Mitochondria house metabolic pathways that support cell growth, survival, function and identity. Mutations in mitochondrial metabolic enzymes are drivers of many mitochondrial diseases, but different diseases arise when certain metabolic functions are disrupted, and the cell types affected are often poorly understood. In recent work published in Cell and Molecular Cell, a research team at Memorial Sloan Kettering Cancer Center, led by Abigail Xie, Julia Brunner and Lydia Finley shed light on when cells use different metabolic pathways within mitochondria and what essential functions are supported by mitochondrial metabolic networks.
The researchers focused on two related metabolic pathways that are required for importing nutrients into mitochondria and converting them into molecules that cells need to function. The tricarboxylic acid (TCA) cycle harnesses reducing equivalents from nutrients to fuel energy production in the electron transport chain (ETC), and the malate-aspartate shuttle transfers reducing equivalents from the cytosol to mitochondria for deposition onto the ETC. Despite the central role of these pathways within cellular metabolism, mammalian cells display surprising heterogeneity in whether, and how, they use these pathways. For example, some reactions of the TCA cycle can run in reverse or be skipped by exporting intermediates that are converted in the cytosol. The authors, therefore, set out to investigate the factors and contexts that dictate how the TCA cycle and related pathways are assembled in mammalian cells.
Reporting in Cell, co-first authors Xie and Brunner sought to determine what makes cells use the complete set of reactions that make up the “canonical” TCA cycle. They found that increasing cellular nutrient consumption by supplying cells with TCA cycle substrate pyruvate increased the production of citrate, the metabolite formed in the first step of the TCA cycle. Enhancing citrate production led to increased forward flux through the TCA cycle and induced dependence on enzyme aconitase 2, the TCA cycle enzyme that that breaks down citrate. To determine if aconitase 2 is also essential to break down citrate in vivo, they generated a mouse model of whole body, inducible aconitase 2 deficiency. Here, they discovered the kidney to be exquisitely sensitive to aconitase 2 loss. Notably, the kidney is unique for its ability to uptake and catabolize circulating citrate. The authors showed that cell autonomous citrate uptake is sufficient to induce reliance on aconitase 2 in cultured cells. Collectively, these results indicate that a major function of the TCA cycle is to remove citrate from mitochondria. This work demonstrates that apart from its known roles in nutrient breakdown and provision of metabolic intermediates, the TCA cycle is also important for metabolite clearance.
In the second study, the authors described how pathways that feed into the TCA cycle are differentially utilized depending on cell state. For cell metabolism to continually function, reducing equivalents generated in the cytosol must be transferred to mitochondria, where they can be safely deposited on the ETC. Reciprocally, oxidized intermediates generated within mitochondria must be delivered to the cytosol where they can be used to fuel biosynthetic pathways. One pathway, the malate-aspartate shuttle, fulfills both needs by transferring reduced nutrients (the TCA cycle intermediate malate) to mitochondria in exchange for aspartate. Mitochondrial production of aspartate is an essential function of the ETC in cultured cells. Here, the authors showed that the ability of aspartate to participate in the malate-aspartate shuttle and transfer reducing equivalents back into mitochondria depends on the relative balance between aspartate supply and demand within cells. Increasing or decreasing cytosolic aspartate levels with bacterial enzymes allowed cells to increase or decrease flux through the malate-aspartate shuttle, respectively. In turn, changing malate-aspartate shuttle flux changed how cells use metabolic pathways that depend on clearing reducing equivalents from the cytosol. Specifically, the ability to oxidize glucose required increased malate-aspartate flux. Accordingly, whereas proliferating cells with high aspartate demand had limited malate-aspartate shuttle flux and reduced glucose oxidation, differentiated cells with lower aspartate demand exhibited higher malate-aspartate shuttle flux that was sufficient to enable increased glucose oxidation—a metabolic hallmark of differentiated cells.
These findings illustrate how metabolic networks adopt different configurations depending on environmental context and cell state. Understanding when, and why, metabolic components become essential for different tissues and contexts will ultimately provide insight into the etiology of metabolic disease and nominate new approaches to target metabolism to manipulate cell states in cancer and other diseases.
A Statement of Significance from Dr. Lydia Finley
Mitochondria play critical roles converting nutrients into the molecules that cells need to function, but which metabolic pathways are used and which outputs are essential for cells are highly context-specific. For example, mutations in mitochondrial enzymes result in highly tissue-specific pathologies, indicating that different tissues—different cell types or cell states—have unique requirements for outputs of individual enzymes. In two papers, Brunner, Xie, and colleagues add to our understanding of how mitochondrial metabolic pathways are wired in to meet the demands of different cell contexts. In one study, they show that some cells depend on the TCA cycle not just to support energy production or anabolic synthesis but also to prevent metabolite accumulation within mitochondria. In another study, they show that as progenitor cells differentiate, they fully engage the malate-aspartate shuttle—an electron shuttle that enables cells to oxidize glucose within mitochondria. Together, these studies show how metabolic programs are wired to meet unique demands of different cell states. These studies support the argument that further identifying when and why metabolic enzymes are required will provide critical insight into how mitochondria support cell fitness and why mutations in mitochondrial genes lead to human disease.
A Conversation with Dr. Lydia Finely:
MitoWorld: How did you become interested in studying mitochondria? What interests you about them?
Dr. Finley: I became interested in metabolism as an undergraduate when I first learned that muscles can continually switch fuels to meet metabolic demands during exercise. This adaptability fascinated me, and I ended up working in a mitochondrial bioenergetics lab studying how mitochondria select different fuels to use during exercise and recovery from exercise. This adaptability fascinates me to this day: mitochondria are constantly sensing and responding to their surroundings and providing information about their decisions to the rest of the cell. They are like a little brain within a cell, taking in information and coordinating cellular responses.
MitoWorld: You mention that the kidney is uniquely sensitive to ACO2 deletion in the TCA cycle. Is that simply because it has to process so much citrate to remove it from circulation, or do you think there may be other reasons for this?
Dr. Finley: Likely many factors contribute to the importance of ACO2 in the kidney. We focused on the role of citrate uptake and showed that citrate uptake is sufficient to induce ACO2 dependence in non-kidney cells. That doesn’t rule out other functions of ACO2 in the kidney. Notably, the kidney proximal tubule cells, which displayed pathological abnormalities following ACO2 loss, are considered to be some of the most energy-demanding cells in the body. It will be interesting for future studies to determine whether this energy requirement contributes to ACO2 dependence in the kidney and, potentially, other organs.
MitoWorld: Other than the kidney, are there other types of cells or disease contexts that have unique characteristics or sensitivities when it comes to the TCA cycle? What does this tell you about them?
Dr. Finley: This is a major open question. Patients with ACO2 mutations often manifest with retinal phenotypes, suggesting that this cell type may have high reliance on ACO2. In cultured cancer cells, ACO2 is one of the most variably essential metabolic genes, meaning that some cells don’t care much about ACO2, while others do. What underlies this variability is a major question for us moving forward.
MitoWorld: The metabolic hallmark of differentiated cells with regard to the malate-aspartate shuttle is very interesting. Is this generally true of all types of differentiated cells, or are there some cell types that behave differently? Are there disease contexts where this changes, such as in cancer?
Dr. Finley: This is a great question. We’ve tested a few contexts where the transition from proliferative, progenitor to differentiated states shows this characteristic metabolic switch. How generalizable this switch is remains to be determined. Likely, some differentiated tissues will have specific metabolic requirements that push them to an alternate metabolic state. Continuing to identify how changes in cell state reorganize metabolism and which metabolic programs are required for certain cell states is a major area for future work.
MitoWorld: How might these pathways be targeted to treat disease, as you suggest in the conclusion? Through pharmaceuticals, through diet, other?
Dr. Finley: To know how to treat disease, we need to know why the disease arises. In many cases, mitochondrial diseases driven by the same genetic mutation affect different tissues (and even different people) differently. Why some tissues care more than others about specific mutations isn’t always clear. This variable dependence suggests that metabolic enzymes are required to meet needs that are specific to some tissues. If we can understand what these needs are—which metabolic outputs support essential functions in different tissues—we can better understand why pathologies emerge and, then, hopefully identify strategies to help tissues meet their specific needs and overturn these pathologies.
MitoWorld: What are the next steps for this research? What questions are you still trying to answer and why are they important?
Dr. Finley: We found that citrate accumulation within mitochondria activates a stress response known as the integrated stress response, which turns on genes that helps cells adapt to stress or other environmental changes. We are working to understand how mitochondrial citrate, or consequences of citrate accumulation within mitochondria, turn on a cytoplasmic stress response. We hope these studies will provide new insight into how changes within mitochondria are communicated throughout the cell to help cells adapt and respond to changes in mitochondrial activity.
MitoWorld: Anything else you think the audience should know?
Dr. Finley: Metabolism is not one-size-fits-all. It highly, highly variable, and there is a lot left to learn about cell metabolism!
References:
Abigail Xie, Julia S Brunner, Sangita Chakraborty, Angela M Montero, Anna E Bridgeman, Katrina I Paras, Ruobing Cui, Maider Fagoaga-Eugui, Monika Komza, Paige K Arnold, Benjamin T Jackson, Santiago Noriega Madrazo, Mohamed I Atmane, Sebastian E Carrasco, Lydia W S Finley (2026) Citrate clearance is a major function of aconitase 2 in the canonical TCA cycle. Cell 189(9):2684-2699.e21.
https://pubmed.ncbi.nlm.nih.gov/41763199/
Julia S Brunner, Anna E Bridgeman, Benjamin T Jackson, Sangita Chakraborty, Maider Fagoaga-Eugui, Katrina I Paras, Abigail Xie, Paige K Arnold, Julia Losner , Lydia W S Finley (2026) Aspartate availability drives differential engagement of the malate-aspartate shuttle. Mol Cell. Mar 5;86(5):954-967.e7.
“What was striking was not simply that mitochondrial transfer was being discussed, but how many different cancer systems it appeared to connect. Across all three talks, mitochondria were presented less as isolated organelles and more as mobile biological assets shaping metastasis, immune exhaustion, therapeutic resistance, and even tumor innervation. You could feel the field beginning to connect previously separate observations into a larger systems-level framework.”
— Alex Sercel, Co-Founder, MitoWorld.org
For decades, mitochondria occupied an uneasy place in cancer research. Everyone knew they mattered. They appeared in discussions of metabolism, apoptosis, oxidative stress, and cellular energetics. But they rarely occupied center stage at major oncology meetings. The mitochondrion was often treated as background infrastructure — essential, certainly, but secondary to the “real” drivers of cancer biology.
Something changed at the American Association for Cancer Research (AACR) Annual Meeting 2026 in San Diego.
For the first time in the history of the AACR Annual Meeting, mitochondrial transfer in cancer was given its own dedicated symposium. That may sound procedural to outsiders, but to researchers working at the intersection of mitochondria, metabolism, immunology, and cancer, it represented something much larger: institutional recognition that mitochondrial dynamics are no longer peripheral to oncology. They are becoming central to it.
The symposium, “Mitochondrial Transfer Networks in Cancer Progression,” brought together three researchers approaching the field from distinct but converging directions:
- Yosuke Togashi, Okayama University
- Simon Grelet, University of South Alabama / Mitchell Cancer Institute
- Luca Gattinoni, University of Regensburg / Leibniz Institute for Immunotherapy (LIT)
Collectively, the presentations argued something profound: mitochondrial transfer is not a niche biological curiosity. It is emerging as a fundamental mode of intercellular communication in cancer biology — one that tumors exploit, immune systems respond to, and future therapies may intentionally manipulate.
After the session, MitoWorld.org reached out to all three panelists with a series of questions about the field, the symposium, and where mitochondrial cancer biology may be headed next. What emerged from those conversations was not just enthusiasm, but the unmistakable sense that an entire area of science is crystallizing in real time.
A Field Arrives
When asked what made the AACR symposium so important, all three researchers independently focused on the same point: this was a first.
“This was, to my knowledge, the first time mitochondrial transfer in cancer had been given its own dedicated special session at AACR,” explained Simon Grelet. “The room was charged with enthusiasm and curiosity.”
Yosuke Togashi emphasized the scale of interest from the oncology community itself:
“The sheer volume of questions indicated a significant surge in interest regarding how mitochondrial dynamics influence oncology.”
For Luca Gattinoni, the significance was not merely that the session existed, but how it was framed.
“The three talks together made an argument that no single one of us could have made alone: that mitochondrial transfer is not a niche phenomenon but a fundamental mode of intercellular communication that tumors exploit and that we can potentially exploit back.”
That framing matters.
Cancer biology has increasingly become the biology of systems: tumor microenvironments, immune interactions, stromal signaling, metabolism, and cellular networking. What mitochondrial transfer research suggests is that mitochondria themselves may function as active biological currency moving between cells — influencing survival, adaptation, immune suppression, metastasis, and therapeutic resistance.
From “Power Plants” to Networks
One of the strongest themes emerging from the symposium was that the classical textbook view of mitochondria is rapidly collapsing.
For generations, mitochondria were taught primarily as intracellular energy factories — isolated organelles generating ATP inside sealed cellular boundaries.
That view now appears incomplete.
“The field is moving away from the traditional view of the mitochondrion as an isolated ‘power plant’ enclosed within a cell,” said Yosuke Togashi. “Instead, we are beginning to understand it as a dynamic component of a larger networking system.”
That conceptual shift may ultimately prove as important as any individual experiment.
Mitochondria are increasingly being understood not simply as metabolic engines, but as signaling entities, stress sensors, inflammatory regulators, and now potentially mobile intercellular participants capable of moving between cells and altering biological outcomes.
Simon Grelet noted how rapidly evidence for mitochondrial transfer has accumulated across multiple dimensions of cancer biology:
“It is proving to touch multiple dimensions of cancer biology: how tumor cells acquire metabolic advantages, how they interact with their microenvironment, how they evade treatment, and more.”
Meanwhile, Luca Gattinoni highlighted how evidence is arriving simultaneously from very different domains:
“Nerve-tumor interactions shaping metastasis, tumor cells offloading dysfunctional mitochondria to suppress immune responses, stromal cells using the same mechanism to sustain T cell fitness.”
“The same biological currency,” he added, “deployed in radically different contexts.”
The Room Itself Told the Story
Scientific meetings often reveal the future of a field less through formal presentations than through hallway conversations afterward.
By all accounts, that happened here.
Yosuke Togashi was struck not only by the engagement during the session, but by what happened after it ended:
“The technical nature of the follow-up questions showed that researchers are already thinking about how to integrate these concepts into their own models.”
Luca Gattinoni described something rarer still:
“The conversation that emerged felt like the field thinking out loud in real time.”
That may ultimately be the most important signal of all.
Not simply that mitochondrial transfer research is growing, but that cancer researchers working in metastasis, immunotherapy, stromal biology, metabolism, and genomics are beginning to realize they are asking overlapping questions about the same underlying system.
The Next Frontier: mtDNA and the Mitonuclear System
If mitochondrial transfer itself is emerging as a major area, the next wave may center on mtDNA and the mitonuclear system.
The mitochondrial genome remains one of the least fully integrated components of modern cancer biology. Heteroplasmy, mutation dynamics, mitochondrial-nuclear coordination, and intercellular mitochondrial inheritance remain only partially understood.
Yosuke Togashi believes advancing sequencing technologies will rapidly change that.
“While the complexities of mutation patterns and heteroplasmy remain largely mysterious, advancing sequencing technologies will soon make this a focal point of cancer genomics.”
Luca Gattinoni sees the mitonuclear axis becoming its own frontier:
“We now have enough mechanistic footing to ask harder questions about directionality, selectivity, and what it truly means for a cell to absorb another cell’s mitochondria and their DNA.”
And perhaps most intriguingly, he believes the future will move beyond observation:
“The ambition should grow: not just observing transfer, but engineering it with intent.”
That single sentence hints at where this field could eventually lead: mitochondrial engineering, mitochondrial immunotherapy, and perhaps entirely new therapeutic architectures built around manipulating cellular energy and signaling systems directly.
A New Scientific Convergence
Historically, mitochondrial biologists and cancer researchers often existed in adjacent but separate scientific cultures. That separation may now be ending.
Simon Grelet noted that mitochondrial biology appeared across multiple AACR tracks far beyond this single symposium.
Meanwhile, Yosuke Togashi offered perhaps the most insightful observation of the entire discussion:
“The most vital ‘transfer’ occurring right now isn’t just between cells, but between disciplines.”
That may ultimately define this moment.
Cancer biology, immunology, mitochondrial medicine, metabolism, genomics, and systems biology are beginning to converge around a shared realization: mitochondria are not passive background organelles. They are dynamic participants in disease.
AACR 2026 may be remembered as one of the first moments when that convergence became visible at scale.
And if the energy in San Diego was any indication, this is only the beginning.
Melanoma cells release abnormal mitochondria into the extracellular compartment. This novel mitochondrial quality-control mechanism points to possible biomarkers for the disease. The results of the study were recently published in a paper in Cancer Letters and led by Francisca Alcayaga-Miranda.
Melanoma cells experience significant levels of oxidative stress. While they depend on glycolysis, they still need mitochondria for other cell functions. Other studies had shown that damaged mitochondria are expelled from a stressed cell. However, it was not known if this process occurred with melanoma cells and how it was accomplished.
The research team sought to clarify this process. Using electron microscopy, they examined mitochondria released from normal and melanoma cells from mice. All cell lines released damaged mitochondria. The differences were found in the amounts of mitochondria released and the routes. The mitochondria were released through a non-vesicular route. Furthermore, the expelled mitochondria lacked cristae and had multiple other indications of loss. Complementary analyses showed that melanoma cells do not degrade mitochondria through canonical mitophagy in conditions of oxidative stress. Instead, melanoma cells upregulate mitochondrial release to the extracellular medium. With this data, the team concluded that the melanoma cells release mitochondria as an alternative mitochondrial quality control mechanism.
Interestingly, the mitochondria expelled from the melanoma cells were detected in the tumor microenvironment and plasma of the mice. The levels of those mitochondria correlated with the tumor burden. In agreement with these findings, more total extracellular mitochondria were also detected in the circulation of melanoma patients, supporting the translational relevance of this phenomenon.
The study revealed a novel mechanism for releasing dysfunctional mitochondria. It also points to new strategies for non-invasive biomarkers and therapies.
A Statement of Significance from Dr. Alcayaga-Miranda:
This study expands the conceptual framework of mitochondrial quality control in cancer by showing that melanoma cells can externalize structurally and functionally altered mitochondria into the tumor microenvironment and circulation. Rather than being confined to intracellular degradation pathways, mitochondrial dysfunction in melanoma may generate extracellular signals that reflect tumor-associated stress, mitochondrial quality-control imbalance, tumor burden, and systemic disease progression. These findings open two important horizons: first, the development of minimally invasive biomarkers based on circulating extracellular mitochondria, and second, the need to define whether tumor-derived mitochondrial material is only a consequence of mitochondrial stress or also an active mediator of immune modulation and metastatic niche formation. Thus, this work provides a foundation for future mechanistic and translational studies aimed at understanding extracellular mitochondria as both measurable indicators and potential functional players in melanoma progression.
A Conversation with Dr. Alcayaga-Miranda:
MitoWorld. This is rich study filled with experimental detail. Can you give us an idea of what you are considering to follow up on this research?
Dr. Alcayaga-Miranda: Our next step is to determine whether extracellular mitochondria released by melanoma cells are merely a consequence of mitochondrial stress or whether they actively contribute to tumor progression. We are particularly interested in understanding how this mitochondrial material interacts with the tumor microenvironment, especially immune cells, and whether circulating extracellular mitochondria can be further developed as minimally invasive indicators of tumor burden and disease progression.
MitoWorld. It is interesting that multiple mechanisms are available to expel mitochondria. Do you have any thoughts on why these exist?
Dr. Alcayaga-Miranda: Cells likely rely on more than one mechanism to eliminate or externalize mitochondria because mitochondrial quality control is highly context-dependent. Depending on the intensity of cellular stress and the capacity of intracellular degradation pathways, damaged mitochondria may either be degraded within the cell or exported through alternative routes. In melanoma, our findings suggest that extracellular mitochondrial release may represent an additional layer of mitochondrial quality control, particularly when mitochondrial stress is sustained or canonical degradation pathways are insufficient.
MitoWorld. You indicate that melanoma release mitochondria into the bloodstream. It is amazing that so many mitochondria are circulating. Do you have any estimates of that or of how long they circulate before being completely eliminated?
Dr. Alcayaga-Miranda: At this stage, we do not yet have precise estimates of how long extracellular mitochondria remain in circulation. This is an important open question. Their persistence is likely influenced by structural integrity, association with vesicular or non-vesicular compartments, recognition by phagocytic cells, and clearance by organs involved in filtering circulating particles. Future kinetic studies will be necessary to define their half-life, clearance routes, and whether these parameters change during tumor progression.
MitoWorld. There have been other reports that mitochondria are transferred from tumor cells to normal cells, such as immune cells. Did you see any evidence of this in your studies?
Dr. Alcayaga-Miranda: In this study, we focused primarily on demonstrating that melanoma cells release dysfunctional mitochondria into the tumor microenvironment and circulation. We did not directly evaluate mitochondrial transfer to immune cells as a central endpoint. However, the detection of tumor-derived mitochondrial material in the tumor microenvironment raises the possibility that these structures may interact with stromal or immune cells. This is one of the directions we are now actively exploring, particularly in relation to how tumor-derived mitochondria may influence antitumor immune function.
MitoWorld. Do you have any plans to pursue the development of biomarkers?
Dr. Alcayaga-Miranda: Yes. One of the translational horizons of this work is to determine whether circulating extracellular mitochondria can be developed as minimally invasive biomarkers. Before clinical implementation, several steps are required, including analytical standardization, rigorous control of pre-analytical variables during blood processing, validation in larger patient cohorts, and comparison with established clinical parameters. Our current data provide a strong rationale for this direction, but biomarker development will require systematic validation.
MitoWorld. We are always interested in what sparked your interest in mitochondria. Can you tell us?
Dr. Alcayaga-Miranda: My interest in mitochondria began with the idea that they are not only intracellular powerhouses, but also dynamic signaling organelles capable of shaping cell behavior and intercellular communication. In cancer, this is particularly fascinating because tumor cells continuously adapt their metabolism under stress. Understanding how mitochondria move beyond the cell may reveal new dimensions of tumor biology and open unexpected translational opportunities.
Reference
Georges-Calderón N, Fuentes C, Hidalgo Y, Grunenwald F, Corrales-Bermúdez J, Figueroa-Valdés AI, Ramirez-Pereira M, Arriagada G, Bustos FJ, Ahumada-Marchant C, Lopez M, Alcayaga-Miranda F (2026) Melanoma cells release dysfunctional mitochondria to the tumor microenvironment and circulation in association with tumor progression. Cancer Letters 647: 218457.
https://www.sciencedirect.com/science/article/pii/S030438352600220X?via%3Dihub
Cancer cells need changes to metabolism to supply energy, especially during metastasis. In a recent paper in Cancer Discovery 1, a research team led by Kivanç Birsoy compared the metabolites of normal and breast cancer cells. They found that metastasis of the cancer cells relied on mitochondrial glutathione. This discovery provides insights into the process of metastasis and implicates glutathione as a potential therapeutic target for breast cancer.
The team compared the primary and metastatic breast cancer cells. This metabolomics study revealed accumulation of more mitochondrial glutathione in metastatic cells. Further analysis identified increased expression of SLC25A39. In previous work, the Birsoy group showed that this mitochondrial membrane carrier regulates glutathione transport into mitochondria.2 SLC25A39 is required for metastases, but its loss has no effect on primary tumors. Interestingly, the team found that the stress-induced transcription factor ATF4 could rescue SLC25A39-deficient metastatic cells. This observation links SLC25A39 to activation of ATF4.
This work provides new insights into the processes of metastasis. It defines a new role for glutathione beyond its well-know role antioxidant role. Finally, it suggests that glutathione, SLKC25A39, and ATF4 as possible therapeutic targets for breast cancer.
A Conversation with Dr. Kıvanç Birsov
MitoWorld: What is the next step in continuing your research?
Dr. Birsov: We’ll dissect how mitochondrial glutathione (mtGSH) is required for ATF4 activation. Specifically, we aim to identify the ISR node that senses mtGSH loss (e.g., GCN2 vs. PERK) and map the molecular steps that couple mitochondrial redox to ATF4. In parallel, we’ll define the precise stresses in the lung that drive this dependency using in vivo stress reporters and targeted perturbations. More broadly, our data suggest there are additional “hidden” metabolites that govern metastatic fitness. With our organelle-resolved metabolomics and genetic tools, we’re poised to systematically uncover these metabolites and their transport pathways.
MitoWorld: Can you speculate on the mechanism by which glutathione enhances metastasis? Do you think the effect is felt by making cells lose their connection to other cells or by helping in the actual colonization at a distant site?
Dr. Birsov: It’s a bit more complex. Sean Morrison’s elegant work has shown that glutathione is essential for tumor cell survival in circulation by buffering oxidative stress. Our findings extend this concept but emphasize that the compartmentalized functions of redox metabolites can differ. In our case, mitochondrial glutathione seems to be particularly important during the colonization phase rather than dissemination. We think its role may go beyond antioxidant defense—potentially involving redox-dependent signaling that supports metabolic adaptation and growth at the metastatic site. But this is still an open question and a major focus of our ongoing work.
MitoWorld: Lung and liver are common sites of metastases. Might this connection be generalized for other forms of metastasis or to other organs?
Dr. Birsov: The environments of metastatic sites are vastly different; each imposes unique metabolic stresses and nutrient availabilities. The lung, for instance, is highly oxidative, and the liver can be hypoxic. Because of these differences, I expect distinct metabolic mechanisms to underlie colonization in each organ. Mitochondrial glutathione may be critical in some contexts, but other metabolites and pathways likely take over in different tissues.
MitoWorld: ATF4 seems to be a two-edged sword. It is activated in stress situations, but aids metastasis. Do you have any thoughts about these strange multiple activities?
Dr. Birsov: That’s exactly what makes ATF4 so fascinating. It’s part of the integrated stress response, normally activated to restore homeostasis when cells face nutrient or redox stress. Cancer cells hijack this pathway—what’s meant to be a transient adaptation becomes chronically active, allowing them to survive and grow in hostile environments. In our system, ATF4 activation seems to compensate for the loss of mitochondrial redox balance, effectively turning a stress response into a metastatic advantage. It’s a perfect example of how tumors repurpose normal adaptive programs for malignant ends.
MitoWorld: Do you have any thoughts as to how these findings on glutathione might be translated to a therapy? Might SLC25A39 or ATF4 be a target?
Dr. Birsov: We are actively trying to find small-molecule inhibitors, and we believe this may be helpful for certain cancers. Additionally, we need to know whether there will be off target effects as well.
MitoWorld: How did you become interested in mitochondria in the first place?
Dr. Birsov: We’re fascinated by how mitochondria connect metabolism to disease and cell function. These organelles contain thousands of metabolites, and yet, we still know very little about what most of them do or how their levels are maintained. Our work on mitochondrial transporters provides an entry point to start decoding this complexity, understanding how metabolites move across membranes and how these movements shape cellular behavior.
References
1 Yeh HW, DelGaudio NL, Uygur B, Millet A, Khan A, Unlu G, Xiao M, Timson RC, Li C, Ozcan K, Smith KW, Nascentes Melo LM, Allies G, Basturk O, Sickmann A, Byraktar EC, Possemato R, Tasdogan A, Birsov K (2025) Mitochondrial glutathione import enables breast cancer metastasis via integrated stress response signaling. Cancer Discovery 15: 2437–2449.
doi: 10.1158/2159-8290.CD-24-1556.
2 Wang Y, Yen FS, Zhu XG, et al. (2021) SLC25A39 is necessary for mitochondrial glutathione import in mammalian cells. Nature 599: 136–140.
A multi-institute research team led by Kelsey H. Fisher-Wellman describes a unique mechanism in mitochondria that might be a therapeutic target in patients with acute myeloid leukemia (AML). The paper was published in Science Advances.
Cancers are thought to need large amounts of energy, and thus, oxidative phosphorylation is a tempting target for cancer therapies. Unfortunately, the attempts to find therapies that could differentiate between healthy and diseased mitochondria have met with limited success. For example, the FDA approved cancer therapy, venetoclax, which inhibits BCL-2 and mediates BAX/BAK-dependent apoptosis, has limited effectiveness due to the development of chemoresistance. Mitochondrial polarization of resistant AML cells is unaffected.
The group led by Dr. Fisher-Wellman noted that AML mitochondria have an action that differs from healthy blood cells. Healthy cells connect ATP synthesis to respiration. However, AML cells maintain inner membrane polarization by consuming ATP. The researchers wondered if the AML cells used this reversal of the ATP synthase reaction to resist chemotherapy. They set out to test this possibility. They discovered a central role for ATP51F1, an F1-ATPase inhibitor. Overexpression of this enzyme heightened sensitivity to venetoclax, and its knockdown venetoclax resistance.
These findings further our understanding of the bioenergetics of AML cells and the relationship between oxidative phosphorylation and AML. This work is especially important since AML relapses have such a dire prognosis. Importantly, they implicate matrix ATP consumption as a potential cancer cell-specific target for inhibiting the development of chemoresistance in AML.
Statement of Significance from Dr. Fisher-Wellman
In AML cell lines and primary patient samples, we discovered that leukemic mitochondria are deficient in their ability to sustain mitochondrial membrane potential through respiratory flux. Maintenance of membrane potential is essential for cell survival. To compensate, AML cells engage a non-canonical—and possibly evolutionarily ancient—bioenergetic strategy: they reverse the ATP synthase enzyme. Rather than using membrane potential to drive ATP production, AML cells hydrolyze ATP to sustain mitochondrial polarization. This distinction is profound. Normal cells do not typically rely on ATP synthase reversal to maintain membrane potential. As a result, this AML-specific mitochondrial wiring represents a near-ideal cancer-selective vulnerability. Importantly, this pathway is most active in drug-resistant AML populations—the very cells responsible for relapse and treatment failure.
Conversation with Dr. Fisher-Wellman:
MitoWorld: Can you give us some idea of how you intend to further advance the results of the current work?
Fisher-Wellman: Most cancer therapies are built around exploiting a dependency or vulnerability that is unique to malignant cells. Our work demonstrates that AML cells maintain mitochondrial membrane potential through a mechanism that is distinct from most normal tissues. We believe this cancer-specific difference represents a therapeutically actionable vulnerability.
MitoWorld: It is interesting that the AML mitochondria have this particular weakness. Do you have any speculation on why it is? Is it possible that other cancers might share this?
Fisher-Wellman: Sustaining mitochondrial membrane potential through ATP hydrolysis is generally viewed as a hallmark of bioenergetic ‘sickness’, typically observed in stressed or damaged cells as a survival mechanism. Our data, together with emerging evidence from the field, indicate that AML mitochondria exist in a persistently ‘sick’ state. Importantly, this bioenergetic liability represents a vulnerability that may be selectively exploited for therapeutic benefit.
MitoWorld: Do you have any plans to pursue the development of the potential clinical relevance of your discovery?
Fisher-Wellman: We are actively translating this discovery into mitochondria-targeted therapeutic strategies that exploit the distinct mechanisms by which AML cells maintain mitochondrial membrane potential.
MitoWorld: Mitochondria seem to be implicated in many diseases. Part of the reason is clearly its fundamental activity in energy production. However, they have assumed key roles in many other cellular functions. As a mitochondria researcher, are you as fascinated by these observations as we are?
Fisher-Wellman: That is an unequivocal yes. My entire research career has been focused on understanding how alterations in this organelle cause and contribute to some of humanity’s most formidable diseases.
MitoWorld: How did you come to be interested in mitochondria? Was it the energy requirements of cancers that connected you to the energy source?
Fisher-Wellman: I have studied mitochondria throughout my entire career and developed a deep appreciation for the remarkable heterogeneity that exists within this organelle across the body’s cells. It was this diversity that ultimately drew me to cancer, where I recognized that vast unexplored biology remained to be discovered.
Reference
Hagen JT, Montgomery MM, Aruleba RT, Chrest BR, Krassovskaia P, Green TD, Pacheco EA, Kassai M, Zeczycki TN, Schmidt CA, Bhowmick D, Tan S-F, Feith DJ, Chalfant CE, Loughran Jr. TP, Liles D, Minden MD, Schimmer AD, Shakil S, McBride MJ, Cabot MC, McClung JM, Fisher-Wellman KH (2025) Acute myeloid leukemia mitochondria hydrolyze ATP to support oxidative metabolism and resist chemotherapy. Science Advances 11(15): eadu5511.
https://www.science.org/doi/full/10.1126/sciadv.adu5511
In a recent paper in Nature Communications, a multi-institute research team reported that cells confined by physical forces display several adaptations. They found that mitochondria accumulate at the nuclear periphery and produce additional ATP for use in the nucleus. These metabolic adaptations prepare the cell for DNA repair processes and cell proliferation.
Cells are occasionally subjected to physical forces that confine their shape and size. Cancer is a good example. Uncontrolled growth can result in physical confinement and pressures on organelles within the cell that can not only change the cytoskeleton but also the integrity of DNA and chromatin organization within the nucleus.
The research, led by Ritobrata Ghose and Fabio Pezzano, in the labs of Sara Sdelci and Verena Ruprecht, wanted to better understand how the physical tissue microenvironment affects cells and the inherent adaptation mechanisms in place to buffer against microenvironmental effects. In particular, they focused on the effects on the nucleus and its proximate organelles. Using an unbiased approach, they discovered a unique functional link between the nucleus and the mitochondria. After the discovery, the team went on to explore this relationship in live cells by high-resolution microscopy.
Interestingly, they found that sustained physical confinement caused mitochondria to reposition themselves at the nuclear membrane and within regions of nuclear deformation. This repositioning was facilitated by the actin cytoskeleton and an endoplasmic reticulum-derived net that pulls them closer to the nuclei. Functionally, this nucleus-mitochondria association or proximity yielded a surge in the amount of ATP available within the nucleus, which is critical for genomic material integrity.
This paper describes a complex interaction of multiple factors that result from the physical confinement of the organelles within a cell. Cells respond by gathering the mitochondria close to the nuclear membrane so that an ATP surge can prepare the cell for DNA repair and cell proliferation after the stress is relieved.
Statement of Significance: Ritobrata Ghose, Ph.D.
This discovery emerged from an organic and energizing interdisciplinary collaboration between the Sdelci lab’s expertise in nuclear metabolism and the Ruprecht lab’s in biophysics. We believe interdisciplinary sciences will underpin the next wave of major discoveries, and we’re proud to have been at the forefront of it.
A Discussion with Ritobrata Ghose:
MitoWorld: What direction might your research take to further expand this work?
Our current work has demonstrated a mechano-metabolic axis which regulates chromatin state, chromatin integrity and cell fitness. This intersection between nuclear biophysics, nuclear metabolism, and epigenetic and transcriptional programs offers a unique and exciting opportunity that promises to reveal previously unimagined regulatory links. Further exploration of this intersection, in both disease and normal physiological conditions, will expand our understanding of fundamental cell biology.
MitoWorld: Can you speculate on the signaling molecules and receptors in the mitochondria and nucleus that might be involved in controlling the actions noted in your paper?
Dr. Ghose: This is one of the most exciting avenues for future exploration. We have identified several factors involved in NAM formation, including the relevance of mitochondrial shape and fusion dynamics. Whether mitochondria fuse with structures beyond themselves remains an intriguing open question. We also observe that the ATP surge is exclusive to the nucleus, suggesting directional shuttling of ATP, possibly through dedicated channels, which warrants further investigation.
MitoWorld: Actin and microtubules are important player in this system. How do you think they are controlled?
Dr. Ghose: Actin plays a critical role in regulating the cellular response to confinement. As cancer cells become migratory and aggressive, they are known to exhibit increased actomyosin contractility, for instance through ROCK-myosin II signaling, which enhances their ability to respond to complex mechanical cues. Consistently, we observed that more aggressive cells, particularly those at the invasive front, displayed significantly higher NAM formation.
Interestingly, the role of microtubules appears to be more nuanced. While microtubules are well-established drivers of mitochondrial transport, we found that depolymerization of microtubules using Nocodazole actually enhanced NAM formation under confinement. This suggests that rather than promoting mitochondrial accumulation at the nucleus, microtubules may normally act to restrict it. Understanding how the balance between actin and microtubule-based mitochondrial positioning is regulated will be an important next step.
MitoWorld: This interesting study has implications for the evolution and development of multicellular organisms. Physical confinement might be one factor that helps them maintain their place and size, but that cancer leads them to forget. Do you have any thoughts on this?
Dr. Ghose: It is likely that these mechano-metabolic adaptations are a conserved cellular response to physical challenge. In our work, we observed this mechanism across multiple cancer types, suggesting it operates across diverse tissue contexts. This points to a fundamental and evolutionarily conserved adaptation, with cancer representing a corruption of these normal cellular programs rather than the emergence of entirely new ones. Immune cells, for instance, are highly motile, constantly traversing physically demanding environments, and would be an interesting model to explore these mechanisms in. Understanding how confinement-induced ATP dynamics operate in such cells, and how they differ in the disease context, could open exciting new directions beyond cancer biology, but also help understand therapeutic vulnerabilities.
MitoWorld: Might your findings have any clinical relevance? Can you envision ways it might be harnessed for future treatment strategies?
Dr. Ghose: We validated our discovery of this mechano-metabolic adaptation in patient tumors and particularly at the invasive front of tumors, revealing a clear dependency and therefore a potential vulnerability of aggressive and metastatic cancer cells. As we deepen our mechanistic understanding of what features are particularly enriched within cancer cells, we expect to identify actionable targets and evaluate their therapeutic potential.
Reference
Ghose R, Pezzano F, Badia R, Kourtis S, Sheraj I, Das S, Gañez Zapater A, Ghose U, Musa-Afaneh S, Espinar L, Coll-Manzano A, Parapatics K, Ivanova S, Sànchez-Fernàndez-de-Landa P, Radivojevikj D, Venturini V, Wieser S, Zorzano A, Müller AC, Ruprecht V, Sdelci S (2025) Mitochondria-derived nuclear ATP surge protects against confinement-induced proliferation defects. Nat Commun 16(1): 6613.
doi: 10.1038/s41467-025-61787-x.
A multi-institute research group led by Thomas MacVicar at the Cancer Research UK Scotland Institute, Glasgow, found that a specific transporter called SLC25A45 is required for the transport of methylated amino acids across the inner mitochondrial membrane and for carnitine synthesis. This study was published as a recent paper in Molecular Cell 1.
For cellular metabolism to function effectively, metabolites must be exchanged between the mitochondria and the cytosol. Crossing the inner mitochondrial membrane requires the action of transporter proteins. Disruptions to these transporters can lead to disease. The most common transporters are the members of the solute carrier (SLC) 25 family. However, the substrates for some transporters are unknown. Among these “orphan transporters” was solute carrier (SLC) 25A45.
Mitochondria are deeply involved in amino acid metabolism, but the researchers wondered how they deal with methylated amino acids. Disruptions to the systems regulating methylated amino acid homeostasis are associated with heart and kidney diseases, and some are associated with tumors. The team found that a specific transporter, SLC25A45, binds to dimethylarginine and trimethyllysine, but not to the unmethylated version of these amino acids.
Identifying the substrate for orphan transporters is valuable knowledge. SLC25A45 is particularly important for its roles in the transport of methylated amino acids and carnitine biosynthesis. This research also suggests some new possible therapeutic strategies.
A conversation with Dr. MacVicar:
MitoWorld: Can you describe the directions of your research to further the findings of this paper?
MacVicar: Now we know that methylated amino acids enter mitochondria via SLC25A45, we are keen to understand how this pathway impacts cancer progression. The Birsoy and Kajimura labs have shown in mice that mitochondrial uptake of trimethyllysine, and subsequent biosynthesis of carnitine, is important for physiological responses that depend on fatty acid oxidation 2,3. We are employing cancer mouse models to explore how mitochondrial metabolism of trimethyllysine and other methylated amino acids impact tumour growth and survival.
MitoWorld: Do you have any plans to tackle other orphan transporters?
MacVicar: Orphan solute carriers are crucial pieces missing from the mitochondrial metabolism jigsaw. With continued collaborative and creative research, I’m optimistic that each member of the SLC25 family will be deorphanised within 5 years. It will be a challenge though, in part because some orphan transporters appear to have specialised tissue-specific roles. As fun as the SLC25A45 project was, we don’t currently have plans to take on any more orphans ourselves. We have much to learn about the regulation of SLC25 protein biogenesis and activity, and I also think it’s important to study non-SLC25 mitochondrial metabolite transporters. This includes interesting metabolite transport proteins that appear to be dual-localised between mitochondria and other cell membranes. I’m excited to see what comes next from this dynamic field.
MitoWorld: Methylation is a common post-translational modification. Can you speculate on why the mitochondria have become specialized in dealing with some of these?
MacVicar: here may be several advantages of compartmentalising methylated amino acid metabolism. As mentioned, cells can control carnitine biosynthesis by regulating mitochondrial import and hydroxylation of trimethyllysine in the matrix. Whereas mitochondrial sequestration of dimethylarginine perhaps controls nitric oxide synthesis, which is inhibited by cytosolic accumulation of dimethylarginine. By importing methylated amino acids, mitochondria may somehow play a role in sensing the downstream products of methionine metabolism and protein catabolism. Of course, this remains very speculative for now!
MitoWorld: We always wonder how you became interested in mitochondria. Can you expand on that?
MacVicar: I was hooked on mitochondria after some live-cell imaging experiments at the beginning of my PhD. I was surprised and fascinated by the interconnected and dynamic behavior of the mitochondrial network, which was not something I’d gathered from textbooks.
References
- Dias MM, King MS, Shokry E, Lilla S, Paul N, Thomason P, Zanivan S, Sumpton D, Kunji ER, MacVicar T (2025) SLC25A45 is required for mitochondrial uptake of methylated amino acids and de novo carnitine biosynthesis. Molecular Cell 85: 4093–4104.
https://www.cell.com/molecular-cell/pdfExtended/S1097-2765(25)00703-8
- Khan A, Yen FS, Unlu G, DelGaudio NL, Erdal R, Xiao M, Wangdu K, Cho K, Gamazon ER, Patti GJ, Birsoy K (2025) Machine-learning-guided discovery of SLC25A45 as a mediator of mitochondrial methylated amino acid import and carnitine synthesis. Cell Metabolism 37: 2220-32.
https://doi.org:10.1016/j.cmet.2025.09.015
- Auger C, Nishida H, Yuan B, Silva GM, Fujimoto M, Li M, Katoh D, Wang D, Granath-Panelo M, Shin J, Witte R (2026) Mitochondrial control of fuel switching via carnitine biosynthesis. Science 391: eady5532.
The activation of T cells is a critical part of our adaptive immune system. T-cell activation requires massive increases in gene expression and cell proliferation, which is dependent on increased energy production. A research team at the Cancer Research UK Scotland Institute in Glasgow, led by Alison Galloway, Victoria H. Cowling and Tom MacVicar, examined RNA splicing mechanisms involved in T-cell activation. Mitochondria act as a signaling nexus in T cells, and they found that T cells regulate their energetic capacity by alternative splicing of proteins involved in mitochondrial fission and fusion to match the demands of T-cell activation. This study was recently published as a paper in Cell Reports.
More specifically, the team focused on the RNA cap methyltransferase 1 (CMTR1). This enzyme methylates the first nucleotide on mRNAs and U2 small nuclear RNA, part of the spliceosome. Using transcriptomics, they found a splicing module, regulated by CMTR1, that changes the protein isoforms of factors that control mitochondrial fission and fusion. CMTR1 promotes expression of protein isoforms that alter the balance between fusion and fission to produce longer mitochondria in activated T cells. Those longer organelles have greater respiratory capacity.
Thus, the researchers show that increasing CMTR1 levels increases oxidative phosphorylation and supports T-cell activation. This study further shows that mitochondria do more than just produce energy. It also adds to the knowledge of the immune system, the highly complex and crucial mechanisms for our health.
A conversation with Drs. Galloway and Cowling
MitoWorld: Can you give us an idea of the next steps for this research? For example, might you further examine how CMTR1 modulates splicing?
We are interested in how T cells function in tumours. Therapies that improve or support T-cell functions are proving successful in the treatment of many cancers. A limitation of these therapies is that T cells become “exhausted”, exhibiting features associated with loss of mitochondrial quality control, such as depolarized mitochondria and mitochondria with disrupted morphology of the cristae. By targeting CMTR1 and other RNA cap methyltransferases, it is possible that we can support mitochondria function in T cells.
MitoWorld: As you note, mitochondria are involved in many aspects of T-cell biology. Any thoughts on how they might regulate T-cell receptor (TCR) signaling strength, memory formation, or T-cell exhaustion?
Mitochondrial dynamics is a very exciting area in T-cell research. TCR signaling strength is increased by the migration of mitochondria to the immunological synapse—the site at which the TCRs are engaged with antigen/MHC complexes on the antigen-presenting cell. This process is facilitated by mitochondrial fission, which generates smaller, more mobile mitochondria and, thus, is very dependent on mitochondrial fission factors, such as DNM1L/DRP1. On the other hand, memory T cells are metabolically very dependent on oxidative phosphorylation. The longer, more complex mitochondrial networks generated by fusion have greater respiratory capacity, thus the generation and maintenance of memory T cells is very dependent on mitochondrial fusion factors, such as OPA1. Therefore, the proper regulation of T-cell activation, effector function, and memory formation depends on dynamic regulation of mitochondrial morphology, as well as metabolism. In exhausted T cells, we are seeing signs that mitochondrial dynamics have been disrupted, resulting in a buildup of depolarized mitochondria. This is linked to impaired mitophagy, the process by which damaged mitochondria are removed.
MitoWorld: T-cell activation requires careful coordination of gene activation in both the nucleus and mitochondria. Do you have any hypotheses about how this signaling is accomplished?
We think that the RNA cap methyltransferases play important roles in coordinating gene expression and energy production during T-cell activation. After T-cell activation, upregulation of the RNA cap methyltransferase, RNMT, co-ordinates gene expression programmes that results in ribosome production. Ribosomes are the most energy hungry component of the cell; it’s interesting that the genome evolved such that upregulation of another RNA cap methyltransferase—CMTR1—increases respiration during T-cell activation.
MitoWorld: There are hundreds to a few thousand mitochondria in each cell. Do you have any idea about the number or portion of mitochondria must be fused to change the energy production within the cell?
This is a tricky question! In our measurements of mitochondrial length in T cells, we saw a huge range in mitochondrial size with the longest measuring in at nearly 2.5 mm long and the shortest under 0.1 mm. Some of this variation will be due to the orientation of each mitochondrion during the microscopy, but it still indicates that there can be big differences between mitochondria within the same cell. There are still a lot of questions to answer around how the length of the mitochondria influences their metabolic activity.
MitoWorld: T-cell activation is obviously related to infections. Can you envision how your findings might inform therapeutic strategies?
Yes, there are several strategies that may improve or support T cells in tumours, focusing on mitochondria. Mitochondrial functionality could potentially be enhanced by engineering deregulated CMTR1 expression or increasing activating phosphorylation on CMTR1. Alternatively, the splicing modules which control mitochondria function could be more directly controlled in T-cell therapeutics.
MitoWorld: Why did you become interested in mitochondria in the first place? Which came first: mitochondria or the immune system?
VC: My first publication (2002!) was about cytochrome C-triggered caspase cascades. Beyond this, I think there is a fascinating relationship between mitochondria and ribosomes. Gene expression is dependent on energy production by mitochondria supporting energy-hungry ribosomes.
AG: For me, the immune system came first, but the mitochondria are making themselves very hard to ignore since they keep showing themselves to be key mediators of immune cell function!
Reference
Galloway A, Knop K, Gomez-Moreira C, Xavier V, Thomson S, Yoshikawa H, Suska O, Lukoszek R, Kaskar A, Lamond AI, MacVicar T, Cowling VH (2025) CMTR1 directs mitochondrial dynamics during T cell activation through epitranscriptomic regulation of splice isoforms. Cell Reports 44(10): 116412.
The immune system is our first line of defense against cancer. However, tumors have developed mechanisms to evade the immune system and even to invade tumor strongholds, such as lymph nodes. A multi-institute research team led by Azusa Terasaki and Derick Okwan-Duodu explored those mechanisms. They found that tumor cells kidnap mitochondria from immune cells and, in doing so, reduce the effectiveness of those cells. The work was published recently in a paper in Cell Metabolism.
The team was intrigued by the observation that tumor cells often metastasize to the lymph nodes, which are typically well stocked with immune cells. In their study, they first noticed that the immune cells lost mitochondria to the tumor cells.
They next determined what resulted from the loss of mitochondria by the immune cells. In fact, a lot happened, and it was not good for the immune cells. The ability of the immune cells to deal with perceived foreign cells, such as tumor cells, was significantly eroded. Reductions were observed in antigen-presentation, co-stimulatory machinery, and the activation and cytotoxicity of natural killer and CD8 T cells. When the transfer of mitochondria was blocked, the tumor cells could not metastasize to the lymph nodes.
The lymph nodes are common targets of metastases, which might seem counter-intuitive. However, Azusa et al. demonstrate how that happens. The findings of this study have clear clinical implications.
A conversation with Drs. Azusa Terasaki and Derick Okwan-Duodu:
MitoWorld: Can you give us an idea of the research you plan to do to follow up on this study?
We are interested in understanding the fate of the mitochondria once they are acquired by cancer cells. The assumption is that cancer cells will integrate the new biomaterial and use it up. But, can they do something else with it?
MitoWorld: What do you think makes the mitochondria of immune cells vulnerable to kidnapping by the tumor cells in a way that the stromal cells are not?
Answer: We are unsure about this. Please note that many other cell types also transfer mitochondria to cancer. Therefore, the question may not be “why are immune cells vulnerable to mitochondria kidnapping (I love the word choice).” I think it should be, why do cells give mitochondria to cancer anyway? We think cancer, the wound that does not heal, “pretends” to be struggling to elicit mitochondria transfer from other cells as part of normal cooperative biology. Remember, the key theme that is emerging from mitochondria transfer is that is a metabolic rescue program.
MitoWorld: Do you have any thoughts on how the loss of mitochondria impairs the functioning of the immune cells? Is it simply a loss of energy or might it be something else?
Answer: I think it may play a key role. Either the loss of energy, or the disruption from losing mitochondria. Inevitably, the mitochondria has to be disrupted one way or another before they are transferred, and I don’t think immune cells would like that.
MitoWorld: How do the tumor cells attract the immune cell mitochondria, and what mechanism might be used in that transfer?
Answer: No idea. All that is currently known is tunneling nanotubes (predominantly). But it is unclear why cancer cell attracts more mitochondria from cell type A compared to cell type B.
MitoWorld: Other recent papers have described how the transfer of mitochondria to tumor cells fortifies the tumor cells, particularly enhancing their energy levels. You mention several effects on the tumor cells. Can you speculate on how those happen?
Answer: A huge one is indeed metabolic. A highly proliferative cell will use new raw material for whatever their bioenergetic or biosynthetic needs may demand. Nonetheless, mitochondria are also signaling units, and so incoming mitochondria could provide a means of cellular communication beyond metabolism From an espionage perspective, think of a cancer cell now having access to information of the host that is coded in the mitochondria it hijacks. The implications are endless.
MitoWorld: This work would seem to suggest possible clinical applications. Do you have plans to pursue any of them?
Answer: Blocking mitochondria transfer should improve cancer therapies because, at the minimum, you may be shutting off metabolic pipeline to cancer cells while leaving immune cells with a full complement of their metabolic resources, which gives them a better chance to mount effective anti-cancer immunity.
Reference
Terasaki A, Bhatnagar K, Weiner AT, Tan Y, Szeifert V, Huang HL, Wiggers L, Rodrigues V, Rada CC, Shankar V, Saito S, Ankomah PO, Roth T, Chiu B, West R, Li L, Reticker-Flynn N, Axelrod JD, Brestoff JR, Li B, Engleman E, Okwan-Duodu D (2026) Mitochondrial transfer from immune to tumor cells enables lymph node metastasis. Cell Metabolism
https://www.cell.com/cell-metabolism/abstract/S1550-4131(25)00545-5
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.