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.
Recently, a multi-institute research team led by Yosuke Togashi reported on a study that showed that cancer cells transfer mitochondria with mutant DNA and inhibitory molecules to immune cells to reduce the antitumor response. This previously unknown mechanism also shows that cancer cells with mutated mitochondrial (mt) DNA indicate a poor prognosis for certain patients.
Cancers use many strategies to avoid immune surveillance. Among those are the acquisition of mitochondria from T cells that infiltrate the tumor. Those mitochondria enhance the cancer cells energy production. But the transfer of mitochondria also works in the other direction. Mitochondria with mutations from the cancer cells are transferred to the immune cells. Those defective organelles degrade the antitumor response. Thus, the metabolic reprogramming resulting from the bidirectional exchange of mitochondria creates an environment that encourages tumor growth.
The Togashi research team sought to determine the mechanisms that promote that exchange. They examined clinical samples of immune cells for mtDNA mutations from the cancer cells. They found similar mutations in mtDNA in the immune cells. In most cases, mitochondria with mutated mtDNA are destroyed by mitophagy. However, the team identified proteins that attach to the mitochondria with mutated mtDNA and are transferred with them to the immune cells. One of these was the mitophagy-inhibiting protein USP30. Those recipient immune cells then failed to undergo mitophagy. In addition, the T cells with the mutant mitochondria became senescent.
This work has valuable clinical implications. Finding of mutant mtDNA in the cancer cells indicates that immune checkpoint inhibitors may be less effective in patients with melanoma and non-small-cell lung cancer.
A conversation with Dr. Togashi
MitoWorld: What directions do you foresee your research taking to advance this work?
Togashi: Our next steps are to clarify the mechanistic basis of mitochondrial replacement in addition to just transfer, the key molecules on donor and recipient cells, and the tumor microenvironmental conditions that promote it. We will then expand the work across additional cancer types and other recipient cell populations (beyond T cells) to build a broader map of who transfers mitochondria to whom and with what functional consequences. We are also interested in whether similar mitochondrial transfer in non-cancer diseases, such as chronic inflammation disease. In parallel, we will determine how transfer intersects with mitochondrial dynamics (fusion-fission, mitophagy, and quality control) that may determine whether transferred mitochondria persist. Ultimately, we aim to translate these findings into biomarkers that predict therapy response and therapeutic strategies that restore mitochondrial quality control to improve immunotherapy efficacy.
MitoWorld: Do you have any thoughts on the mechanism by which the immune cells receiving the mutated mtDNA become senescent?
Togashi: We think senescence is likely driven by a combination of mitochondrial dysfunction and stress signaling. Mutant mitochondria can impair respiratory capacity and elevate reactive oxygen species, which may trigger DNA-damage responses and activate pathways, such as p53–p21 and/or p16. Importantly, if mitophagy is suppressed, these damaged organelles may persist, making the dysfunction more durable.
MitoWorld: As you noted, mitochondria might be mediated by various mechanisms. Do you have a favorite candidate for this process?
Togashi: Several mechanisms could plausibly mediate mitochondrial transfer, including tunneling nanotubes, extracellular vesicles, and direct cell-cell contact-dependent processes. From our observations so far, a leading candidate is tunneling nanotubes and/or EVs. At the same time, we have the impression that the dominant route may differ, depending on the cell type and context. So these mechanisms are not mutually exclusive and may operate in parallel in different tumor microenvironments.
MitoWorld: Your work here and that of others have provided good evidence for the concept of mitochondrial transfer. However, some researchers have been slow to warm to this idea. Can you speculate on why there has been this reluctance to accept this?
Togashi: I think the hesitation is understandable. Demonstrating mitochondrial transfer convincingly in vivo is technically challenging: mitochondria are abundant, dynamic, and easy to mis-attribute due to imaging limitations, labeling artifacts, or contamination during cell isolation. In addition, the field has long emphasized mitochondria as strictly cell-autonomous organelles, so the conceptual shift takes time. In our case, we view the evidence as particularly strong because we can identify transferred mitochondria by shared genetic mutations in both clinical specimens and in vivo models, providing an orthogonal line of support beyond imaging alone. As methods improve, particularly lineage tracing, spatial approaches, and rigorous controls, I expect the evidence base will continue to strengthen and the community will converge.
MitoWorld: Do you have any speculation on how your findings might be translated to clinical applications?
Togashi: We see a few translational opportunities. First, tumor mtDNA mutation profiles could serve as biomarkers to stratify patients who are less likely to benefit from immune checkpoint inhibitors and, thus, help to guide treatment selection. Second, therapeutically targeting the transfer process or restoring mitochondrial quality control in recipient immune cells may help to preserve anti-tumor immunity. Third, these insights may inform combination strategies (e.g., pairing immunotherapy with mitochondria-targeted agents), thereby converting non-responders into responders.
MitoWorld: How did you become interested in mitochondria?
Togashi: My original training is in pulmonary medicine and thoracic oncology. From there, I became increasingly interested in cancer immunology, and during my postdoctoral period, I worked primarily on regulatory T cells. I was already aware of the accumulating evidence that mitochondrial dysfunction is an important feature of exhausted T cells, but when I was preparing to start my own laboratory, I was searching for an original research direction. Around that time, I learned about the phenomenon of mitochondrial transfer, and it immediately struck me as a fascinating and potentially transformative concept for understanding tumor-immune interactions. That was the starting point that led me to pursue this line of work.
Reference
Ikeda H, Kawase K, Nishi T, Watanabe T, Takenaga K, Inozume T, Ishino T, Aki S, Lin J, Kawashima S, Nagasaki J, Ueda Y, Suzuki S, Makinoshima H, Itami M, Nakamura Y, Tatsumi Y, Suenaga Y, Morinaga T, Honobe-Tabuchi A, Ohnuma T, Kawamura T, Umeda Y, Nakamura Y, Togashi Y (2025) Immune evasion through mitochondrial transfer in the tumour microenvironment. Nature 638: 225-236.
A paper in Nature Cancer by a multi-institute research team, led by Michael Cangkrama and Sabine Werner at the ETH Zurich, describes how cancer cells use the transfer of mitochondria to highjack fibroblasts to support the cancer. The study also implicates a protein as critical for the transfer that may be useful in novel therapeutic strategies.
The transfer of mitochondria from various cell types into cancer cells has been reported to enhance cancer cell proliferation, motility and more. Fibroblasts associated with tumors are known to adopt certain characteristics, and they frequently support cancer development. The Cangkrama-Werner team sought to determine if the transfer of mitochondria might work in the opposite direction. In other words, do cancer cells transfer mitochondria to the fibroblasts?
To answer this question, the team examined cancer cells and fibroblasts in co-cultures and xenograft tumors. Intriguingly, mitochondria were transferred to the fibroblasts where they caused changes in the metabolism of the recipient cells. The fibroblasts began to express markers associated with cancer-associated fibroblasts and to release secreted soluble and extracellular matrix proteins that support tumor growth. The team also found that the transfer of mitochondria depends on the mitochondrial trafficking protein MIRO2. Without MIRO2, the transfer and the other changes failed. These findings are consistent with the overexpression of MIRO2 at the leading edge of epithelial skin cancers and other malignancies. Finally, they found that the mitochondria are transferred through thin membranous structures called tunneling nanotubes.
This study demonstrates that mitochondrial transfer from cancer cells to fibroblasts is a key regulator of CAF differentiation. The findings also implicate MIRO2 and mitochondrial transfer as potential targets for strategies to treat cancers.
A conversation with Drs. Cangkrama and Werner
MitoWorld: Can you give us an idea of what studies you might do to advance the findings presented here?
Werner: There are several open issues, including the signals that induce the transfer, the genes and proteins that promote the transfer and the targets of the transferred mitochondria, which induce the pro-tumorigenic phenotype in fibroblasts.
MitoWorld: You showed that oxidative phosphorylation is the main activity that is influenced by the mitochondrial transfers. Can you speculate on how that process translates into the changes in gene expression in the fibroblasts? Might there be other mitochondrial activities involved in activating the interferon-response genes?
Werner: Oxidative phosphorylation is highly relevant in this context, but it is probably not the only relevant factor. Oxidative phosphorylation results in the production of various metabolites, which are likely to regulate transcription factors that control gene expression in fibroblasts. We found that the interferon-response genes are not regulated by transferred mitochondria, but likely by transfer of other molecules from cancer cells to fibroblasts in co-cultures, which remain to be identified.
MitoWorld: The transfer of mitochondria from cell to cell has been somewhat controversial. Can you comment on the seeming reluctance of some researchers to embrace this concept?
Werner: Many results were obtained with MitoTracker, which is known to be leaky. Several studies did not include appropriate controls to address this problem, which might have contributed to skepticism about mitochondrial transfer. The concept was also unexpected when first proposed. Even when transfer occurs, it is difficult to predict and appears to depend on specific conditions, such as cellular stress or high metabolic demand, further fueling doubts about its physiological relevance. However, many exciting and well-controlled studies have recently been published, which show the relevance of mitochondrial transfer under various conditions. This makes mitochondrial transfer a promising area of research, with the potential to uncover new mechanisms of intercellular communication and to develop innovative therapeutic strategies.
MitoWorld: Can you speculate how your findings might translate to therapies for cancer?
Werner: There is a long way from this discovery to a cancer drug. Nevertheless, our work suggests that inhibition of mitochondrial transfer (e.g., by blocking MIRO2 or other proteins important for the transfer) could be a novel approach for cancer treatment. In addition, identification of the relevant targets of the mitochondrial transfer in recipient fibroblasts could provide new therapeutic opportunities.
MitoWorld: How did you first become interested in mitochondria?
Werner: Several previous studies of our laboratory revealed the important role of mitochondria in the pro-tumorigenic cancer-associated fibroblast phenotype. This raised our interest in these exciting organelles.
Reference
Cangkrama M, Liu H, Wu X, Yates J, Whipman J, Gäbelein CG, Matsushita M, Ferrarese L, Sander S, Castro-Giner F, Asawa S, Sznurkowska MK, Kopf M, Dengjel J, Boeva V, Aceto N, Vorholt JA, Werner S (2025) MIRO2-mediated mitochondrial transfer from cancer cells induces cancer-associated fibroblast differentiation. Nature Cancer 6: 1714–1733.
A recent paper in Science Advances describes the findings of a research team led by Mondira Kundu, MD, PhD, at St. Jude Children’s Research Hospital. The study investigates how mitochondrial (mt) DNA mutations influence leukemia pathology. Unexpectedly, their research showed that a moderate burden of mtDNA mutations can enhance the development of leukemia. They also show that cancer can be re-initiated by inhibiting a specific enzyme in cells carrying a high burden of mtDNA mutations.
Cancers are highly energy dependent, with the mitochondria serving as the cell’s main energy producers. While most research into this connection has focused on mutations in nuclear DNA that affect mitochondrial function, Dr. Kundu’s team explored whether mutations directly in the mtDNA contribute to tumor development.
The researchers began with three lines of mice expressing a mutant exonuclease-inactive mitochondrial DNA polymerase (Polgmut) that lacks accurate proofreading ability. These lines possess either zero (Polgwt/wt), one (Polgwt/mut), or two (Polgmut/mut) copies of the mutated allele, resulting in a graded accumulation of mtDNA mutations. Hematopoietic progenitor cells (HPCs) were isolated from these mice and engineered to express NMyc, a member of the MYC family of transcription factors. Members of the MYC family are commonly dysregulated in many blood cancers, such as leukemia. By transplanting these HPCs into irradiated recipient mice, the team assessed the impact of different levels of mtDNA mutations on cellular metabolism and cancer development.
The findings were unexpected: while metabolism was reduced in mice with either heterozygous or homozygous mutant cells, mice with a moderate mutation load (Polgmut/wt) were more prone to tumor formation than those with a high mutation load (Polgmut/mut). Metabolic plasticity was affected by the number of mtDNA mutations and was critical to the tumorigenic potential of the HPCs. In essence, a moderate number of mutations makes cells more metabolically flexible and more carcinogenic, whereas extensive mutations diminish both their metabolic flexibility and cancerous potential.
Conversation with Dr. Kundu
MitoWorld. Your results are unexpected. Do you have any thoughts on why the partially damaged mitochondria would be beneficial to the cancer? Yes, it appears that partially damaged mitochondria create a unique metabolic environment that cancer cells can exploit. Moderate mitochondrial dysfunction may allow for metabolic reprogramming—enhancing glycolysis and other pathways that support rapid cell growth—without fully compromising energy production. This balance may give cancer cells a survival and growth advantage.
MitoWorld. Can you speculate on how the damaged mitochondria are able to increase their metabolic support for the tumors? Damaged mitochondria may trigger adaptive responses in cancer cells, activating alternative metabolic pathways and stress responses. For instance, partial mitochondrial dysfunction can increase the reliance on glycolysis (the Warburg effect) and other biosynthetic pathways, thereby supporting both energy needs and the synthesis of cellular building blocks required for proliferation. The cells remain metabolically flexible, which is crucial for tumor growth.
MitoWorld. You note both similar and different results with this mutation and different cancers. To what would you attribute those varying results? The impact of mtDNA mutations likely depends on the tissue context and the specific metabolic requirements of different cancers. Some tumors may be more resilient to mitochondrial dysfunction, while others are more dependent on intact mitochondrial metabolism. Additionally, the interplay between mtDNA mutations and nuclear gene mutations can vary, influencing how cells adapt metabolically and whether they become more or less tumorigenic.
MitoWorld. Your results show that inhibiting pyruvate dehydrogenase kinase improved the ability of the homozygous mutant to cause tumors. Does this observation have any therapeutic implications? While our findings are not immediately translatable to therapy, they do highlight the critical role of metabolic plasticity in leukemogenesis. The fact that inhibiting pyruvate dehydrogenase kinase (PDK) restored the proliferative capacity of homozygous mutant HPCs suggests that metabolic pathways can profoundly influence tumor development. This raises the possibility that targeting metabolic enzymes like PDK could one day be leveraged to modulate cancer cell growth, either by restricting the metabolic flexibility of cancer cells or by exploiting specific metabolic vulnerabilities. However, more research is needed, especially since the mutation burden in human leukemias typically comes from single mtDNA mutations, unlike the mouse model, where the burden comes from the cumulative effect of many mutations.
MitoWorld. What do you see as the next steps to follow up on this work? The next step is to introduce specific mtDNA mutations into primary cells and then add oncogenes. This will allow us to examine how individual mtDNA mutations—and their allele fractions—impact tumorigenesis. By better modeling the mutation patterns seen in human cancers, we can determine whether particular mtDNA mutations or metabolic states make cancer cells more susceptible to targeted metabolic therapies. Ultimately, this line of research could guide the development of new therapeutic strategies that exploit the metabolic dependencies created by mtDNA mutations in cancer cells.
MitoWorld. What attracted you to the study of mitochondria? As a hematopathologist, I have a strong interest in hematologic diseases, but my research has always spanned a variety of biological systems. My interest in mitochondria began during my postdoctoral fellowship in Craig Thompson’s lab, where I used red blood cell maturation as a model to study mitophagy—the process by which cells selectively remove damaged or superfluous mitochondria. That experience highlighted for me how central mitochondrial function and dysfunction are to cell biology and disease, including cancer. I am particularly intrigued by how cells sense and respond to mitochondrial dysfunction—especially when it’s caused by mtDNA mutations—and how these adaptive pathways can contribute to cancer development. Understanding the complex interplay between mitochondrial function and cellular responses not only deepens our knowledge of cancer biology but also points to new possibilities for therapeutic intervention.
Reference
Li-Harms X, Lu J, Fukuda Y, Lynch J, Sheth A, Pareek G, Kaminski MM, Ross HS, Wright CW, Smith AL, Wu H, Wang Y-D, Valentine M, Neale G, Vogel P, Pounds S, Schuetz JD, Ni M, Kundu M (2025) Somatic mtDNA mutation burden shapes metabolic plasticity in leukemogenesis. Science Advances 11(1): eads8489.
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