefore unique by focusing a lens on mtDNA and effectively bringing together many of the senior researchers who have long influenced our understanding of mtDNA with exciting new investigators in the field.
Carlos T. Moraes, University of Miami
It was right time for a meeting focused on my favorite genome (mtDNA). There have been so many advances in our understanding and manipulation of mtDNA in the last few years, and it was exhilarating to hear and discuss them with experts and colleagues. My recent area of work is mtDNA editing, and new techniques have opened a whole area of investigations and therapeutic development. As always, new knowledge raises many questions, so this meeting was a great forum to generate new ideas and how to overcome barriers, such as the off-target edits of mtDNA base editing.
Amutha Boominathan, MitoSENS
The conference provided a comprehensive overview of recent advances in mitochondrial DNA research, with a strong focus on its role in cellular function and pathology. A key highlight was the application of advanced sequencing technologies to resolve mitochondrial heteroplasmy at the single-cell level and to establish genotype-phenotype correlations. It brought together students and junior and established researchers, with particular emphasis on emerging topics, such as mitochondrial regulation of immune responses, novel metabolic functions, and targeted approaches to silence/modulate the mitochondrial genome. The meeting was highly interactive and engaging. Looking forward to the follow-up!
Olvia Conway, Duke University
This meeting was extremely valuable to me as a trainee because of the networking and learning opportunities available. My mtDNA project is a new area for the lab, so this meeting was a way to meet others focused on this topic, receive feedback on some of my early work, and determine in which direction the field is heading. I am grateful for the opportunity to talk to other scientists during the conference sessions, and I am planning on implementing many of the suggestions I received. This was my first meeting as a graduate student, and I had a great experience.
Ana Andreazza, PhD, professor of pharmacology and toxicology at the University of Toronto’s Temerty Faculty of Medicine, leads the Mitochondrial Innovation Initiative, Mito2i, a research hub at University and affiliated institutions and hospitals.
The new project, MitoRevolution: Mitochondrial Transplantation Transforming Regenerative Medicine — from research to patient care to global impact, is part of the university’s
Institutional Strategic Initiative portfolio, is supported by a $23.8-million grant from the Canadian federal government’s New Frontiers in Research Fund Transformation Stream and brings together an interdisciplinary team that is committed to transforming regenerative medicine through mitochondrial transplantation.
Mitochondrial transplantation is defined as the process of introducing new mitochondria into cells, tissues or organs, and mitochondrial transfer is the natural movement of mitochondria between cells or into bodily fluids.
These processes are both controversial, and mitochondrial transplantation as a therapy is viewed with a considerable skepticism. Nevertheless, there is a growing interest in research into transplantation for emergency, resuscitation and regenerative purposes. Some cases have yielded positive results. However, those results cannot be attributed to an increase in mitochondrial capacity and function or to actions by the immune system or other reactions.
The infusion of federal funding in Canada to explore the wide-ranging question posed by mitochondrial transplantation marks the first nationally funded initiative of its kind.
Discussion with Dr. Andreazza
MitoWorld: There seems to be a real divergence in the thinking in the scientific community of whether transplantation is real in terms of transplanted mitochondria taking up their full functions once transplanted. How do you and the team answer those questions?
Andreazza: Indeed, this divergence is a major reason our team has come together under the NFRF-Transformation grant. Rather than assuming one mechanism over another, our approach is to systematically evaluate how transplanted mitochondria interact with host cells, whether by integrating functionally, or by initiating signaling pathways that support recovery or regeneration. Using innovative tools such as live imaging, mitochondrial tagging, and 3D tissue models, we aim to directly observe and measure mitochondrial behavior post-transplantation.
MitoWorld: On the other hand, there is the fear that the patient communities, especially those who have mitochondrial genetic diseases or are parents of children who do, will have their hopes falsely raised in the short term. How do you and your team counsel the mitochondrial patient community at this point?
Andreazza: We are deeply aware of the responsibility we have to the patient community. Transparency is central to our approach. While mitochondrial transplantation holds promise, we are careful not to frame it as a near-term therapeutic option for genetic mitochondrial diseases. Instead, we emphasize that this is an early-stage scientific endeavor with an initial potential for ex-vivo organ regeneration. We engage with patient groups regularly. In fact, the MitoCanada Foundation was part of the design of the project from the beginning, and it is now forming patient and communities committee that will oversee the project development. Most importantly, listening to concerns and co-developing knowledge translation strategies are central to ensure expectations remain grounded in the realities of where the science currently stands.
MitoWorld: Where do you and the cross-disciplinary and cross-institutional team hope to focus first, and what solutions or findings do you anticipate?
Andreazza: Our first focus is to establish the mechanism that underlies mitochondrial transplantation. Using 3D tissue and animal models, we hope to determine how mitochondria survive transfer, how long they persist in recipient cells, what cells uptake mitochondria, and what outcomes they influence. We’re particularly interested in ex-vivo organ regeneration for improvement of organ transplant. From this foundational science, we hope to develop tools that can guide future clinical applications, including standardized protocols and safety metrics.
MitoWorld: It would seem that Canada is the first national government to make an investment in mitochondria transplantation. What do you think motivated decision from a policy, scientific, and treatment perspective?
Andreazza: Canada’s investment reflects the country’s forward-looking research framework that embraces high-risk, high-reward strategies. It aims to elucidate the roles of mitochondria in health and in nearly every major disease with an opportunity to transform our understanding, and hopefully treatment strategies. In my view, these opportunities made this a compelling story for support under the NFRF’s Transformation Stream. Additionally, the interdisciplinary and community-driven nature of the project aligns well with Canada’s emphasis on collaboration and innovation.
The UMDF Mitochondrial Medicine for Scientists and Clinicians Mitochondrial Medicine 2025 conference provides an international stage for leaders in mitochondrial medicine and offers programs to inspire the next generation of researchers. Attendees will learn about the latest developments in the field of mitochondrial medicine, including industry advancements, potential treatments, therapies and cutting-edge research. The event also gives the scientific communities the unique experience of engaging with affected patients to better understand symptoms and work faster towards a cure. This year’s conference is being held in St. Louis, Missouri on June 18-21, 2025. https://www.umdfconference.org/
Jonathan Brestoff, MD, PhD, MPH, leads the Brestoff Lab and is Associate Professor of Pathology & Immunology, Director of the Initiative for Immunometabolism, and Medical Director in the BJH Clinical Flow Cytometry Lab at WashU Medicine in St. Louis.
We asked Jon to explain a bit about this his work and what is being organized from the scientific and medical community at UMDF 2025.
MitoWorld: Jon, how did you become involved with the UMDF Clinical & Scientific Program?
Brestoff: My lab has been working on trying to develop mitochondria transplantation as a new therapy for primary mitochondrial diseases, and this work has gotten me engaged with the UMDF. With the meeting being in St. Louis, they sought a local presence on the organizing committee. I’m very honored to help with this meeting and think it will be very exciting!
MitoWorld: What can researchers and clinicians expect from this year’s program?
Brestoff: This conference includes an amazing lineup of speakers on diverse scientific topics on mitochondrial biology and clinical issues in mitochondrial medicine. Main scientific sessions include Inflammation and Metabolic Diseases, Mitochondria on the Move, Mechanisms of Clearing Damaged Mitochondria, and Multi-omics. Clinical sessions include the NAMDAC Registry Session, Mitochondrial Medicine Society Platform, and Clinical Trial Updates. On Saturday, there are 2 parallel Master Classes, one on emerging clinical topics chaired by Dr. Michio Hirano and one on scientific career development chaired by me.
MitoWorld: Is there any particular theme or emphasis this year?
Brestoff: The main themes are around emerging scientific discoveries about mitochondria and clinical updates. One of the most exciting aspects of this meeting is that patients, families, clinicians, and scientists all come together for one conference. This creates a unique experience that, in my experience, has been incredibly motivating and inspiring.
MitoWorld: With your lab at Washington University in St. Louis, will you be discussing or your lab members presenting on your lab’s work?
Brestoff: Yes! While I am not speaking to yield time to other investigators, a couple exceptionally talented scientists from my group are presenting their work on mitochondria transfer and transplantation.
MitoWorld: What are your hopes in your work for the next year and what issues are on the forefront that may materialize over the next year?
Brestoff: There are so many new and exciting discoveries about mitochondria — how they work, what they do, and how we can leverage their biology to develop new therapeutics. There is tremendous untapped potential in this field for many diseases, not just primary mitochondrial diseases but also others like obesity, heart disease, and even aging. I hope we can find ways to team up with each other, industry partners, and investors to make some of these new therapeutics a reality for patients who need them. For my own lab, we’re currently working to make mitochondria transplantation a future possibility for patients with primary mitochondrial diseases. I hope we can get there.
The special issue of Journal of Cell Science (JCS) on the “Cell Biology of Mitochondria” looks to be one of the most comprehensive open series of papers, opinions, perspectives, interviews, reviews and posters on the subject of mitochondria biology, perhaps ever.
This incredibly in-depth examination of mitochondria covers the subject in research, interviews and commentary and does so in what can only be described as a community spirit from the Journal of Cell Science (JCS) a publication of the Company of Biologists, which is “dedicated to supporting and inspiring the biological community.”
A Good Place to Start [Editorial]
The Cell Biology of Mitochondria Special Issue is a collaboration led by Ana J. Garcia-Saez, Max Planck Institute of Biophysics and Heidi McBride, Department of Neurology and Neurosurgery McGill University, guided by Cell Biology Executive Editor Seema Grewal, who has a deep publishing and research biology background. McBride is also a member of the MitoWorld Scientific Advisory Board (SAB).
MitoWorld was so impressed with this collection, enough reading for a month, that the questions arose of how does such an issue come together and how does it stand to help the mitochondrial research world as the subject becomes more popular. To get a sense of this, Executive Editor Seema Grewal answered a few questions.
MitoWorld: What prompted the special issue?
Grewal: JCS has a long and rich history of publishing papers in the field of mitochondrial cell biology; indeed, some of the early papers examining the factors that contribute to mitochondrial fusion and fission were published in JCS. We wanted to remind the community about this, so what better way to do this than to coordinate a special issue on the topic.
MitoWorld: This was a huge undertaking, how did this get going and how long has it taken?
Grewal: We started discussing the idea at the journal’s annual gathering of editors back in February 2024. Heidi and Ana are on the journal’s Editorial Advisory Board and are experts in the field, so the team felt that they would be well-placed to serve as Guest Editors for the issue. After some discussion with them, we decided on the aim, scope and timeline for the special issue. We put out a call for papers in the Spring of 2024 and had an encouraging response from the community, resulting in lots of research articles being submitted for consideration in the special issue. In parallel, we also identified and invited experts from across the field to contribute review-type articles.
MitoWorld: Can you talk about the Journal and its mission and how you are able to put together projects at this scale.
Grewal: JCS prides itself in being a community journal that is published by a not-for-profit publisher (The Company of Biologists) that exists to benefit scientists not shareholders. Coordinating a special issue is hard work, but we’re fortunate to have an in-house team that can support Guest Editors in coordinating the issue, so that they can focus on the science. This team works closely with the Guest Editors to ensure the smooth and efficient handling of articles.
MitoWorld: What do you hope comes from such a publication? Who should be reading this issue?
Grewal: We’re hoping that the issue will inspire the community and stimulate debate and discussion. It contains a range of research and technical articles that showcase the advances in the field. It also contains some in-depth reviews that synthesize the latest findings. We’ve also included some perspective and opinion articles that challenge our view of mitochondria. Finally, we strongly believe that it’s important to highlight the scientists that actually do the work, so the issue includes some interviews with researchers at different career stages. We’re hoping there’s something in the issue for everyone. It’s also worth pointing out that, thanks to our ‘Forest of Biologists’ initiative, we planted 24 trees to represent the 24 peer-reviewed articles published in the issue, so that’s another really positive outcome!
MitoWorld: There is so much material, do you have suggestions on what busy people should concentrate on or how to best use the whole resource.
Grewal: The Opinion piece is a good place to start, as it provides an over-arching view of mitochondria. After that, we suggest that people just bookmark the full table of contents and dip in and out of any reviews or research articles that appeal to them
MitoWorld: What do you hope the take-aways are for the serious reader of this special issue?
Grewal: That we’ve made lots of progress, largely thanks to new technologies…but there’s still so much to learn!
Since the days of van Leeuwenhoek and his microscope, new technologies have allowed researchers to look at life, quite literally, in new ways. As technologies have grown in power, they also increased in cost and complexity, often putting them beyond the means of individual researchers. Many research organizations solved this challenge by developing core facilities in which an expensive instrument is purchased for multiple researchers. Knowledgeable individuals are hired to operate it.
While many research organizations have core facilities, they typically focus on one instrument type (e.g., imaging, bioinformatics, HPLC). At UCLA, Orian Shirihai (professor of medicine and molecular and medical pharmacology) took this concept to the next level by combining advanced technologies of different modalities into a single integrative core. His Mitochondria and Metabolism Core (Core) brings together capabilities in bioenergetics, imaging, and biochemistry to facilitate the study of mitochondria metabolism. The Core may be unique in this comprehensive approach to research on mitochondria.
“Our mission is to empower scientists across academia, biotechnology, and pharmaceutical industries to design, execute, and interpret experiments related to mitochondria and metabolism. By doing so, we aim to accelerate scientific discovery and the development of novel therapies and diagnostics,” said Dr. Shirihai.
The Core comprises three sections. The bioenergetics section, led by Linsey Stiles, features several Seahorse instruments that measure oxygen consumption and extracellular acidification providing readouts of mitochondrial respiratory function, glycolysis, ATP production rates, and other metabolic measurements. The imaging section, led by Cristiane Beninca, has a broad selection of microscopes (brightfield, widefield, confocal, FLIM, and super-resolution microscopes as well as a transmission electron microscope) and techniques to study mitochondrial structure and function (e.g., membrane potential, reactive oxygen species, and NADH measurements, mitophagy flux, mitochondrial and cristae dynamics, organelle interactions) in live and fixed samples. A biochemistry section, led by Lucia Fernandez-del-Rio complements the other sections with enzyme assays, western blots, non-denaturing gels to examine mitochondria supercomplexes, and mtDNA-based assays.
The Core provides an exceptional resource for basic, clinical, and industry researchers who are interested in mitochondria research. It helps in all phases of mitochondrial research from study design to data interpretation. The Core operates on a fee-for-service recharge system, offering a range of options from full-service support to specialized training for autonomous use of advanced equipment, and everything in between.
In recent years, physicians and researchers have come to appreciate the intimate involvement of mitochondrial dysfunction in human disease. The Core provides a unique resource to accelerate research in this critical area. Its value is documented by its broad spectrum of users, including researchers at UCLA and many other organizations, such as CalTech, UC Santa Barbara, and USC.
David Shackelford, PhD (professor of medicine, UCLA), said, “The mitochondrial metabolism and the imaging cores at UCLA have been an incredible resource and been transformative with respect to our research.” Amy Wang, PhD (CEO, Enspire Bio Inc.), added, “The UCLA mitochondria cores are indispensable collaborators and have transformed the direction and focus of our research and were important for informing our scientific strategy.” Clearly, the Core is having an impact on research into metabolism and mitochondria.
For more information about the Core, please visit their website: https://medschool.ucla.edu/research/themed-areas/metabolism-research/metabolism-core.
The Core directors respond to our questions
The UCLA Core seems to be a unique resource for researchers. Are you aware of anyone else who has combined so many powerful technologies to the study of mitochondria?
Providing services as we do, no. We are the only place that can offer services and access to cutting-edge equipment to internal and external scientists in need of the techniques provided. There are certainly places with multiple researchers working in mitochondria research and sharing expertise and access to equipment, but the only way for other researchers to have access to their techniques is through collaborations. In the Core, we offer a fee-by-service system, so anybody can “hire” us to work for them.
Do you plan to add any new resources to your collection (e.g., mass spec, HPLC, new imaging methods)?
At UCLA, additional Core facilities (e.g., Lipidomics, Metabolomics, or Proteomics) are available to clients interested in a multi-omic approach, so we are not considering an expansion in that direction. In the Biochemistry Core, we are working to incorporate mitochondrial DNA (mtDNA)-based assays, such as mtDNA copy number, mutation frequency, or mtDNA nanopore sequencing, into our services. But our portfolio is always expanding as new techniques are constantly in development, and in certain cases, we even work with the clients to develop or improve the techniques they need. Particularly, in the Imaging Core, new dyes, imaging, and analysis techniques are always in development. And in the Bioenergetics Core, new ways to measure mitochondrial function or optimization of different samples are always happening. Once techniques are optimized, they can be added to our portfolio as a service to clients.
Can you describe the general idea of a couple of the studies that the Core has participated in where each of the three sections were involved?
One example is the research paper https://doi.org/10.15252/embj.2022111699. In this project, we started with a Sponsored Research Agreement with a Company that provided us with a compound to be tested. The story progressed into a scientific discovery that was published and even a new technique was developed 10.26508/lsa.202201628
The three sections work very closely together, and we also have researchers with Grants in need of the expertise of all three Cores, and we can work together with them almost as if we were part of their laboratory personnel too.
What would you estimate as the breakdown of your time spent in training, planning experiments and evaluating data, and actual experimenting?
Our top priority is to address the needs of our clients in the best way possible. So, we work together to find the best approach to do so. There are times when we have clients with more knowledge of the techniques needed, and they can be more independent on planning and even running the experiments, so training is just needed in the beginning. Other times, samples are shipped to us, and we are responsible for the whole process until the delivery of results.
How did each of your become interested in the study of mitochondria?
Cristiane Beninca: For me, it was during my PhD that my mentor discovered a new protein localizing at the mitochondria, and since that, everything became mitochondria related.
Lucia Fernandez del Rio: Back in my undergrad days, I joined the Cell Biology Department and started working in a lab that focused on oxidative stress. Since this phenomenon is deeply interconnected to mitochondria, that is where my mitochondria journey started.
Linsey Stiles: I did a rotation focused on the role of mitochondrial fusion and fission in erythropoiesis and knew immediately that I wanted to continue to study mitochondria for my PhD project.
We were honored to hold an interactive session on the work of www.mitoworld.org at the CELL: Multifaceted Mitochondria Symposium in Sitges, Spain, October 27-29.
Three members of the MitoWorld scientific advisory board (Gerry Shadel, Salk Institute for Biological Studies, Mike Murphy, University of Cambridge Mitochondrial Biology Unit, and Heidi McBride, McGill University and I spoke about MitoWorld’s efforts to “mainstream” mitochondria for the public and to the medical sector, pushing also toward a more encompassing mitochondrial science, and beginning a mitochondrial informatics effort.
As a new organization, we were able to hear from the attendees on what they felt was necessary to help the mitochondrial field get more attention and to communicate how essential mitochondria are to health, disease mitigation and solving complex issues from childhood mitochondrial mutation diseases to the issues of aging and age-related diseases, many of which are without therapies.
Symposium attendance was over four hundred mitochondrial researchers from around the world with strong representation from the U.S., UK, Australia, China, Korea, Finland, Germany, Spain and Italy among others. It was also a powerful venue for the interaction between senior researchers and postdocs coming into their positions into the field which is now growing.
Attendees shared with our panel that the public and professional dialog needs to be widened globally. There was an interest in participation with MitoWorld from many of the labs.
The panel invited comments on MitoWorld’s interest in building task forces in various arenas of mitochondrial research mapped to medical practice areas and well-known research subjects. While the task forces idea was well received, the most interest was in finding ways to educate or inform doctors and the medical profession about mitochondria in specific practice areas.
In this case, mitochondria are like the hidden hand in physiology that is not often considered in diagnoses or treatment.
Additionally, there was a sense that the subject of mitochondrial research and eventual practice has to be seen as “across the lifespan,” that mitochondria are ubiquitous and consequential at every stage while, at present, the practice areas are the mutation diseases of early life and the complications of mitochondrial decline in the diseases of aging.
The subject of education, starting in school and college and in medical training, came up several times as a way to anchor mitochondria in culture and eventually in practice. It should be noted that MitoWorld is a project of the R & D nonprofit National Laboratory for Education Transformation, www.NLET.org in California.
We hope the momentum from the Symposium will help build MitoWorld globally.
Mitochondria World is the first step in a process to set up a collaborative and informative mitochondria portal that is designed to service three primary communities: a) patients and clinics through listings and referrals, b) researchers, investigators, labs and institutes to manage a flow of up-to-date research, build working groups and communicate about issues in a single place, and c) to inform and build awareness in the public and among professionals about the significance of mitochondrial research for translation into treatments for diseases and conditions across the entire lifespan, including issues of personal and global health.
Together, as MitoWorld expands, we hope to influence the levels of funding and support for research, collaborations and dialogue beyond seeing mitochondria only through the lens of their individual functions, which has not led to success in developing new drugs for mitochondrial diseases.
By widening awareness and collaborations, we hope we can stimulate more investment for broad-based mitochondrial research to support the difficult path to successful therapies for primary mitochondrial diseases as well other secondary mitochondrial dysfunctions observed in the mostly terminal diseases of aging – cancer, diabetes, neurodegenerative diseases, autoimmune problems and many more.
To further our collaborative mitochondria work, we partner with investigators, institutes and labs across the globe: our mission is to expand our reach as far as possible. We support, publicize, and participate in conferences and symposia like the Cell: Multifaceted Mitochondria Symposium in Spain at the end of October. We schedule lab visits to expand our understanding and coverage of labs and institutes, promoting their work as well. Recent visits to Douglas Wallace’s Lab at Children’s Hospital Philadelphia and at Jared Rutter’s Lab at University of Utah were instructive and we plan to meet with several more investigators by the end of the year.
Critically, our work does not stop at creating awareness and sharing information. As part of an active and still-evolving cellular symbiosis, we believe much is to be learned about how mitochondria regulate health and contribute to many yet untreatable diseases and conditions. A key aspect of our mission is to support leaders in the scientific and medical communities to drive technical advances in mitochondrial biology and medicine. The Scientific Advisory Board of MitoWorld and its staff firmly believe that the time has come to define and name a mitochondrial science and informatics effort that elevates mitochondria from single investigations into categories of research that feed into a general understanding of the basic science of mitochondrial dynamics, systems and complex interactions.
We are open to engaging, presenting and collaborating on both the mitochondrial awareness and basic science fronts. We invite your involvement in our efforts to “mainstream” mitochondria with the public, patient groups, medical practice and across the various research communities to support our collective mission to stimulate more investment and involvement into a broader understanding of the trillions of mitochondria in each of us.