Mitochondria house metabolic pathways that support cell growth, survival, function and identity. Mutations in mitochondrial metabolic enzymes are drivers of many mitochondrial diseases, but different diseases arise when certain metabolic functions are disrupted, and the cell types affected are often poorly understood. In recent work published in Cell and Molecular Cell, a research team at Memorial Sloan Kettering Cancer Center, led by Abigail Xie, Julia Brunner and Lydia Finley shed light on when cells use different metabolic pathways within mitochondria and what essential functions are supported by mitochondrial metabolic networks.
The researchers focused on two related metabolic pathways that are required for importing nutrients into mitochondria and converting them into molecules that cells need to function. The tricarboxylic acid (TCA) cycle harnesses reducing equivalents from nutrients to fuel energy production in the electron transport chain (ETC), and the malate-aspartate shuttle transfers reducing equivalents from the cytosol to mitochondria for deposition onto the ETC. Despite the central role of these pathways within cellular metabolism, mammalian cells display surprising heterogeneity in whether, and how, they use these pathways. For example, some reactions of the TCA cycle can run in reverse or be skipped by exporting intermediates that are converted in the cytosol. The authors, therefore, set out to investigate the factors and contexts that dictate how the TCA cycle and related pathways are assembled in mammalian cells.
Reporting in Cell, co-first authors Xie and Brunner sought to determine what makes cells use the complete set of reactions that make up the “canonical” TCA cycle. They found that increasing cellular nutrient consumption by supplying cells with TCA cycle substrate pyruvate increased the production of citrate, the metabolite formed in the first step of the TCA cycle. Enhancing citrate production led to increased forward flux through the TCA cycle and induced dependence on enzyme aconitase 2, the TCA cycle enzyme that that breaks down citrate. To determine if aconitase 2 is also essential to break down citrate in vivo, they generated a mouse model of whole body, inducible aconitase 2 deficiency. Here, they discovered the kidney to be exquisitely sensitive to aconitase 2 loss. Notably, the kidney is unique for its ability to uptake and catabolize circulating citrate. The authors showed that cell autonomous citrate uptake is sufficient to induce reliance on aconitase 2 in cultured cells. Collectively, these results indicate that a major function of the TCA cycle is to remove citrate from mitochondria. This work demonstrates that apart from its known roles in nutrient breakdown and provision of metabolic intermediates, the TCA cycle is also important for metabolite clearance.
In the second study, the authors described how pathways that feed into the TCA cycle are differentially utilized depending on cell state. For cell metabolism to continually function, reducing equivalents generated in the cytosol must be transferred to mitochondria, where they can be safely deposited on the ETC. Reciprocally, oxidized intermediates generated within mitochondria must be delivered to the cytosol where they can be used to fuel biosynthetic pathways. One pathway, the malate-aspartate shuttle, fulfills both needs by transferring reduced nutrients (the TCA cycle intermediate malate) to mitochondria in exchange for aspartate. Mitochondrial production of aspartate is an essential function of the ETC in cultured cells. Here, the authors showed that the ability of aspartate to participate in the malate-aspartate shuttle and transfer reducing equivalents back into mitochondria depends on the relative balance between aspartate supply and demand within cells. Increasing or decreasing cytosolic aspartate levels with bacterial enzymes allowed cells to increase or decrease flux through the malate-aspartate shuttle, respectively. In turn, changing malate-aspartate shuttle flux changed how cells use metabolic pathways that depend on clearing reducing equivalents from the cytosol. Specifically, the ability to oxidize glucose required increased malate-aspartate flux. Accordingly, whereas proliferating cells with high aspartate demand had limited malate-aspartate shuttle flux and reduced glucose oxidation, differentiated cells with lower aspartate demand exhibited higher malate-aspartate shuttle flux that was sufficient to enable increased glucose oxidation—a metabolic hallmark of differentiated cells.
These findings illustrate how metabolic networks adopt different configurations depending on environmental context and cell state. Understanding when, and why, metabolic components become essential for different tissues and contexts will ultimately provide insight into the etiology of metabolic disease and nominate new approaches to target metabolism to manipulate cell states in cancer and other diseases.
A Statement of Significance from Dr. Lydia Finley
Mitochondria play critical roles converting nutrients into the molecules that cells need to function, but which metabolic pathways are used and which outputs are essential for cells are highly context-specific. For example, mutations in mitochondrial enzymes result in highly tissue-specific pathologies, indicating that different tissues—different cell types or cell states—have unique requirements for outputs of individual enzymes. In two papers, Brunner, Xie, and colleagues add to our understanding of how mitochondrial metabolic pathways are wired in to meet the demands of different cell contexts. In one study, they show that some cells depend on the TCA cycle not just to support energy production or anabolic synthesis but also to prevent metabolite accumulation within mitochondria. In another study, they show that as progenitor cells differentiate, they fully engage the malate-aspartate shuttle—an electron shuttle that enables cells to oxidize glucose within mitochondria. Together, these studies show how metabolic programs are wired to meet unique demands of different cell states. These studies support the argument that further identifying when and why metabolic enzymes are required will provide critical insight into how mitochondria support cell fitness and why mutations in mitochondrial genes lead to human disease.
A Conversation with Dr. Lydia Finely:
MitoWorld: How did you become interested in studying mitochondria? What interests you about them?
Dr. Finley: I became interested in metabolism as an undergraduate when I first learned that muscles can continually switch fuels to meet metabolic demands during exercise. This adaptability fascinated me, and I ended up working in a mitochondrial bioenergetics lab studying how mitochondria select different fuels to use during exercise and recovery from exercise. This adaptability fascinates me to this day: mitochondria are constantly sensing and responding to their surroundings and providing information about their decisions to the rest of the cell. They are like a little brain within a cell, taking in information and coordinating cellular responses.
MitoWorld: You mention that the kidney is uniquely sensitive to ACO2 deletion in the TCA cycle. Is that simply because it has to process so much citrate to remove it from circulation, or do you think there may be other reasons for this?
Dr. Finley: Likely many factors contribute to the importance of ACO2 in the kidney. We focused on the role of citrate uptake and showed that citrate uptake is sufficient to induce ACO2 dependence in non-kidney cells. That doesn’t rule out other functions of ACO2 in the kidney. Notably, the kidney proximal tubule cells, which displayed pathological abnormalities following ACO2 loss, are considered to be some of the most energy-demanding cells in the body. It will be interesting for future studies to determine whether this energy requirement contributes to ACO2 dependence in the kidney and, potentially, other organs.
MitoWorld: Other than the kidney, are there other types of cells or disease contexts that have unique characteristics or sensitivities when it comes to the TCA cycle? What does this tell you about them?
Dr. Finley: This is a major open question. Patients with ACO2 mutations often manifest with retinal phenotypes, suggesting that this cell type may have high reliance on ACO2. In cultured cancer cells, ACO2 is one of the most variably essential metabolic genes, meaning that some cells don’t care much about ACO2, while others do. What underlies this variability is a major question for us moving forward.
MitoWorld: The metabolic hallmark of differentiated cells with regard to the malate-aspartate shuttle is very interesting. Is this generally true of all types of differentiated cells, or are there some cell types that behave differently? Are there disease contexts where this changes, such as in cancer?
Dr. Finley: This is a great question. We’ve tested a few contexts where the transition from proliferative, progenitor to differentiated states shows this characteristic metabolic switch. How generalizable this switch is remains to be determined. Likely, some differentiated tissues will have specific metabolic requirements that push them to an alternate metabolic state. Continuing to identify how changes in cell state reorganize metabolism and which metabolic programs are required for certain cell states is a major area for future work.
MitoWorld: How might these pathways be targeted to treat disease, as you suggest in the conclusion? Through pharmaceuticals, through diet, other?
Dr. Finley: To know how to treat disease, we need to know why the disease arises. In many cases, mitochondrial diseases driven by the same genetic mutation affect different tissues (and even different people) differently. Why some tissues care more than others about specific mutations isn’t always clear. This variable dependence suggests that metabolic enzymes are required to meet needs that are specific to some tissues. If we can understand what these needs are—which metabolic outputs support essential functions in different tissues—we can better understand why pathologies emerge and, then, hopefully identify strategies to help tissues meet their specific needs and overturn these pathologies.
MitoWorld: What are the next steps for this research? What questions are you still trying to answer and why are they important?
Dr. Finley: We found that citrate accumulation within mitochondria activates a stress response known as the integrated stress response, which turns on genes that helps cells adapt to stress or other environmental changes. We are working to understand how mitochondrial citrate, or consequences of citrate accumulation within mitochondria, turn on a cytoplasmic stress response. We hope these studies will provide new insight into how changes within mitochondria are communicated throughout the cell to help cells adapt and respond to changes in mitochondrial activity.
MitoWorld: Anything else you think the audience should know?
Dr. Finley: Metabolism is not one-size-fits-all. It highly, highly variable, and there is a lot left to learn about cell metabolism!
References:
Abigail Xie, Julia S Brunner, Sangita Chakraborty, Angela M Montero, Anna E Bridgeman, Katrina I Paras, Ruobing Cui, Maider Fagoaga-Eugui, Monika Komza, Paige K Arnold, Benjamin T Jackson, Santiago Noriega Madrazo, Mohamed I Atmane, Sebastian E Carrasco, Lydia W S Finley (2026) Citrate clearance is a major function of aconitase 2 in the canonical TCA cycle. Cell 189(9):2684-2699.e21.
https://pubmed.ncbi.nlm.nih.gov/41763199/
Julia S Brunner, Anna E Bridgeman, Benjamin T Jackson, Sangita Chakraborty, Maider Fagoaga-Eugui, Katrina I Paras, Abigail Xie, Paige K Arnold, Julia Losner , Lydia W S Finley (2026) Aspartate availability drives differential engagement of the malate-aspartate shuttle. Mol Cell. Mar 5;86(5):954-967.e7.
“What was striking was not simply that mitochondrial transfer was being discussed, but how many different cancer systems it appeared to connect. Across all three talks, mitochondria were presented less as isolated organelles and more as mobile biological assets shaping metastasis, immune exhaustion, therapeutic resistance, and even tumor innervation. You could feel the field beginning to connect previously separate observations into a larger systems-level framework.”
— Alex Sercel, Co-Founder, MitoWorld.org
For decades, mitochondria occupied an uneasy place in cancer research. Everyone knew they mattered. They appeared in discussions of metabolism, apoptosis, oxidative stress, and cellular energetics. But they rarely occupied center stage at major oncology meetings. The mitochondrion was often treated as background infrastructure — essential, certainly, but secondary to the “real” drivers of cancer biology.
Something changed at the American Association for Cancer Research (AACR) Annual Meeting 2026 in San Diego.
For the first time in the history of the AACR Annual Meeting, mitochondrial transfer in cancer was given its own dedicated symposium. That may sound procedural to outsiders, but to researchers working at the intersection of mitochondria, metabolism, immunology, and cancer, it represented something much larger: institutional recognition that mitochondrial dynamics are no longer peripheral to oncology. They are becoming central to it.
The symposium, “Mitochondrial Transfer Networks in Cancer Progression,” brought together three researchers approaching the field from distinct but converging directions:
- Yosuke Togashi, Okayama University
- Simon Grelet, University of South Alabama / Mitchell Cancer Institute
- Luca Gattinoni, University of Regensburg / Leibniz Institute for Immunotherapy (LIT)
Collectively, the presentations argued something profound: mitochondrial transfer is not a niche biological curiosity. It is emerging as a fundamental mode of intercellular communication in cancer biology — one that tumors exploit, immune systems respond to, and future therapies may intentionally manipulate.
After the session, MitoWorld.org reached out to all three panelists with a series of questions about the field, the symposium, and where mitochondrial cancer biology may be headed next. What emerged from those conversations was not just enthusiasm, but the unmistakable sense that an entire area of science is crystallizing in real time.
A Field Arrives
When asked what made the AACR symposium so important, all three researchers independently focused on the same point: this was a first.
“This was, to my knowledge, the first time mitochondrial transfer in cancer had been given its own dedicated special session at AACR,” explained Simon Grelet. “The room was charged with enthusiasm and curiosity.”
Yosuke Togashi emphasized the scale of interest from the oncology community itself:
“The sheer volume of questions indicated a significant surge in interest regarding how mitochondrial dynamics influence oncology.”
For Luca Gattinoni, the significance was not merely that the session existed, but how it was framed.
“The three talks together made an argument that no single one of us could have made alone: that mitochondrial transfer is not a niche phenomenon but a fundamental mode of intercellular communication that tumors exploit and that we can potentially exploit back.”
That framing matters.
Cancer biology has increasingly become the biology of systems: tumor microenvironments, immune interactions, stromal signaling, metabolism, and cellular networking. What mitochondrial transfer research suggests is that mitochondria themselves may function as active biological currency moving between cells — influencing survival, adaptation, immune suppression, metastasis, and therapeutic resistance.
From “Power Plants” to Networks
One of the strongest themes emerging from the symposium was that the classical textbook view of mitochondria is rapidly collapsing.
For generations, mitochondria were taught primarily as intracellular energy factories — isolated organelles generating ATP inside sealed cellular boundaries.
That view now appears incomplete.
“The field is moving away from the traditional view of the mitochondrion as an isolated ‘power plant’ enclosed within a cell,” said Yosuke Togashi. “Instead, we are beginning to understand it as a dynamic component of a larger networking system.”
That conceptual shift may ultimately prove as important as any individual experiment.
Mitochondria are increasingly being understood not simply as metabolic engines, but as signaling entities, stress sensors, inflammatory regulators, and now potentially mobile intercellular participants capable of moving between cells and altering biological outcomes.
Simon Grelet noted how rapidly evidence for mitochondrial transfer has accumulated across multiple dimensions of cancer biology:
“It is proving to touch multiple dimensions of cancer biology: how tumor cells acquire metabolic advantages, how they interact with their microenvironment, how they evade treatment, and more.”
Meanwhile, Luca Gattinoni highlighted how evidence is arriving simultaneously from very different domains:
“Nerve-tumor interactions shaping metastasis, tumor cells offloading dysfunctional mitochondria to suppress immune responses, stromal cells using the same mechanism to sustain T cell fitness.”
“The same biological currency,” he added, “deployed in radically different contexts.”
The Room Itself Told the Story
Scientific meetings often reveal the future of a field less through formal presentations than through hallway conversations afterward.
By all accounts, that happened here.
Yosuke Togashi was struck not only by the engagement during the session, but by what happened after it ended:
“The technical nature of the follow-up questions showed that researchers are already thinking about how to integrate these concepts into their own models.”
Luca Gattinoni described something rarer still:
“The conversation that emerged felt like the field thinking out loud in real time.”
That may ultimately be the most important signal of all.
Not simply that mitochondrial transfer research is growing, but that cancer researchers working in metastasis, immunotherapy, stromal biology, metabolism, and genomics are beginning to realize they are asking overlapping questions about the same underlying system.
The Next Frontier: mtDNA and the Mitonuclear System
If mitochondrial transfer itself is emerging as a major area, the next wave may center on mtDNA and the mitonuclear system.
The mitochondrial genome remains one of the least fully integrated components of modern cancer biology. Heteroplasmy, mutation dynamics, mitochondrial-nuclear coordination, and intercellular mitochondrial inheritance remain only partially understood.
Yosuke Togashi believes advancing sequencing technologies will rapidly change that.
“While the complexities of mutation patterns and heteroplasmy remain largely mysterious, advancing sequencing technologies will soon make this a focal point of cancer genomics.”
Luca Gattinoni sees the mitonuclear axis becoming its own frontier:
“We now have enough mechanistic footing to ask harder questions about directionality, selectivity, and what it truly means for a cell to absorb another cell’s mitochondria and their DNA.”
And perhaps most intriguingly, he believes the future will move beyond observation:
“The ambition should grow: not just observing transfer, but engineering it with intent.”
That single sentence hints at where this field could eventually lead: mitochondrial engineering, mitochondrial immunotherapy, and perhaps entirely new therapeutic architectures built around manipulating cellular energy and signaling systems directly.
A New Scientific Convergence
Historically, mitochondrial biologists and cancer researchers often existed in adjacent but separate scientific cultures. That separation may now be ending.
Simon Grelet noted that mitochondrial biology appeared across multiple AACR tracks far beyond this single symposium.
Meanwhile, Yosuke Togashi offered perhaps the most insightful observation of the entire discussion:
“The most vital ‘transfer’ occurring right now isn’t just between cells, but between disciplines.”
That may ultimately define this moment.
Cancer biology, immunology, mitochondrial medicine, metabolism, genomics, and systems biology are beginning to converge around a shared realization: mitochondria are not passive background organelles. They are dynamic participants in disease.
AACR 2026 may be remembered as one of the first moments when that convergence became visible at scale.
And if the energy in San Diego was any indication, this is only the beginning.
In a recent study by Dr. Ana Andreazza of The University of Toronto, a team of researchers generated 3D brain organoids from patient blood cells to study how cells from patients with bipolar disorder differed from those without. Culturing these brain organoids from 3 normal controls and 3 patients with bipolar disorder (BD), they find significant metabolic and immune differences that impact neuronal function. The study published in Translational Psychiatry points to mitochondria as key players in this complex psychiatric condition.
Comparing BD-derived brain organoids to normal controls, Andreazza finds many abnormalities. While their structure, organization and cell types are normal (consisting of neurons and astrocytes), their metabolic function is impaired. Deficits in ATP within these cells can be traced back to dysfunctional mitochondria, which exhibit altered morphology and weaker membrane potentials. BD brain organoids have small, rounded mitochondria, indicative of immature organelles experiencing oxidative stress and fragmentation. Indeed, these mitochondria show deficits in membrane potential and polarization, which are essential to generate ATP. As a result, these cells are not able to keep up with the high energy demands of neurons in the brain, leading to misfiring and hyperactive neural networks that are a hallmark of BD. This energy deficit also impairs neurogenesis, with BD brain organoids containing fewer cells than controls.
Not only do dysfunctional mitochondria impact brain function via energy deficits, but they also drive a neuroinflammatory cascade that further damages neurons. When mitochondria are stressed they release reactive oxygen species (ROS) and mitochondrial DNA (mtDNA) into the cell, both of which are elevated in the BD brain organoids compared to controls. These molecules trigger innate inflammatory pathways, including inflammasome activation, that drive neuroinflammation and pathology in a self-reinforcing cycle. These impacts are observed in neurons and astrocytes, supporting cells that promote neuronal health but can perpetuate inflammatory damage when dysregulated.
Many of Andreazza’s findings in brain organoids parallel observations in patients with BD. For example, high ROS and mtDNA are associated with symptom severity in patients. As such, she attempts to correct some of these abnormalities with molecules that block inflammasome activation. Applying the inflammasome inhibitor MCC950 normalizes inflammasome activity in BD brain organoids and also reduces mtDNA release, indicating a reduction in mitochondrial stress. However, phase II studies of MCC950 for the treatment of autoinflammatory and autoimmune disorders suggest it may cause liver toxicity, so Andreazza also tested a new compound: Bioactive Flavonoid Extract (BFE), which has antioxidant, anti-inflammatory and neuroprotective effects via partial inflammasome inhibition. While inflammasome inhibition was not as strong with BFE, it did reduce mtDNA release to a similar extent. There may be opportunities for elevating the dose or combining it with other treatments to achieve greater impacts.
Altogether Andreazza’s study deconstructs molecular and cellular mechanisms at the intersection of metabolic and immune dysregulation in bipolar disorder. With the novel patient-derived 3D brain organoid model, she aims to bridge the gap between molecular pathology and clinical interventions.
Statement of Significance from Dr. Andreazza:
This study provides a patient-derived, human brain model that links mitochondrial dysfunction, inflammasome activation, and abnormal neuronal activity in bipolar disorder. Led by first author Dana El Soufi El Sabbagh, our team generated cerebral organoids from induced pluripotent stem cells derived from individuals with bipolar disorder and matched controls. The bipolar disorder organoids showed reduced ATP production, altered mitochondrial morphology and membrane potential, increased release of reactive oxygen species and cell-free mitochondrial DNA, and heightened NLRP3 inflammasome sensitivity, accompanied by hyperactive neuronal firing. Importantly, pharmacological inhibition of NLRP3 and a bioactive flavonoid extract partially restored cellular homeostasis, supporting the mitochondria-inflammasome axis as a tractable therapeutic pathway. This work was made possible through a close partnership with Australian collaborators at Deakin University, IMPACT and Barwon Health, who enabled patient recruitment and sample preparation. We are especially grateful to the patients and controls whose participation made this research possible.
A Conversation with Dr. Andreazza:
MitoWorld: Do you have an idea or theory on how mitochondrial dysfunction may play a role in the flip between manic and depressive episodes in bipolar disorder? Are the mitochondria acting differently in these different circumstances?
Dr. Adreazza: Our study did not directly compare cells from manic versus depressive states, so I would be cautious about assigning a specific mitochondrial profile to each episode. What we can say is that mitochondria sit at the centre of processes that are highly relevant to mood-state transitions: ATP production, calcium buffering, oxidative stress, inflammatory signalling, and neuronal excitability. One working model is that an intrinsic mitochondrial vulnerability reduces the energetic flexibility of neurons and astrocytes. During periods of high demand, such as sleep disruption, psychosocial stress, or systemic inflammation, cells may compensate by increasing excitability and stress signalling. This could contribute to manic symptoms in some contexts. Over time, the same system may become energetically depleted, inflammatory pathways may remain activated, and neuronal networks may lose resilience, contributing to depressive symptoms. Rather than mitochondria being entirely different organelles in mania and depression, I think their function may shift dynamically across a spectrum of energetic compensation, oxidative stress, and inflammatory burden.
MitoWorld: Bipolar disorder, and many other psychological conditions where mitochondria are implicated, arise during late adolescence and early adulthood. Do you expect this is when the mitochondria start dysfunctioning, or have they been dysfunctioning all along and reach a certain threshold around this time? Why now?
Dr. Adreazza: I suspect that, in many individuals, mitochondrial vulnerability is present before the first clinical episode, but it may not become functionally limiting until the brain reaches a developmental and environmental threshold. Late adolescence and early adulthood are periods of intense synaptic refinement, circuit maturation, hormonal change, circadian instability, increased psychosocial stress, and, for many people, changes in sleep, diet, and substance exposure. All of these factors place substantial demands on mitochondrial metabolism and redox regulation. If mitochondrial reserve capacity is already reduced, the system may tolerate early development but become less able to adapt when neuronal circuits require more precise energy regulation. Our cerebral organoid data support the idea of an intrinsic, patient-derived cellular vulnerability, because the mitochondrial, inflammatory, and electrophysiological phenotypes emerged in vitro. However, clinical illness likely reflects the interaction between this vulnerability and developmental timing, genetic background, medications, lifestyle, immune activation, and environmental exposures.
MitoWorld: The use of therapeutics to target the inflammasome in your study sounds promising… what are the next steps for potential treatments along those lines? Are there other therapies targeting mitochondria directly that have been tried? What are the challenges to this approach?
Dr. Adreazza: The next step is replication and refinement. We need to test a larger and more clinically diverse set of patient-derived organoids, define dose-response and timing effects, and determine whether inflammasome modulation improves not only inflammatory markers, but also mitochondrial function and neuronal activity. MCC950 was useful experimentally because it is a selective NLRP3 inhibitor, but concerns about hepatotoxicity make it less straightforward as a clinical path. This is why compounds such as the bioactive flavonoid extract are interesting: they may provide broader antioxidant and anti-inflammatory effects, although their potency, active components, pharmacokinetics, safety, and ability to reach the brain need careful evaluation. Mitochondria-directed strategies have also been explored in mood disorders, including agents that influence oxidative stress, bioenergetics, and mitochondrial resilience, such as N-acetylcysteine, coenzyme Q10, creatine, and the mitochondrial effects of lithium. The challenge is that mitochondria are essential in every tissue, and bipolar disorder is biologically heterogeneous. We will need biomarkers to identify who has a mitochondria-inflammatory phenotype and to monitor target engagement.
MitoWorld: How did you become interested in the connection between mitochondria and bipolar disorder? Were you surprised to find this integral relationship?
Dr. Adreazza: My interest developed from the observation that bipolar disorder is not only a disorder of mood regulation, but also a disorder associated with systemic metabolic and inflammatory abnormalities. Over many years, studies from our group and others identified oxidative stress, altered mitochondrial enzymes, and cell-free mitochondrial DNA in blood and brain samples from individuals with bipolar disorder. Those findings made mitochondria a compelling biological link between cellular metabolism, immune activation, and neuronal function. I was not surprised that mitochondria were involved, but I was struck by how clearly the organoid model connected these domains. In the same patient-derived system, Dana El Soufi El Sabbagh and the team could observe impaired mitochondrial energetics, increased mitochondrial stress signals, heightened NLRP3 inflammasome sensitivity, and altered neuronal firing. That integration is important because it moves us beyond isolated biomarkers and toward a mechanistic framework for understanding how cellular stress may influence brain circuit function.
MitoWorld: What is next for this research?
Dr. Adreazza: The immediate priority is to expand the cohort and incorporate clinical information that may explain biological heterogeneity, such as illness stage, predominant polarity, medication exposure, metabolic status, inflammatory burden, and treatment response. We also want to improve the organoid platform by adding greater cellular complexity, including microglia and vascular-like components, because immune and metabolic signalling in the brain depends on interactions among multiple cell types. Longitudinal organoid studies will allow us to follow mitochondrial function, inflammasome activity, and neuronal excitability over developmental time. Another important direction is therapeutic screening. Patient-derived organoids can help us test whether targeting the mitochondria-inflammasome axis restores cellular homeostasis and whether responses differ among individuals. Ultimately, our goal is to integrate organoid biology with blood-based biomarkers, such as cell-free mitochondrial DNA and metabolomic profiles, to move toward more precise, mechanism-based interventions for bipolar disorder.
MitoWorld: Anything else you would like the audience to know?
Dr. Adreazza: I would like to emphasize that this work was highly collaborative. Dana El Soufi El Sabbagh, the first author, led the experimental work across iPSC culture, cerebral organoid generation, mitochondrial assays, inflammatory assays, data analysis, interpretation, and manuscript preparation. The project also depended on an international partnership with our Australian colleagues at Deakin University, IMPACT and Barwon Health, whose expertise in clinical phenotyping, patient selection, and sample preparation made the patient-derived model possible. We are deeply grateful to the individuals living with bipolar disorder, as well as the healthy control participants, who contributed samples and trusted us to use them responsibly. Their participation allows us to study disease mechanisms in a human cellular context that would otherwise be inaccessible. I hope the audience sees this study not as a final answer, but as a platform for building more biologically precise and compassionate approaches to understanding and treating bipolar disorder.
Reference:
iPSC-derived cerebral organoids reveal mitochondrial, inflammatory and neuronal vulnerabilities in bipolar disorder. El Soufi El Sabbagh, D., Kolinski Machado, A., Pappis, L., Beroncal, E. L., Ji, D., Nader, G., Ravi Chander, P., Choi, J., Duong, A., Jeong, H., Panizzutti, B., Bortolasci, C. C., Szatmari, A., Carlen, P., Hahn, M., Attisano, L., Berk, M., Walder, K., & Andreazza, A. C. (2025). Translational Psychiatry, 15, Article 303. https://doi.org/10.1038/s41398-025-03529-7
Melanoma cells release abnormal mitochondria into the extracellular compartment. This novel mitochondrial quality-control mechanism points to possible biomarkers for the disease. The results of the study were recently published in a paper in Cancer Letters and led by Francisca Alcayaga-Miranda.
Melanoma cells experience significant levels of oxidative stress. While they depend on glycolysis, they still need mitochondria for other cell functions. Other studies had shown that damaged mitochondria are expelled from a stressed cell. However, it was not known if this process occurred with melanoma cells and how it was accomplished.
The research team sought to clarify this process. Using electron microscopy, they examined mitochondria released from normal and melanoma cells from mice. All cell lines released damaged mitochondria. The differences were found in the amounts of mitochondria released and the routes. The mitochondria were released through a non-vesicular route. Furthermore, the expelled mitochondria lacked cristae and had multiple other indications of loss. Complementary analyses showed that melanoma cells do not degrade mitochondria through canonical mitophagy in conditions of oxidative stress. Instead, melanoma cells upregulate mitochondrial release to the extracellular medium. With this data, the team concluded that the melanoma cells release mitochondria as an alternative mitochondrial quality control mechanism.
Interestingly, the mitochondria expelled from the melanoma cells were detected in the tumor microenvironment and plasma of the mice. The levels of those mitochondria correlated with the tumor burden. In agreement with these findings, more total extracellular mitochondria were also detected in the circulation of melanoma patients, supporting the translational relevance of this phenomenon.
The study revealed a novel mechanism for releasing dysfunctional mitochondria. It also points to new strategies for non-invasive biomarkers and therapies.
A Statement of Significance from Dr. Alcayaga-Miranda:
This study expands the conceptual framework of mitochondrial quality control in cancer by showing that melanoma cells can externalize structurally and functionally altered mitochondria into the tumor microenvironment and circulation. Rather than being confined to intracellular degradation pathways, mitochondrial dysfunction in melanoma may generate extracellular signals that reflect tumor-associated stress, mitochondrial quality-control imbalance, tumor burden, and systemic disease progression. These findings open two important horizons: first, the development of minimally invasive biomarkers based on circulating extracellular mitochondria, and second, the need to define whether tumor-derived mitochondrial material is only a consequence of mitochondrial stress or also an active mediator of immune modulation and metastatic niche formation. Thus, this work provides a foundation for future mechanistic and translational studies aimed at understanding extracellular mitochondria as both measurable indicators and potential functional players in melanoma progression.
A Conversation with Dr. Alcayaga-Miranda:
MitoWorld. This is rich study filled with experimental detail. Can you give us an idea of what you are considering to follow up on this research?
Dr. Alcayaga-Miranda: Our next step is to determine whether extracellular mitochondria released by melanoma cells are merely a consequence of mitochondrial stress or whether they actively contribute to tumor progression. We are particularly interested in understanding how this mitochondrial material interacts with the tumor microenvironment, especially immune cells, and whether circulating extracellular mitochondria can be further developed as minimally invasive indicators of tumor burden and disease progression.
MitoWorld. It is interesting that multiple mechanisms are available to expel mitochondria. Do you have any thoughts on why these exist?
Dr. Alcayaga-Miranda: Cells likely rely on more than one mechanism to eliminate or externalize mitochondria because mitochondrial quality control is highly context-dependent. Depending on the intensity of cellular stress and the capacity of intracellular degradation pathways, damaged mitochondria may either be degraded within the cell or exported through alternative routes. In melanoma, our findings suggest that extracellular mitochondrial release may represent an additional layer of mitochondrial quality control, particularly when mitochondrial stress is sustained or canonical degradation pathways are insufficient.
MitoWorld. You indicate that melanoma release mitochondria into the bloodstream. It is amazing that so many mitochondria are circulating. Do you have any estimates of that or of how long they circulate before being completely eliminated?
Dr. Alcayaga-Miranda: At this stage, we do not yet have precise estimates of how long extracellular mitochondria remain in circulation. This is an important open question. Their persistence is likely influenced by structural integrity, association with vesicular or non-vesicular compartments, recognition by phagocytic cells, and clearance by organs involved in filtering circulating particles. Future kinetic studies will be necessary to define their half-life, clearance routes, and whether these parameters change during tumor progression.
MitoWorld. There have been other reports that mitochondria are transferred from tumor cells to normal cells, such as immune cells. Did you see any evidence of this in your studies?
Dr. Alcayaga-Miranda: In this study, we focused primarily on demonstrating that melanoma cells release dysfunctional mitochondria into the tumor microenvironment and circulation. We did not directly evaluate mitochondrial transfer to immune cells as a central endpoint. However, the detection of tumor-derived mitochondrial material in the tumor microenvironment raises the possibility that these structures may interact with stromal or immune cells. This is one of the directions we are now actively exploring, particularly in relation to how tumor-derived mitochondria may influence antitumor immune function.
MitoWorld. Do you have any plans to pursue the development of biomarkers?
Dr. Alcayaga-Miranda: Yes. One of the translational horizons of this work is to determine whether circulating extracellular mitochondria can be developed as minimally invasive biomarkers. Before clinical implementation, several steps are required, including analytical standardization, rigorous control of pre-analytical variables during blood processing, validation in larger patient cohorts, and comparison with established clinical parameters. Our current data provide a strong rationale for this direction, but biomarker development will require systematic validation.
MitoWorld. We are always interested in what sparked your interest in mitochondria. Can you tell us?
Dr. Alcayaga-Miranda: My interest in mitochondria began with the idea that they are not only intracellular powerhouses, but also dynamic signaling organelles capable of shaping cell behavior and intercellular communication. In cancer, this is particularly fascinating because tumor cells continuously adapt their metabolism under stress. Understanding how mitochondria move beyond the cell may reveal new dimensions of tumor biology and open unexpected translational opportunities.
Reference
Georges-Calderón N, Fuentes C, Hidalgo Y, Grunenwald F, Corrales-Bermúdez J, Figueroa-Valdés AI, Ramirez-Pereira M, Arriagada G, Bustos FJ, Ahumada-Marchant C, Lopez M, Alcayaga-Miranda F (2026) Melanoma cells release dysfunctional mitochondria to the tumor microenvironment and circulation in association with tumor progression. Cancer Letters 647: 218457.
https://www.sciencedirect.com/science/article/pii/S030438352600220X?via%3Dihub
Dysfunctional mitochondria are associated with serious diseases (e.g., neurodegenerative disorders, heart failure), and transplantation of healthy mitochondria to diseased cells has been suggested as a possible therapeutic strategy. Recently, a research team, led by Botond Roska, developed a system for transplanting mitochondria to specific cell types. Their MitoCatch system is an exciting advance in harnessing mitochondria in therapies. The study was published recently in a paper in Nature.
The Roska team sought to identify protein binders that would facilitate the uptake of donor mitochondria by specific target cells. They engineered a series of such binders for their MitoCatch system. Using this system, they showed that the donor mitochondria were internalized into the cytosol and that they behaved as normal mitochondria exhibiting movement, fusion, and fission. In addition, the researchers showed that the mitochondria could be targeted to specific cell types, including retinal, cardiac, endothelial, and immune cells, and neurons. Most importantly, the diseased or damaged cells receiving the donor mitochondria had improved survival and function.
In a relatively short time, mitochondrial transfer has moved from fantasy to reality. The development of MitoCatch now provides a method for targeting specific disease cell types. This exciting advancement brings mitochondrial transfer closer to a therapeutic strategy for serious disease conditions.
A Statement of Significance from Dr. Roska:
Many diseases that involve malfunctioning mitochondria currently have no effective treatment. Transplanting healthy mitochondria into diseased cells has emerged as a promising therapeutic approach, but until now, there has been no reliable way to deliver them to the right cell types in the body. We developed a system called ‘MitoCatch’ that uses protein-based targeting tools to guide healthy mitochondria directly to affected cells. In laboratory experiments with human cells and in live mice, MitoCatch-delivered mitochondria improved the survival of damaged nerve cells. MitoCatch thus offers a new strategy for treating diseases linked to mitochondrial dysfunction by delivering healthy mitochondria precisely where they are needed.
A Conversation with Dr. Roska:
MitoWorld. Your work offers lots of intriguing possibilities. Can you give us an idea of where you are going next to follow up on this paper?
Dr. Roska: We are particularly interested in understanding how long donor mitochondrial DNA can persist in recipient human cells, as this information is important for therapy development. We are also optimizing our bispecific protein binders for specific human applications.
MitoWorld. Your work also has obvious clinical possibilities. Do you plan to exploit those as well?
Dr. Roska: Yes. Our goal is to develop MitoCatch into a therapy. We are in discussions with leading physicians across different medical fields to identify which mitochondrial diseases would be the best fit for the first MitoCatch-based treatments. LHON is among the first candidates.
MitoWorld. We have been following the emergence of mitochondrial transfer for some time. Are you as amazed as we are about how quickly it has been accepted as a fact and as a potential therapy?
Dr. Roska: This is indeed a fascinating field that is moving ahead at lightning speed. There are still sceptics who question the usefulness of mitochondrial transfer as a therapy, but this is healthy in science. The best way to respond to skepticism is to demonstrate the value of mitochondrial transfer in the clinic.
MitoWorld. In the Discussion, you mention that your system, like mitochondria free in the blood, did not elicit an immune response upon transfusions. That’s an interesting observation for your work and evolution. Can you speculate on that?
Dr. Roska: The key question is what these free mitochondria in the blood are doing — whether they are functional or waste products. This is not yet known, and the answer will have important implications for therapy.
MitoWorld. Clearly, mitochondria are the focus of MitoWorld, and we also enjoy hearing what brought researchers to the study of these amazing organelles. Can you tell us how you became interested in mitochondria?
Dr. Roska: About eight years ago I was thinking about the complexities of different therapeutic modalities. Gene therapy introduces one or at most a few genes into the body and so carries very low genetic complexity. Cell therapy, on the other hand, brings all of a cell’s genes into the body and, therefore, operates at extremely high complexity. I wondered whether therapies with an intermediate level of genetic complexity were possible. This led me to think about organelles and mitochondria in particular. At the time, very few papers had been published on mitochondrial transfer, but this has since changed dramatically, and I am very happy to be part of such an exciting and fast-growing field.
Reference
Ayupov T, Moreno-Juan V, Curtoni S, Fratzl A, et al. (2026) Cell-type-targeted mitochondrial transplantation rescues cell degeneration. Nature 15:
Cancer cells need changes to metabolism to supply energy, especially during metastasis. In a recent paper in Cancer Discovery 1, a research team led by Kivanç Birsoy compared the metabolites of normal and breast cancer cells. They found that metastasis of the cancer cells relied on mitochondrial glutathione. This discovery provides insights into the process of metastasis and implicates glutathione as a potential therapeutic target for breast cancer.
The team compared the primary and metastatic breast cancer cells. This metabolomics study revealed accumulation of more mitochondrial glutathione in metastatic cells. Further analysis identified increased expression of SLC25A39. In previous work, the Birsoy group showed that this mitochondrial membrane carrier regulates glutathione transport into mitochondria.2 SLC25A39 is required for metastases, but its loss has no effect on primary tumors. Interestingly, the team found that the stress-induced transcription factor ATF4 could rescue SLC25A39-deficient metastatic cells. This observation links SLC25A39 to activation of ATF4.
This work provides new insights into the processes of metastasis. It defines a new role for glutathione beyond its well-know role antioxidant role. Finally, it suggests that glutathione, SLKC25A39, and ATF4 as possible therapeutic targets for breast cancer.
A Conversation with Dr. Kıvanç Birsov
MitoWorld: What is the next step in continuing your research?
Dr. Birsov: We’ll dissect how mitochondrial glutathione (mtGSH) is required for ATF4 activation. Specifically, we aim to identify the ISR node that senses mtGSH loss (e.g., GCN2 vs. PERK) and map the molecular steps that couple mitochondrial redox to ATF4. In parallel, we’ll define the precise stresses in the lung that drive this dependency using in vivo stress reporters and targeted perturbations. More broadly, our data suggest there are additional “hidden” metabolites that govern metastatic fitness. With our organelle-resolved metabolomics and genetic tools, we’re poised to systematically uncover these metabolites and their transport pathways.
MitoWorld: Can you speculate on the mechanism by which glutathione enhances metastasis? Do you think the effect is felt by making cells lose their connection to other cells or by helping in the actual colonization at a distant site?
Dr. Birsov: It’s a bit more complex. Sean Morrison’s elegant work has shown that glutathione is essential for tumor cell survival in circulation by buffering oxidative stress. Our findings extend this concept but emphasize that the compartmentalized functions of redox metabolites can differ. In our case, mitochondrial glutathione seems to be particularly important during the colonization phase rather than dissemination. We think its role may go beyond antioxidant defense—potentially involving redox-dependent signaling that supports metabolic adaptation and growth at the metastatic site. But this is still an open question and a major focus of our ongoing work.
MitoWorld: Lung and liver are common sites of metastases. Might this connection be generalized for other forms of metastasis or to other organs?
Dr. Birsov: The environments of metastatic sites are vastly different; each imposes unique metabolic stresses and nutrient availabilities. The lung, for instance, is highly oxidative, and the liver can be hypoxic. Because of these differences, I expect distinct metabolic mechanisms to underlie colonization in each organ. Mitochondrial glutathione may be critical in some contexts, but other metabolites and pathways likely take over in different tissues.
MitoWorld: ATF4 seems to be a two-edged sword. It is activated in stress situations, but aids metastasis. Do you have any thoughts about these strange multiple activities?
Dr. Birsov: That’s exactly what makes ATF4 so fascinating. It’s part of the integrated stress response, normally activated to restore homeostasis when cells face nutrient or redox stress. Cancer cells hijack this pathway—what’s meant to be a transient adaptation becomes chronically active, allowing them to survive and grow in hostile environments. In our system, ATF4 activation seems to compensate for the loss of mitochondrial redox balance, effectively turning a stress response into a metastatic advantage. It’s a perfect example of how tumors repurpose normal adaptive programs for malignant ends.
MitoWorld: Do you have any thoughts as to how these findings on glutathione might be translated to a therapy? Might SLC25A39 or ATF4 be a target?
Dr. Birsov: We are actively trying to find small-molecule inhibitors, and we believe this may be helpful for certain cancers. Additionally, we need to know whether there will be off target effects as well.
MitoWorld: How did you become interested in mitochondria in the first place?
Dr. Birsov: We’re fascinated by how mitochondria connect metabolism to disease and cell function. These organelles contain thousands of metabolites, and yet, we still know very little about what most of them do or how their levels are maintained. Our work on mitochondrial transporters provides an entry point to start decoding this complexity, understanding how metabolites move across membranes and how these movements shape cellular behavior.
References
1 Yeh HW, DelGaudio NL, Uygur B, Millet A, Khan A, Unlu G, Xiao M, Timson RC, Li C, Ozcan K, Smith KW, Nascentes Melo LM, Allies G, Basturk O, Sickmann A, Byraktar EC, Possemato R, Tasdogan A, Birsov K (2025) Mitochondrial glutathione import enables breast cancer metastasis via integrated stress response signaling. Cancer Discovery 15: 2437–2449.
doi: 10.1158/2159-8290.CD-24-1556.
2 Wang Y, Yen FS, Zhu XG, et al. (2021) SLC25A39 is necessary for mitochondrial glutathione import in mammalian cells. Nature 599: 136–140.
A multi-institute research team led by Kelsey H. Fisher-Wellman describes a unique mechanism in mitochondria that might be a therapeutic target in patients with acute myeloid leukemia (AML). The paper was published in Science Advances.
Cancers are thought to need large amounts of energy, and thus, oxidative phosphorylation is a tempting target for cancer therapies. Unfortunately, the attempts to find therapies that could differentiate between healthy and diseased mitochondria have met with limited success. For example, the FDA approved cancer therapy, venetoclax, which inhibits BCL-2 and mediates BAX/BAK-dependent apoptosis, has limited effectiveness due to the development of chemoresistance. Mitochondrial polarization of resistant AML cells is unaffected.
The group led by Dr. Fisher-Wellman noted that AML mitochondria have an action that differs from healthy blood cells. Healthy cells connect ATP synthesis to respiration. However, AML cells maintain inner membrane polarization by consuming ATP. The researchers wondered if the AML cells used this reversal of the ATP synthase reaction to resist chemotherapy. They set out to test this possibility. They discovered a central role for ATP51F1, an F1-ATPase inhibitor. Overexpression of this enzyme heightened sensitivity to venetoclax, and its knockdown venetoclax resistance.
These findings further our understanding of the bioenergetics of AML cells and the relationship between oxidative phosphorylation and AML. This work is especially important since AML relapses have such a dire prognosis. Importantly, they implicate matrix ATP consumption as a potential cancer cell-specific target for inhibiting the development of chemoresistance in AML.
Statement of Significance from Dr. Fisher-Wellman
In AML cell lines and primary patient samples, we discovered that leukemic mitochondria are deficient in their ability to sustain mitochondrial membrane potential through respiratory flux. Maintenance of membrane potential is essential for cell survival. To compensate, AML cells engage a non-canonical—and possibly evolutionarily ancient—bioenergetic strategy: they reverse the ATP synthase enzyme. Rather than using membrane potential to drive ATP production, AML cells hydrolyze ATP to sustain mitochondrial polarization. This distinction is profound. Normal cells do not typically rely on ATP synthase reversal to maintain membrane potential. As a result, this AML-specific mitochondrial wiring represents a near-ideal cancer-selective vulnerability. Importantly, this pathway is most active in drug-resistant AML populations—the very cells responsible for relapse and treatment failure.
Conversation with Dr. Fisher-Wellman:
MitoWorld: Can you give us some idea of how you intend to further advance the results of the current work?
Fisher-Wellman: Most cancer therapies are built around exploiting a dependency or vulnerability that is unique to malignant cells. Our work demonstrates that AML cells maintain mitochondrial membrane potential through a mechanism that is distinct from most normal tissues. We believe this cancer-specific difference represents a therapeutically actionable vulnerability.
MitoWorld: It is interesting that the AML mitochondria have this particular weakness. Do you have any speculation on why it is? Is it possible that other cancers might share this?
Fisher-Wellman: Sustaining mitochondrial membrane potential through ATP hydrolysis is generally viewed as a hallmark of bioenergetic ‘sickness’, typically observed in stressed or damaged cells as a survival mechanism. Our data, together with emerging evidence from the field, indicate that AML mitochondria exist in a persistently ‘sick’ state. Importantly, this bioenergetic liability represents a vulnerability that may be selectively exploited for therapeutic benefit.
MitoWorld: Do you have any plans to pursue the development of the potential clinical relevance of your discovery?
Fisher-Wellman: We are actively translating this discovery into mitochondria-targeted therapeutic strategies that exploit the distinct mechanisms by which AML cells maintain mitochondrial membrane potential.
MitoWorld: Mitochondria seem to be implicated in many diseases. Part of the reason is clearly its fundamental activity in energy production. However, they have assumed key roles in many other cellular functions. As a mitochondria researcher, are you as fascinated by these observations as we are?
Fisher-Wellman: That is an unequivocal yes. My entire research career has been focused on understanding how alterations in this organelle cause and contribute to some of humanity’s most formidable diseases.
MitoWorld: How did you come to be interested in mitochondria? Was it the energy requirements of cancers that connected you to the energy source?
Fisher-Wellman: I have studied mitochondria throughout my entire career and developed a deep appreciation for the remarkable heterogeneity that exists within this organelle across the body’s cells. It was this diversity that ultimately drew me to cancer, where I recognized that vast unexplored biology remained to be discovered.
Reference
Hagen JT, Montgomery MM, Aruleba RT, Chrest BR, Krassovskaia P, Green TD, Pacheco EA, Kassai M, Zeczycki TN, Schmidt CA, Bhowmick D, Tan S-F, Feith DJ, Chalfant CE, Loughran Jr. TP, Liles D, Minden MD, Schimmer AD, Shakil S, McBride MJ, Cabot MC, McClung JM, Fisher-Wellman KH (2025) Acute myeloid leukemia mitochondria hydrolyze ATP to support oxidative metabolism and resist chemotherapy. Science Advances 11(15): eadu5511.
https://www.science.org/doi/full/10.1126/sciadv.adu5511
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