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
Mitochondria consist of an outer membrane, a highly folded inner membrane, an inner matrix, and an intermembrane space (IMS). In an excellent recent review, Fara van der Schans, Kostas Tokatlidis, and Daniela G. Vitali of the University of Glasgow describe the mitochondrial IMS, its proteome, and functions. The review was published in the journal Protein Science.
The IMS lies between the outer and inner membranes. This location makes it a key transit area for the movement of proteins and other material and makes it a signaling hub for the mitochondria. In fact, nuclear genes encode all of the proteins in the IMS (about 130 proteins). Those proteins are imported into the IMS by various pathways, including the mitochondrial intermembrane space assembly import (MIA) pathway, stop-transfer pathway, and other non-canonical mechanisms. They are important in various cellular pathways (e.g., redox regulation, calcium signaling, apoptosis, and hypoxia response). In addition, most mitochondria-encoded proteins pass through the IMS on the way to their final destinations.
About a third of IMS proteins are imported via the MIA pathway. A number of specific topologies are involved in the transport, and those proteins are then folded in the IMS to become mature proteins. The coordination and targeting of nuclear and mitochondrial proteins are complex operations. There is a high risk of mutations, misfolding, and damage from reactive oxygen species that are produced in mitochondria. A mitochondrial quality control system helps to protect against these risks. Together, these mechanisms maintain cellular homeostasis and mitochondrial function.
This is an excellent overview of the IMS. It carefully examines the path of proteins into and through the mitochondria as they are imported, processed, reach their site of function, and eventually are exported back out of the mitochondria to the proteasome for degradation.
A Statement of Significance from Dr. Tokatlidis:
Understanding how proteins are targeted, sorted, and monitored within the mitochondrial intermembrane space (IMS) is crucial because this compartment acts as a central checkpoint for mitochondrial proteostasis. Although small in volume, the IMS oversees the maturation and quality control of nearly all mitochondrial proteins as they traverse the organelle, ensuring that only correctly folded and functional proteins proceed to their destinations while harmful intermediates are removed. This surveillance is vital for maintaining mitochondrial integrity, as disruptions in IMS protein handling can compromise respiration, redox balance, apoptosis, calcium signaling, and cellular stress responses. By synthesizing recent insights into IMS protein import and quality-control pathways, this review clarifies how this compartment integrates protein sorting with broader mitochondrial homeostasis. Appreciating the IMS as an active regulatory node highlights its fundamental role in safeguarding mitochondrial function and underscores why its dysregulation contributes to diverse human diseases, from neurodegeneration to metabolic disorders.
A Conversation with Dr. Tokatlidis:
MitoWorld: This is an excellent review of the structure and functions of the ISM. Can you give us an idea of how your research relates to findings in this review and where you are going next?
Dr. Tokatlidis We have been studying for a number of years now how proteins get to the IMS initially focusing on the stop transfer pathway and then on the discovery and characterization of the MIA pathway. Our work on the MIA import and assembly system started with a surprising finding for the small Tim chaperone proteins. These small proteins (about 10 kDa) form essential chaperones assemblies in the IMS that are critically needed to assist membrane proteins negotiate their passage across the aqueous IMS. In the absence of these dedicated chaperones membrane proteins like the metabolite transporters (including the ADP/ATP transporter) and even proteins of the outer membrane on their way to be inserted would aggregate and become nonfunctional, with detrimental effects for mitochondria. We wondered how these small TIM chaperones themselves get imported, as they do not have any sort of mitochondrial targeting sequence. We found to our surprise that a critical step in the import, folding and retention of these proteins in the IMS is the formation of internal disulfide bridges once they are imported into the IMS, which indicated that this compartment has the capacity for generating disulfide bonds in proteins (the process of oxidative folding). This was quite a significant departure from the prevailing dogma that disulfide bonds in eukaryotic cell can only be generated in the endoplasmic reticulum and was not widely accepted for a couple of years. The work of several groups, including ours, then showed that the protein Mia40 is the key player to catalyse the process of oxidative folding in the IMS. We further went on to define the structure of Mia40, how it interacts in transient manner with its import substrates, the unusual targeting signal that underpins this pathway and is very different from the conventional mitochondrial signals and the mechanistic features and structural and thermodynamic basis of the interactions that guide this IMS import pathway. The MIA pathway is unique among all import pathways into mitochondria as it is the only one that chemically modifies the imported protein by introducing covalent bonds (disulfide bridges). This is pathway is also linked to redox control in mitochondria and the more general redox homeostasis cues in the cell, so it is critical to understand the links between this aspect of mitochondria biogenesis and redox balance. This is where our research focuses next. We want to understand how redox balance is maintained in the IMS and how this is connected to cellular redox signalling, particularly looking for non-conventional import pathways of antioxidant proteins that make their way to the IMS and how these processes work in stress conditions. Recent work in our lab with pancreatic cancer cells shows that such pathways may hold the key to understanding vulnerabilities in come of the most therapy resistant cells and we want to tease out these links. We are also interested in establishing the crosstalk between these redox-regulated mitochondria biogenesis processes and mitochondria dynamics and contacts with other organelles, which are at the heart of mitochondria function and mitochondrial damage.
MitoWorld: We are always intrigued by how the nuclear and mitochondrial genes interact to share the genetic control of the cell. The IMS seems like a location where much of this cooperation is manifested. Do you have any thoughts on this?
Dr. Tokatlidis Yes, it is true that the IMS is like a buffer zone between the cytosol and the inner most mitochondrial compartment, the matrix. Because of the presence of porins in the OM, small molecules up to about 5 kDa can freely diffuse in and out of the IMS. This allows several signalling molecules to contribute to the communication between the mitochondria core and the cytosol. Additionally, the IMS is the compartment that discharges to the rest of the cell several of the apoptosis factors upon selective permeabilization of the OM in conditions of programmed cell death. A very fine regulation of the IMS both structurally and functionally in response to changing metabolic and stress conditions is therefore fundamental to control such processes and allow the function of mitochondria as a signalling organelle. All of the IMS proteins are nuclear-encoded, but many of them act as assembly factors of the OXPHOS complexes in the IM, which contain subunits encoded by the mtDNA. It is therefore critical that the coordination of these interactions in the IMS works well to allow assembly and stability of OXPHOS and eventually maintenance of mitochondrial fitness.
MitoWorld: Can you speculate on the signaling mechanisms that facilitate that joint control of cellular activities?
Dr. Tokatlidis All current research points to the direction that the IMS acts as a signaling nexus rather than a passive compartment and is able to coordinate and integrate cellular activities. The IMS sits at a fascinating intersection: chemically oxidizing, topologically distinct and structurally constrained. That combination makes it uniquely suited for rapid and reversible signaling. Some of the several mechanistic “modules” that plausibly operate together to allow the IMS to exert joint control over cellular activities are: (1) Import flux as a proxy for cellular metabolic state, (2) Mia40 oxidation cycles encoding redox information, (3) IMS glutathione pool (more oxidized than matrix) acting as a tunable buffer, (4) H₂O₂ microdomains near respiratory complexes acting as localized second messengers (5) protein conformational switching as a signaling currency, (6) IMS proteins may act as electrochemical translators, converting changes in Δψ or proton leak into structural or redox signals that regulate OM channels (VDAC, BAX/BAK priming, TOM complex dynamics). (7) the IMS may regulate OM mechanotransduction, where changes in cristae architecture alter OM tension, influencing cytosolic signaling platforms, such as cytosolic Ca²⁺ signaling, metabolic fluxes (ATP/ADP exchange), apoptotic priming, innate immune signaling (e.g., MAVS activation indirectly via OMM tension and ROS), (8) the IMS redox and structural states may be decoded by cytosolic kinases or ubiquitin ligases that sense OM conformational changes, forming a mechano-redox signaling axis, and finally (9) cells may use “IMS leakage pulses”—brief, reversible permeability events—to communicate mitochondrial stress without committing to apoptosis.
MitoWorld: The quality control of proteins as they are imported and processed is quite complex to maintain a delicate balance involving chaperones, modifiers, and degradation in the proteosome. Much of this takes place in the IMS. Can you elaborate on that balance?
Dr. Tokatlidis Mitochondrial protein quality control hinges on a finely tuned equilibrium in which the IMS acts as a critical decision point, coordinating chaperone buffering, oxidative folding, and degradation. As precursors enter the IMS, small TIM chaperones and the Mia40–Erv1 oxidative folding system manage their stability, ensuring hydrophobic or cysteine‑rich substrates remain import‑competent while avoiding over‑oxidation that traps misfolded intermediates. The IMS redox environment, more oxidizing than the cytosol or matrix, sensitively dictates whether proteins fold productively, undergo corrective modification, or are flagged for removal. Stalled or misfolded IMS intermediates can be retro‑translocated for cytosolic proteasomal degradation or passed inward to matrix chaperones and proteases, but excessive degradation risks depleting essential IMS components and disrupting respiratory chain assembly. The overall balance emerges from the interplay of IMS redox poise, chaperone capacity, import flux, and protease thresholds, making the IMS a central hub for maintaining mitochondrial proteostasis under fluctuating metabolic and stress conditions.
MitoWorld: We are always interested in what attracted researchers to mitochondria. How did you become interested in them in the first place?
Dr. Tokatlidis I was trained as a chemical engineer during my undergraduate studies and became fascinated by how interdisciplinary research can be used to tackle major scientific problems. This interest led me to pursue a PhD in biochemistry, where I worked on protein folding and the functions of molecular chaperones. In the era before AlphaFold, protein folding was considered essentially intractable, and even now, despite enormous advances, it remains a highly complex challenge for cells.
My growing interest in the principles of protein folding and assembly naturally drew me toward mitochondria, given their central importance in cellular life. I was fortunate to join the laboratory of Jeff Schatz at the Biozentrum in Basel. Jeff was a towering figure in mitochondrial biology—the co‑discoverer of mitochondrial DNA in the 1960s and a pioneer in elucidating the mitochondrial protein import machinery. Working with him had a profound influence on me and shaped the entire trajectory of my scientific career.
Following the discoveries I made early on, I have remained committed to mitochondrial research for nearly 30 years. Throughout my career—in Manchester, then in Crete, and now in Glasgow—I have been lucky to work with exceptionally engaged and driven colleagues from around the world. Together, we have explored fundamental pathways that not only deepen our understanding of mitochondria but also provide a foundation for translational applications in health and disease.
I believe mitochondrial biology is central to understanding many common human pathologies, including cancer, neurodegeneration, and cardiovascular disease, as well as rare mitochondrial disorders and the biology of ageing. One of the most rewarding aspects of working in this field is the constant sense of discovery: mitochondria continually surprise us with their involvement in nearly every aspect of cellular homeostasis.
Finally, collaborating with talented and motivated young researchers has made this journey even more exciting, and it remains one of the most fulfilling parts of my work.
Reference
van der Schans F, Tokatlidis K, Vitali DG (2026) In and out of the mitochondrial intermembrane space. Protein Science 35(3): e70493.
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.
Healthy skeletal muscle is critical to our overall quality of life. In turn, muscle health depends on the ability of mitochondria to perform their many essential functions. David Hood and his colleagues at York University in Toronto recently described the complex relationship between muscle use and mitochondrial health. Their review was published in a recent issue of the Journal of Sport and Health Science.
Many aspects of the quality of life involve mitochondrial health. For example, exercise promotes mitochondrial biogenesis, networking and efficiency. However, lack of exercise results in decreased mitochondrial quality. In addition, it can increase the activity of the innate immune system. Mitochondrial damage-associated molecular patterns (DAMPs) resulting from the activation of the immune system can also affect muscle function.
In this review, the authors describe the effects on mitochondrial biogenesis, fusion, fission and mitophagy. More specifically, they review the involvement of nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome complex activation with mitochondrial quality. That complex regulates innate immunity and cell death by controlling caspase-1, interleukin-1b and -18, and gasdermin-D. Despite considerable work in these areas, the relationship between metabolic states and these compounds is still unclear.
The review provides an overview of the state of current research into how muscle activity, mitochondrial health, and the immune system are linked in a complex system. Interestingly, modulating skeletal muscle activity may suggest a promising therapeutic strategy to manage inflammatory responses in skeletal muscle. Further research is needed to determine the value of this possible treatment strategy.
A Conversation with Dr. Hood.
MitoWorld: This review again highlights the multiple and unexpected activities of mitochondria. Can you give us some idea of where you future is heading?
Hood: The future in this field is moving toward understanding the role of mitochondria as a signaling hub for the activation of retrograde pathways back to the nucleus. These signals activate the transcription of genes that ultimately alter the cellular phenotype. This varies considerably among tissues with divergent mitochondrial morphologies and metabolic functions (e.g., liver vs. muscle vs. heart) and also between health and disease states. This makes studying mitochondria very interesting.
MitoWorld: You note that other signaling molecules (other than the NLRP3 complex) might be involved. Can you speculate on what those might be? Do you plan to follow up on them?
Hood: Mitochondria are the only organelles with their own separate genome, which adds to their fascination. Mitochondrial defects can lead to the release of mtDNA into the cytoplasm of the cell, leading to the activation of a separate immune response. Some of this mtDNA actually also leaves the cell and can be measured in blood, providing a useful biomarker for cellular stress.
MitoWorld: You ask an interesting question in the limitations section about possible different responses to exercise programs other than endurance exercise. Any thought?
The immune response to exercise varies considerably with exercise intensity. Thus, it would be interesting to evaluate the innate immune response within muscle as a function of high-intensity interval training (HIIT) or with a strenuous bout of resistance exercise.
MitoWorld: Some mitochondrial diseases feature extreme fatigue in patients. Could even modest exercise help them or is that an entirely different question?
Hood: Patients with mitochondrial disease obviously have defective mitochondria and energy production, leading to rapid fatigue during exertion. These defective mitochondria likely elicit a heightened immune response. Regular exercise is known to improve muscle function, work capacity, oxygen consumption and performance in mtDNA disease patients, but it is not yet known whether exercise can attenuate the immune signaling in these patients.
MitoWorld: As you note, it is easy to imagine exercise as a therapeutic strategy to improve mitochondrial health and to moderate the innate immune system? Can you expand on how this might be done?
Hood: We have shown that the exaggerated immune signaling pathway evident in aged muscle is strongly attenuated with regular exercise (Khemraj, P et al. J. Appl. Physiol. 2025). This involves an exercise-induced reduction in the expression of NLRP3 and downstream signaling, and it shows that exercise is a very promising therapeutic for maintaining and preserving muscle health as we age.
MitoWorld: We are always interested in learning what it was that brought you to study mitochondria. Can you describe that?
Hood: My PhD thesis many years ago involved the study of an amino acid metabolizing enzyme that is located in muscle mitochondria. That research helped me develop an interest in mitochondria. And since I was always fairly athletic, I began to wonder what exercise also did to mitochondria. I never looked back.
Reference
Khemraj P, Kuznyetsova A, Hood DA (2025) Adaptations in mitochondrial quality control and interactions with innate immune signaling within skeletal muscle: A narrative review. Journal of Sport and Health Science 15: 101049.
https://www.sciencedirect.com/science/article/pii/S2095254625000274
Led by Kathryn Cullen, a research team at the University of Minnesota, the University of Queensland, and the Mayo Clinic studied depression and fatigue in young adults with and without early-stage depression. They found a positive correlation between ATP levels and levels of depression in young adults that correlates with depression and suggests a compensatory mechanism early in the disease. Their findings were published in a recent paper in Translational Psychiatry.
Fatigue is a common feature of major depressive disorder (MDD). The Cullen team wanted to better understand the origins of that fatigue to improve the quality of life of young MDD patients. To accomplish that, they compared ATP levels in cells from MDD patients and healthy controls. ATP levels were measured in brain cells by magnetic resonance spectroscopy and in peripheral blood mononuclear cells with a Seahorse instrument.
They found that the MDD patients had higher levels of ATP production than the controls, and those levels correlated positively with the measures of fatigue. In addition, those
This study is the first to show higher levels of ATP in brains and blood of MDD patients. The
findings suggest a compensatory mechanism early in the disease and may suggest strategies for future therapies.
A Conversation with Drs. Cullen and Tye
MitoWorld: Your discovery of a biosignature for fatigue in depressed youth is exciting. Can you give us an idea of where your research is going next? For example, do you plan to expand the sample size or to control for various drug treatments?
Cullen & Tye: Yes, we are actively seeking funding for this important work. Our hope is to confirm the findings from our paper in a larger group of young people. Controlling for medication can be a challenge due to ethical constraints, but it becomes more feasible with a large sample, to allow us to look at subgroups.
MitoWorld: The depression connection noted between your results and those for early Parkinson’s disease patients is interesting. It is reminiscent of the connection between early brain injury and Alzheimer’s disease. Do you have any thoughts on that?
Cullen & Tye: Given that depression is already an established risk factor for Alzheimer’s disease, we speculate that the bioenergetic signature we find could possibly represent a precursor reflecting physiological risk for dementia. If so, this biosignature could be a critical mechanistic link between the two conditions.
MitoWorld: Another recent paper showed a connection between mitochondrial health and depression. Could this be a common phenomenon? Do you think your findings would apply to muscle tissues?
Cullen & Tye: We suspect that impaired mitochondrial efficiency and capacity is likely to be reflected across all tissues. We are interested in the immune system as it is also closely linked to depression, as a mechanistic risk factor. The findings summarized in this review paper on mitochondrial health and inflammation in skeletal muscle hold potential relevance to depression, since the fatigue and low motivation in depression often contributes to sedentary behavior and muscle disuse. Taken together, an examination of mitochondrial health in muscle tissues in individuals with depression may be warranted.
MitoWorld: One of the mysteries that intrigue us is the “shared governance” of the mitochondrial and nuclear genomes. Do you have any speculation on how the nucleus signals to the mitochondria to increase the ATP levels in depression?
Cullen & Tye: This is a great question. The nucleus regulates mitochondrial ATP production indirectly through coordinated energy-sensing and transcriptional pathways, particularly via AMPK and PGC-1α, as well as rapid calcium and redox signaling that tune mitochondrial efficiency and capacity in real time. In depression, we speculate that this shared governance becomes dysregulated by chronic stress and immunometabolic adaptations to ongoing inflammatory load, resulting in the impairment of mitochondrial ATP production capacity to meet cellular demand.
MitoWorld: Do you think that your results might lead to clinical applications? For example, might the results from your MRI or PBMC studies might translate to a clinical test?
Cullen & Tye: Yes. While we are currently still in the foundational research stage, we strongly further stages of this research will have the potential to guide personalize clinical care. Part of the next steps include translating these findings to the clinic through biomarker-driven, companion diagnostic approaches.
Reference
Cullen KR, Tye SJ, Klimes-Dougan B, Wiesner HM, Varela RB, Morath B, Zhang L, Chen W, Zhu XH (2026) ATP bioenergetics and fatigue in young adults with and without major depression. Translational Psychiatry https://doi.org/10.1038/s41398-026-03904-y.
Now On-Demand: Keystone Symposia’s Mitochondria Signaling in Physiology and Disease
If you missed the Keystone Symposia conference Mitochondria Signaling in Physiology and Disease—held February 9–12, 2026 at Keystone Resort in Colorado—you now have a second chance. On Demand registration is open, giving you access to the full main-session program from one of the most significant gatherings in mitochondrial biology in recent years. See: keystonesymposia.org/conferences/conference-listing/meeting/onpage-program/b12026.
What the Meeting Was About
Co-organized by Navdeep S. Chandel, Ph.D. (Northwestern University), and Aleksandra Trifunovic, Ph.D. (University of Cologne), the symposium brought together basic scientists, clinicians, and industry researchers around a single ambitious premise: that mitochondria are not simply the cell’s power generators, but dynamic signaling hubs that coordinate metabolism, stress responses, redox biology, proteostasis, and immune activation across virtually every tissue in the body.
In Their Own Words
Dr. Chandel reflected on what the symposium set out to accomplish and what it achieved:
“The objective was to convene a cross-disciplinary community of basic scientists, clinicians, and industry researchers to redefine mitochondria not merely as bioenergetic organelles, but as dynamic signaling hubs that coordinate metabolism, stress responses, redox biology, proteostasis, and immune activation across tissues. By all measures, the meeting achieved these aims. Sessions were intellectually rigorous and highly interactive, trainees were prominently featured through talks and poster sessions, and discussions frequently extended beyond scheduled programming. Many attendees remarked on the collaborative atmosphere and the breadth of disciplines represented, reflecting a field that is both expanding and increasingly integrated.”
Maulik Patel, Ph.D., Associate Professor, Metabolism and Nutritional Programming, Van Andel Institute, offers succinct summary of the Symposium, underscoring the objectives of the gathering.
“It had been some time since I last attended a mitochondrial meeting, so the Keystone Symposium on Mitochondrial Signaling in Physiology and Disease provided a valuable snapshot of where the field now stands. While the idea of mitochondria as signaling hubs is not new, what was striking is how pervasive and mechanistically defined these roles have become—spanning metabolism, immunity, proteostasis, and aging.
The level of technical sophistication was particularly impressive: researchers can now trace signaling events from a mitochondrial metabolite all the way to specific molecular targets, sometimes down to single-residue modifications, making the conclusions far more rigorous and convincing. The meeting also showcased the extraordinary range of scales at which mitochondria are studied, from atomic-resolution structural work to whole-organism physiology, underscoring just how integrative and exciting mitochondrial biology has become.”
Janine H. Santos, Ph.D., Group Leader, National Institute of Environmental Health Sciences (NIEHS), underscores bridging basic science with translational and clinical work.
The Keystone Symposia meeting “Mitochondria Signaling in Physiology and Disease” stands out for its forward-looking reframing of mitochondria as dynamic, cell-type–specific signaling hubs that actively shape cell fate, adaptation, and disease. This perspective places mitochondrial biology at the center of physiology and pathophysiology, including in aging. The program is especially compelling for its integration of diverse areas of mitochondrial research such as metabolite, mtDNA, and redox signaling alongside stress adaptation and emerging technologies. By bridging basic science with translational and clinical insights, it highlights shared mechanisms and therapeutic opportunities across diseases. Its highly interactive format further fosters learning, cross-disciplinary collaboration, and networking, which are particularly attractive and important for young investigators.
Antonio Enriquez, Ph.D., from the Centro Nacional de Investigaciones Cardiovasculares in Madrid, offered a framing of why this meeting stands apart from other conferences in the field:
“The Keystone Symposia meeting explicitly reframes mitochondria from a ‘powerhouse’ housekeeping role into central signaling hubs capable of being tailored for cell type and physiologically changing conditions, shaping cell fate and disease—bringing together basic, translational, and clinical perspectives in one tightly integrated program. In addition to the scientific sessions, the meeting format was designed to maximize cross-career and cross-sector interactions (e.g., poster sessions, a therapy-focused panel, and a dedicated Career Roundtable), making it particularly strong for generating collaborations and for trainees to get targeted career guidance.”
Lena Pernas, PhD, Associate Professor in the Department of Microbiology, Immunology & Molecular Genetics at UCLA and session chair for the Mitochondria Metabolite Signaling session, highlights broad participation:
“The Keystone Mitochondria Signaling in Physiology and Disease showcased talks from researchers who do not traditionally identify as mitochondrial biologists, which brought fresh conceptual approaches to the field. The meeting also highlighted the power of emerging technologies being applied to mitochondrial questions, opening exciting new experimental possibilities. I also very much enjoyed the panel discussions on therapeutic translation, which underscored the impact of mitochondrial research beyond basic biology.”
Mike Murphy, Ph.D., Program Leader at the MRC Mitochondrial Biology Unit and a panelist on the therapy challenges session, appreciates the scientific breadth:
“Some highlights of the meeting were the expansion of metabolic perspectives and regulatory networks on how mitochondria operate in health and disease. Related to this is the development of multiomic approaches and tools, such as that of Dave Pagliarini, that are empowering this next stage in mitochondrial research. The links of these approaches to understanding pathology and potential therapies were also inspiring.”
David J. Pagliarini, Ph.D., HHMI and BJC Investigator, Hugo F. and Ina C. Urbauer Professor, Washington University Medicine, emphasizes the new tools he was exposed to and the value they bring to the field:
“This Keystone meeting featured cutting-edge tool development (e.g., new mitochondrial sensors and screening modalities), new signaling paradigms (via metabolites and PTMs), unexpected mitochondrial interactions with other organelles and external pathogens, and a beautiful summary of where the field stands in our collective quest for new therapeutics.”
Pol Castellano Escuder, Ph.D., a computational biologist and AI researcher currently at the Duke Molecular Physiology Institute (DMPI) and CTO of https://www.heurekalabs.co/, brings a new AI perspective into the mitochondrial research and clinical community.
“Heureka Labs was thrilled to attend the Keystone Symposium on Mitochondria Signaling in Colorado. It was energizing to see the breadth of pathways being explored and the discoveries coming out of this community, and particularly fascinating to watch how so many threads of modern multi-omics research keep converging. As one researcher put it, ‘all roads lead to the mitochondria eventually.’ Between the new tools, methods, and technologies being shared, it’s a genuinely exciting time to study mitochondria and their role in physiology. What the conference also made clear is that data proliferation and the push toward cross-disciplinary integration are outpacing what traditional approaches can handle.
Larissa Govers, a doctoral candidate in the Lab for Retinal Cell Biology at the University of Zurich gave perhaps the most personal account. She presented her work on the metabolic consequences of chronic hypoxia on mitochondrial function in photoreceptor cells:
“What began as a nerve-wracking solo trip across the pond turned into an experience that strengthened my scientific foundation and expanded my network within the field. I left the meeting feeling energized and deeply motivated to continue to grow as a researcher within this collaborative environment. As an early investigator who is relatively new to the field of mitochondrial signaling, attending a conference by yourself specifically focusing on this topic can be an overwhelming experience. There are countless new people to meet and so much to learn from the experts who have shaped the field. Still, deciding to attend this Keystone meeting to deepen my foundation in mitochondrial research was one of the best decisions I could have made.
Beyond the opportunity to expand my knowledge and generate new research ideas, I was blown away by the open culture within this community. I got to meet a lot of new people, and every person I met was inspiring and motivating in their own way. I was particularly grateful for the leaders in the field, who made time to listen to early investigators, gave us direction in our projects, supported us in our career development, and most importantly encouraged us to become the next generation of scientists who will continue advancing mitochondrial research.”
How to Register for the On-Demand Program
The On Demand recordings cover all main-session presentations from the Grays Peak conference room. On Demand Registration here: https://www.keystonesymposia.org/conferences/conference-listing/meeting/pricing/B12026
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
We welcome Dr. A. Phillip West to the board of directors of the California-based nonprofit National Laboratory for Education Transformation, www.NLET.org. “NLET” is the parent nonprofit of www.MitoWorld.org, our global mitochondrial community web-hub and blog site, and www.mitos.global, our collaborative platform for multi-institution and multi-PI single-subject projects, grants, and funding opportunities.
“We are honored to welcome Phillip to the NLET Board,” said Board Chair David Andrews. “His deep scientific expertise and international research stature will enhance our ability to convene and empower the global mitochondrial research community. Together, we will accelerate discoveries, build collaborative research platforms, and support the translation of mitochondrial science into clinical and societal solutions.”
Dr. West’s leadership, understanding of the growing mitochondrial field, and his scientific credentials will be pivotal in guiding these mitochondrial efforts to benefit the wider mitochondrial research and clinical communities by bringing support, awareness, and new tools to the field.
“I am delighted to join the NLET board at such a pivotal moment for mitochondrial science,” said Dr. West. “We are witnessing a fundamental shift in how mitochondria are understood, not merely as cellular powerhouses, but as central regulators of cellular signaling, immunity, and much more. MitoWorld and MITOS.Global represent exactly the kind of collaborative infrastructure our field needs to increase awareness of mitochondrial biology and translate discoveries into meaningful advances for human health. I look forward to contributing to NLET’s mission of building bridges between researchers, clinicians, and the general public as we work to elevate mitochondrial medicine on the global stage.”
Dr. West is an associate professor and principal investigator at The Jackson Laboratory (JAX) in Bar Harbor, ME. In addition, he serves as a research program co-lead for the NCI-designated JAX Cancer Center, which is focused on understanding the role of aging in cancer development and progression. The West lab explores how mitochondria regulate innate immune and inflammatory responses in health and disease. His team has significantly advanced understanding of mitochondrial DNA (mtDNA) signaling and its influence on disease susceptibility and progression, including inflammatory heart failure, cancer, and rare mitochondrial diseases. He received his PhD in Immunobiology from Yale University and completed postdoctoral training at Yale School of Medicine. Learn more at www.westlaboratory.com. (JAX)
As a member of the NLET board, Dr. West will support strategic efforts to grow NLET’s biomedical informatics and collaboration initiatives. NLET’s MitoWorld™ platform serves as a global web hub connecting researchers, clinicians, and patient advocates to accelerate research and clinical collaboration in mitochondrial medicine. This platform disseminates cutting-edge research, supports patient communities, and fosters interdisciplinary science in mitochondrial health and disease.
Complementing this, NLET will be looking for resources to support frontline research with MITOS.Global as a networked institute devoted to comprehensively understanding mitochondrial biology across health, aging, and disease—integrating basic science with AI-driven informatics and global research collaboration to forge new frontiers in mitochondrial science.
About National Laboratory for Education Transformation
The National Laboratory for Education Transformation (www.NLET.org) is a nonprofit dedicated to innovative research and transformative strategies in education, science, and health. NLET convenes experts and stakeholders across domains to challenge traditional paradigms and advance interdisciplinary research and practice. As part of its mission, NLET fosters initiatives connecting global research communities, with a special focus on emerging scientific priorities, including mitochondrial science and biomedical informatics.
Media Contact:
Gordon Freedman
gordon.freedman@nlet.org