A paper in Nature Cancer by a multi-institute research team, led by Michael Cangkrama and Sabine Werner at the ETH Zurich, describes how cancer cells use the transfer of mitochondria to highjack fibroblasts to support the cancer. The study also implicates a protein as critical for the transfer that may be useful in novel therapeutic strategies.
The transfer of mitochondria from various cell types into cancer cells has been reported to enhance cancer cell proliferation, motility and more. Fibroblasts associated with tumors are known to adopt certain characteristics, and they frequently support cancer development. The Cangkrama-Werner team sought to determine if the transfer of mitochondria might work in the opposite direction. In other words, do cancer cells transfer mitochondria to the fibroblasts?
To answer this question, the team examined cancer cells and fibroblasts in co-cultures and xenograft tumors. Intriguingly, mitochondria were transferred to the fibroblasts where they caused changes in the metabolism of the recipient cells. The fibroblasts began to express markers associated with cancer-associated fibroblasts and to release secreted soluble and extracellular matrix proteins that support tumor growth. The team also found that the transfer of mitochondria depends on the mitochondrial trafficking protein MIRO2. Without MIRO2, the transfer and the other changes failed. These findings are consistent with the overexpression of MIRO2 at the leading edge of epithelial skin cancers and other malignancies. Finally, they found that the mitochondria are transferred through thin membranous structures called tunneling nanotubes.
This study demonstrates that mitochondrial transfer from cancer cells to fibroblasts is a key regulator of CAF differentiation. The findings also implicate MIRO2 and mitochondrial transfer as potential targets for strategies to treat cancers.
A conversation with Drs. Cangkrama and Werner
MitoWorld: Can you give us an idea of what studies you might do to advance the findings presented here?
Werner: There are several open issues, including the signals that induce the transfer, the genes and proteins that promote the transfer and the targets of the transferred mitochondria, which induce the pro-tumorigenic phenotype in fibroblasts.
MitoWorld: You showed that oxidative phosphorylation is the main activity that is influenced by the mitochondrial transfers. Can you speculate on how that process translates into the changes in gene expression in the fibroblasts? Might there be other mitochondrial activities involved in activating the interferon-response genes?
Werner: Oxidative phosphorylation is highly relevant in this context, but it is probably not the only relevant factor. Oxidative phosphorylation results in the production of various metabolites, which are likely to regulate transcription factors that control gene expression in fibroblasts. We found that the interferon-response genes are not regulated by transferred mitochondria, but likely by transfer of other molecules from cancer cells to fibroblasts in co-cultures, which remain to be identified.
MitoWorld: The transfer of mitochondria from cell to cell has been somewhat controversial. Can you comment on the seeming reluctance of some researchers to embrace this concept?
Werner: Many results were obtained with MitoTracker, which is known to be leaky. Several studies did not include appropriate controls to address this problem, which might have contributed to skepticism about mitochondrial transfer. The concept was also unexpected when first proposed. Even when transfer occurs, it is difficult to predict and appears to depend on specific conditions, such as cellular stress or high metabolic demand, further fueling doubts about its physiological relevance. However, many exciting and well-controlled studies have recently been published, which show the relevance of mitochondrial transfer under various conditions. This makes mitochondrial transfer a promising area of research, with the potential to uncover new mechanisms of intercellular communication and to develop innovative therapeutic strategies.
MitoWorld: Can you speculate how your findings might translate to therapies for cancer?
Werner: There is a long way from this discovery to a cancer drug. Nevertheless, our work suggests that inhibition of mitochondrial transfer (e.g., by blocking MIRO2 or other proteins important for the transfer) could be a novel approach for cancer treatment. In addition, identification of the relevant targets of the mitochondrial transfer in recipient fibroblasts could provide new therapeutic opportunities.
MitoWorld: How did you first become interested in mitochondria?
Werner: Several previous studies of our laboratory revealed the important role of mitochondria in the pro-tumorigenic cancer-associated fibroblast phenotype. This raised our interest in these exciting organelles.
Reference
Cangkrama M, Liu H, Wu X, Yates J, Whipman J, Gäbelein CG, Matsushita M, Ferrarese L, Sander S, Castro-Giner F, Asawa S, Sznurkowska MK, Kopf M, Dengjel J, Boeva V, Aceto N, Vorholt JA, Werner S (2025) MIRO2-mediated mitochondrial transfer from cancer cells induces cancer-associated fibroblast differentiation. Nature Cancer 6: 1714–1733.
Recently, a multi-institute team led by Thomas Langer, PhD, at the Max-Planck-Institute for Biology of Ageing examined the effects on ribonucleotide incorporation into mitochondrial (mt)DNA on inflammation. Published in Nature, the study found that increased incorporation of ribonucleotides into mtDNA during replication resulted in the release of mtDNA fragments into the cytosol and an increase in inflammation.
Mitochondria are now recognized as far more than just producers of ATP. They have many critical activities, and disruption of those functions is associated with inflammation, cell death, and disease. Dr. Langer´s team previously showed that disturbances in the nucleotide metabolism result in the release of mtDNA into the cytosol and, like pathogenic DNA, the mtDNA elicits an inflammatory response by the cell. Now they found that this is caused by an increased incorporation of ribonucleotides into mtDNA. The incorporation of ribonucleotides is a problem for mitochondria because they lack the enzyme that removes those molecules from DNA.
More specifically, they looked at mice that lacked MGME1, a mitochondrial exonuclease that maintains mtDNA, and observed increased ribonucleotide incorporation into mtDNA. Similarly, cells lacking the mitochondrial protease YME1L or senescent cells that have decreased deoxynucleotide levels accumulate ribonucleotides in their mtDNA. As a result, mtDNA leaks into the cytosol, and induces an inflammatory senescence-associated secretory phenotype, which can be reduced by adding deoxyribonucleosides.
Based on these findings, they conclude that throwing nucleotide metabolism out of balance leads to incorporation of ribonucleotides into mtDNA and age- and mtDNA-dependent inflammatory responses and SASP in senescence. The study results provide clues to several diseases, such as renal failure, systemic lupus erythematosus, cancers, and neurodegenerative diseases
A Conversation with Dr. Langer
MitoWorld: What are the likely next steps to continue this research?
Langer: This work can be taken in many different directions. Since we observe the incorporation of ribonucleotides into mtDNA in aged tissues and in senescent cells, it will be of interest to better understand the relevance of this phenomenon for the increased chronic inflammation with age. Which cells are predominantly affected and vulnerable to metabolic disturbances inducing mtDNA-dependent inflammation? From a mechanistic angle, we would like to understand better how replication stress ultimately lead to the release of mtDNA into the cytosol.
MitoWorld: Detection of double-stranded DNAs in the cytosol is a key feature of the innate immune system, but the leaking mtDNA fragments in senescent cells seems to be an “oversight” of evolution. Is this another example of the problems we face with living longer now?
Langer: The accumulation of ribonucleotides in mtDNA in aged tissues may indeed suggest that this problem worsens with age and, in this sense, it may contribute to problems associated with long life. However, we should keep in mind that mtDNA-driven inflammation is not necessarily always bad, as it was shown previously in models for mitochondrial disease that low rates of mtDNA release can prime cells and tissues to better respond to viral inflammation.
MitoWorld: Your finding that mtDNA fragments accumulate in senescent cells is intriguing, especially given that so many diseases of aging (especially neurodegenerative disease) feature inflammation. Could you expand on that idea?
Langer: A cell-cycle arrest and inhibition of nuclear DNA replication is a hallmark of senescent cells that therefore reduce the synthesis of deoxynucleotides, the building blocks of DNA. However, mtDNA replication still occurs in senescent cells (i.e., in the presence of low deoxynucleotide levels). This leads to increased ribonucleotide incorporation into mtDNA and inflammatory SASP. Indeed, this response is detrimental in many diseases settings, stimulating intense efforts to identify senolytics to selectively remove senescent cells from tissues. Our findings suggest that rebalancing the nucleotide metabolism helps to suppress the SASP, which therefore might represent an alternative approach for the treatment of at least some aging associated diseases.
MitoWorld: Can you speculate on how your findings might be translated into potential treatments beyond simply treating the inflammation?
Langer: Although it remains speculative at this point, it is an attractive possibility to use deoxynucleoside therapy to restore the nucleotide balance and to alleviate inflammation in autoimmune diseases or in ageing. Just recently, the FDA has approved a nucleoside therapy for thymidine kinase 2 deficiency, a rare mitochondrial disorder affecting children.
MitoWorld: How did you come to be interested in mitochondria in the first place?
Langer: Mitochondria are in many ways fascinating organelles. They are dynamic and very heterogeneous in different cells and tissues, reflecting their diverse functions. I originally studied protein folding and turnover in bacteria and then got interested in mitochondrial proteins and only realized with time that these processes often drive adaptative responses of mitochondria that are so important to understand their role in aging and disease. The fascination never stops!
Reference
Bahat A, Milenkovic D, Cors E, Barnett M, Niftullayev S, Katsalifis A, Schwill M, Kirschner P, MacVicar T, Giavalisco P, Jenninger L, Clausen AR, Paupe V, Prudent J, Larsson N-J, Rogg M, Schell C, Muylaert O, Larsson E, Nolte H, Falkenberg M, Langer L (2025) Ribonucleotide incorporation into mitochondrial DNA drives inflammation. Nature 24: 1-9.
Unlike the nuclear genome, which contains genes from both parents, the mitochondrial genome is inherited only from the mother. This presents a problem since mitochondrial DNA (mtDNA) is prone to mutations that can accumulate over generations and threaten species survival. To avoid this, two still poorly understood mechanisms have been selected for in evolution to counteract the accumulation of harmful mtDNA mutations: the bottleneck, whereby only a small number of mtDNA molecules is passed on to the next generation and purifying selection, a mechanism that prevents mtDNA molecules with severe mutations from being transmitted.
A recent study published in Science Advances sought to better understand how these two mechanisms cooperate to ensure healthy mitochondria in offspring. The research was led by Professor Nils-Göran Larsson, MD, PhD, and performed at the Department of Medical Biochemistry and Biophysics at Karolinska Institutet, Sweden. Dr Laura Kremer, first author of the study is currently an independent researcher at University of Göttingen and was conducting the research as a postdoc at Karolinska Institutet.
To explore the role of the bottleneck and purifying selection in the transmission of mutant mtDNA, the team produced mouse models with random mtDNA mutations along with alleles that modulated mtDNA levels or decreased autophagy.
They found that tightening the bottleneck, by decreasing the amount of mtDNA in the mother, resulted in greater variability in the levels of mtDNA mutations between individuals but reduced the overall mutational burden. Vice versa, decreasing autophagy weakened the selection, allowing more mutant mtDNA molecules to be passed on to the offspring leading to an increased mutation burden.
This study yielded novel insight by showing that the two mechanisms directly interact. Learning how cells protect the mitochondrial genome is valuable not only from an evolutionary perspective but also has medical relevance. Mutations in mtDNA are associated with many human diseases, including mitochondrial disorders, cancer, neurodegeneration, and ageing.
A conversation with Dr. Larsson
MitoWorld: You have a prolific laboratory, and this paper represents a great deal of work. Perhaps the work in this paper has progressed since its publication. Could you summarize the direction of any newer work?
Larsson: Since the publication, one direction we have undertaken involves the development of new mouse models that allows us to track different type of mtDNA variants and understand whether there are differences in the selective mechanisms that limit their transmission.
MitoWorld: At first glance, a reader might assume that increasing heteroplasmy would lead to more mtDNA mutations being transmitted. Can you simplify that concept?
Larsson: It may seem intuitive that higher levels of mutant mtDNA would facilitate mutation transmission, but our study shows that purifying selection is more efficient if mutation levels increase. A tighter bottleneck increases the heteroplasmy variance between individuals, but it also allows selection to act more efficiently. In other words, harmful variants can be identified and purged more effectively when individual mutations are present at higher levels.
MitoWorld: Can you expand on what triggers autophagy? It’s interesting that the one protein Bcl2l13 attaches mitochondria with a high HF ratio to the autophagosome.
Larsson: Autophagy is triggered by several cellular stress signals, nutrient limitation, energy imbalance, or structural damage to the organelles. In the germline, we think the process is tuned specifically to identify dysfunctional mitochondria. Bcl2l13 appears to act as a recognition factor, marking mitochondria with a high proportion of mutant genomes for degradation. This selective role is still only partly understood, but it suggests a remarkable level of specificity during mtDNA transmission.
MitoWorld: The conservation of aspects of these mechanisms across most metazoa is interesting. Most eukaryotes feature maternal inheritance of mitochondria. These mechanisms must have evolved very early in evolution. Any speculation?
Larsson: Yes, these systems likely arose very early. Once organisms started relying on oxidative phosphorylation, mutations in the mitochondrial genome became a genuine threat to fitness. Mechanisms such as bottlenecks and selective degradation would have been strongly favored by evolution. Their conservation suggests they were effective solutions and have remained largely unchanged across hundreds of millions of years.
MitoWorld: Your extensive work on mitochondria has covered many topics, including cancer, inflammation, obesity, and much more. Is the central role of mitochondria in all these areas a function of energy production or are there other activities involved?
Larsson: Energy production is certainly fundamental, but mitochondria do far more. They influence signaling pathways, metabolite synthesis, innate immunity, and cell death. Their dysfunction sends ripple effects through many biological systems, so it is not surprising that mitochondrial defects appear across diverse diseases. Understanding mtDNA inheritance is one aspect of a much broader picture of mitochondrial biology.
MitoWorld: Can you imagine how your findings might be translated into clinical treatments? Will your lab be following up on that possibility?
Larsson: We are cautious about translating findings prematurely, but the work does suggest conceptual avenues. If we can identify the key factors that guide purifying selection, it may eventually be possible to enhance this process in patients carrying pathogenic mtDNA variants. Our immediate focus remains on basic mechanisms, but we collaborate closely with clinical groups, and we certainly see therapeutic potential in the long term.
MitoWorld: In you brief bio on the MitoWorld website, you stated that you became interested in mitochondrial DNA in diseases during your PhD training. Since then, you have contributed significantly to the understanding of mitochondria. Could you comment on your thoughts on these organelles today?
Larsson: My appreciation for mitochondria has only deepened over the years. They are extraordinarily dynamic organelles, genetically, metabolically, and evolutionarily. What continues to inspire me is how much remains unknown. Every time we think we understand a pathway, we find additional complexity. That curiosity is what keeps our field vibrant, and I believe mitochondria will continue to surprise us for many years to come.
Reference
Kremer LS, Golder Z, Barton-Owen T, Papadea P, Koolmeister C, Chinnery PF, Larsson NG (2025) The bottleneck for maternal transmission of mtDNA is linked to purifying selection by autophagy. Science Advances 11(46): eaea4660.
The energy resistance principle (ERP) describes behavior and transformation of energy in the carbon-based circuitry of biology. We show how energy resistance (éR) is the fundamental property that enables transformation, converting into useful work the unformed energy potential of food-derived electrons fluxing toward oxygen. (Picard, Murugan)
In a recent Perspective published in Cell Metabolism, Drs. Martin Picard and Nirosha Murugan offer a new perspective about the nature of living systems that amounts to a powerful tool for life scientists to orient themselves amidst the seemingly infinite convolutions of biology. They call it the energy resistance principle (ERP), and, bearing a tantalizing resemblance to Einstein’s mass-energy equation, it states that EP = éR⋅f2, where EP is energy potential, éR is energy resistance, and f is electron flux.
The deep insight of the ERP derives from its recognition that living systems, from the scale of organisms to organelles, are analogous to electrical circuits. In the same way that the Power law (P = R⋅I2) captures how current flowing through resistive elements converts electrical energy into heat or mechanical work, the ERP contends that the energy behavior of living systems ultimately comes down to the flux of electrons from food to oxygen. In its path, the flow of electrons meets resistance through the myriad mechanisms of the body itself, with its cells and organs, continuously perfused by a vast and undulating network of blood vessels, driving countless enzymatic activities across layers upon layers of membranes to maintain homeostasis.
Indeed, from the perspective of the ERP, we can chart the movement of electrons across the body as a simple electrical flow diagram, where the organism and its metabolism behaves like an integrated electrical circuit. Derived from photosynthesis, the food we eat carries electrons into our bodies as we ingest it; and these electrons are ultimately attracted by the electronegative force of molecular oxygen, held in place by respiratory complex IV embedded within the folds of the inner mitochondrial membrane (IMM).
Importantly, the electrons stored in carbohydrates, fats, and proteins, have a long journey from the mouth to the mitochondrion. Our teeth and a host of enzymes along the gastrointestinal tract break down these macromolecules into individual carbohydrates, fatty acids, and amino acids enabling their selective transport across the walls of the intestines and conveying them into the circulatory system to be dispersed to the trillions of cells that depend on them. After arriving at the plasma membrane of a cell, however, a glucose molecule, for example, still must pass through one of a number of GLUT transporters and be shuttled through glycolysis where it is converted into pyruvate, before being imported into the mitochondrial matrix. In the matrix, pyruvate’s electrons are moved along the citric acid cycle and carried by NADH to the electron transport chain, which pumps hydrogen ions across the IMM, forming a proton motive force, which, in turn, is consumed by the ATP synthase to generate the molecular energy carrier, ATP. Step by step, as electrons get closer and closer to molecular oxygen in mitochondria, they encounter energy resistance (éR) that enables energy transformation (e.g., chemical to electrical). It is important to note that if there were no resistance there would be no transformation. Ultimately, this incremental resistance to the flux of electrons is harnessed to perform work of all different kinds, which sustains life from moment to moment.
Picard and Murugan argue that what we call health and disease is best understood through the lens of the ERP, where either too much or too little energy resistance is incompatible with life. Molecular theories of biology, health, and disease are appropriate to address some important questions, like designing an antibiotic against the molecular feature of a bacterial ribosome. But molecular theories have yet to yield the hoped-for insights into complex health/disease dynamics in humans.
Whether the ERP turns out to be true depends on whether it can be falsified: i.e., can it be rigorously put to the test? Intriguingly, as the authors note, we are already aware of the results of a key experiment: What happens to a living system if the flux of electrons (i.e., f) is blocked by cyanide, the respiratory chain poison that interferes with the binding of oxygen to complex IV? According to the formulation éR = EP/f2, the electron flux would approach zero, sending the energy resistance to infinity, which is another way of saying that the organism would die. Conversely, if the system contained a superabundance of mitochondria, possessing, theoretically, an unlimited capacity for electron flux, the energy resistance would go to zero, precluding the ability to perform useful work. These situations emphasize an important aspect of the ERP—namely, that in the flux of electrons from food to oxygen, there is a sort of goldilocks zone of energy resistance according to which the organism will approach optimal health; and, critically, the symptoms of disease are tantamount to deviations from this favorable zone.
In the final analysis, the ERP represents a durable framework according to which biologists can bring everything back to the bioenergetic girders of complex physiological processes. What’s more, the authors invite life scientists to put their formulation to the test. While they recognize that it may require further elaboration, the ERP promises, at the very least, to serve as a useful scaffold for understanding how living systems operate, because, at its core, it emphasizes that there is no life, and therefore, no health, without the continuous flux and transformation of energy.
MitoWorld: It is far from routine for biologists to endeavor to formulate general principles of life. What compelled you to look for basic biological trends that could be boiled down into an equation?
Picard and Murugan: We were motivated to address a central gap in biology. Biomolecular descriptions tell us what the components are, but they do not explain how living systems coordinate energy flow in time and space or why physiology and behaviors obey energy constraints that molecular biology alone cannot account for. Empirical work across mitochondrial biology and whole-body energetics shows principled relations among energy potential, electron flux, metabolic demands, and stress responses, pointing to an underlying energetic basis shaping how organisms function.
So our aim was to address this missing link by building a quantitative framework that connects energy flow to the behavior of living systems, grounded in the same physical constraints that govern how energy moves and transforms in other, simpler domains of physics. The Energy Resistance Principle (ERP) emerged as a physics-inspired heuristic to formalize these empirical patterns—mostly from the physics of electricity and the Power Law. Expressing the relation among energy potential, flux, and resistance created by biological structures provides a simple way to understand and describe how organisms regulate energy transformation and how this regulation shifts across health, aging, and disease. We don’t propose the ERP as a universal law, but as a biophysical scaffold that bridges biology and energetic principles to interpret data and generate questions about how organisms transform energy across scales.
MitoWorld: The presentation of this principle focuses on the role of oxygen in the mitochondrial electron transport chain as the ultimate sink for the flux of electrons. How can this principle apply to rare eukaryotes that have lost their mitochondria or to archaeal or bacterial life forms that do not make use of oxygen?
Picard and Murugan: When systems are alive, electrons must move from donor to acceptor, like in an electrical circuit. Energy must flow. This flux is the defining signature of life. The ERP is not restricted to oxygen-based respiration but to the more general process of energy transformation through boundary conditions that create resistance. Oxygen happens to be the terminal electron acceptor in most eukaryotes, but the same logic applies to any system in which energy flows through gradients and encounters resistive constraints. In anaerobic bacteria and archaea, other molecules such as sulfur, nitrate, or carbon dioxide serve as electron sinks, and the resulting redox cascades similarly generate transformation through energy resistance.
In rare eukaryotes that have lost mitochondria, alternative metabolic circuits still regulate electron flow through non-oxygen redox systems. Cytosolic and organellar enzymes enable electron transfer to other acceptors, preserving the gradients required for energy transformation and information processing. These reactions maintain a measurable resistance to electron flow, allowing energy to be converted into chemical work that sustains metabolism and repair. What matters is not necessarily the particular molecules involved, but the physical principle that a finite resistance to energy flow is required for transformation. This boundary or constraint, which is where that energy meets resistance is transformed, marks the distinction between life and non-life.
The ERP therefore emphasizes the physics of energy transformation rather than the species-specific biochemistry of that enables and subserves energy transformation.
MitoWorld: If you had unlimited resources and time, how would you test the ERP empirically?
Picard and Murugan: One key element of the ERP that appears critical is the oscillation, or regular shift between low and high energy resistance states. For example, states of high activity, followed by states of relaxation. That’s how neurons work—firing, then relaxing (refractory period). That’s also how the heart works—systole, then diastole. Cell division also goes through similar phases of the cycle.
In humans, at the scale of the whole body, we see this phenomenon manifest in the sleep-wake cycle. We’d love to know if energy resistance at the whole-body level fluctuates between high éR during wakefulness, and low éR during sleep. We know that a number of things that contribute to energy potential decrease during sleep—muscles stop contracting for example, heart rate decreases, cortisol is at its lowest. This is predicted to decrease energy potential. And if EP drops, flux should also decrease—which is what happens. We’d love to run 24-hour studies where we can monitor whole-body physiology and blood biomarkers (metabolites, proteins) in parallel with sleep stages, to ask what happens with éR when we sleep and the body enters the state of repair and restoration. Good evidence shows significant energetic shifts also during states achieved with meditation and mindfulness—do these things have positive health effects because they reduce éR? With unlimited resources, we’d measure this in at least a hundred people, on multiple day-night cycles to see how stable these patterns are. We’d also use non-invasive methods like magnetic resonance, biophotons, and bioelectricity to tap into the systems’ integrated energetic state.
MitoWorld: The ERP resembles the Power law. What distinguishes it from a nonliving electrical system involving power (P), current (I2), and resistance (R)?
Picard and Murugan: Nonliving electrical systems are closed circuits built from fixed components. These systems do not sense or respond to the energy moving through them. They simply dissipate or convert energy according to their material properties. Because nothing inside the circuit adapts, its resistance, current, and power are fully determined by the hardware and remain static unless the circuit is deliberately altered from the outside.
Living systems, like our bodies, operate very differently. They are open systems that take in energy and matter and rely on energy transformation to sustain their existence and go against entropy. In animals, internal resistance is continuously reshaped by physiological processes. Cells, membranes, enzymes, and mitochondria actively adjust their resistance as nutrient supply, oxygen availability, hormonal signals, and metabolic demands shift. Blood vessels dilate or constrict, mitochondrial content changes with training or stress, and whole-body physiology reallocates energy across organs depending on need. Our subjective experiences and behaviors, too, we suspect, reflect éR. These adaptive networks allow energy flow to be redistributed and transformed in real time to maintain function, support recovery, and prevent damage. The ERP leverages the relationships within the Power law to this physiological setting by framing resistance as a variable that organisms generate and tune to sustain life.
MitoWorld: The modern world is beset by a range of metabolic diseases, from diabetes mellitus to cancer. How can the ERP shed light on the nature of these disorders and provide insights into how to mitigate them?
Picard and Murugan: Simply put, we can understand diseases as energy sinks. Diseases arise when the system’s components can’t perform their normal functions optimally. This diverts resources—energetic resources, towards the dysfunctional component in an attempt to mend, repair, or restore function. That’s the healing process—an energy-demanding, dynamic process. When analyzed molecularly, through transcriptomics, for example, almost all diseases feature an upregulation of various genes. The system is struggling and mobilizing pathways, enzymes, components to cope. But nothing is free in biology. Resolving a disease requires additional work being done. Genes expressed. More blood flow. Cytokines. And all sorts of things that we think contribute to raise the energy potential (EP) of the system. If the system can increase flux to match the demand, éR doesn’t creep up too much. But if flux is limited by evolutionary-driven physiological and biological constraints, then diseases should chronically elevate éR. We think that’s why diseases accelerate damage accumulation and biological aging.
Seen through the lens of the ERP, diseases localized or systemic elevations in éR. And healing is the set of processes that aim to restore éR back to normal.
MitoWorld: Conversely, more and more people are taking an active interest in optimizing their health. How can appreciating the ERP help people achieve their health goals?
Picard and Murugan: Appreciating the relationship between the flow of energy and resistance through the ERP allows us to think about health in a more integrated and actionable way. Instead of focusing on isolated organs or single biomarkers, the ERP reframes our perspective towards how energy moves through the body and how that flow is shaped by daily behaviors. Every experience that changes metabolic demand, circulation, mental states, or mitochondrial activity influences the resistance that energy encounters as it flows through our body. When resistance is persistently too high, in states of disease for example, we think that feels like fatigue—that would be why fatigue is the most universal, cross-diagnostic marker of any disease.
Beyond what’s described in the initial ERP paper, we suspect that health emerges from maintaining a dynamic éR balance. Not staying in a constant low resistance state but moving within a goldilocks zone or high and low resistance. Like the firing-resting neuron, the contracting-relaxing heart, and the waking-sleeping body. Seeing the body as an energetic process helps explain why simple behaviors matter. Why we need to sleep (period of low éR). And why eating all the time and never feeling hungry is damaging to our health—overeating increases éR, while fasting likely decreases éR.
When we start to see the body as an integrated network that uses energy flow as information, it also becomes easier to connect the biochemical and physiological layers. Molecules and pathways are snapshots of a deeper, dynamic energetic process. Social connection, meaningful interaction with the environment, the types of food we eat, and states of calm or stress all influence these biochemical signatures because they change how energy moves.
Finally, this energetic perspective codified as the ERP helps make sense of emerging therapeutic tools that work through non-chemical modalities. Light, magnetic fields, electrical stimulation, breath work, temperature, and other energetic interventions could work by shifting resistance to energy flow in quantifiable ways that are harder to make sense of molecularly. For example, near-infrared light therapy could act directly on the mitochondrial electron transport chain to facilitate electron flow—thus, decreasing the system’s éR. Because éR propagates through our biological circuitry (as redox balance and other intermediates) such a change in éR would be expected to influence metabolism at every step of the way from cellular energy metabolism to blood glucose, as a recent study suggested. All of which could happen without a single molecularly tractable alteration or change in gene expression.
Thinking in terms of energy and resistance provides a common language for linking diverse inputs ranging from the biochemistry of food, macronutrients, and light to physiology, health, and disease states.
MitoWorld: Life inevitably requires energy to survive and replicate. Can the ERP help us to understand the origin of life on Earth?
Picard and Murugan: Big question! It is unlikely that the ERP can directly explain the origin of life on Earth, we should be cautious about making that leap. But what it can offer is a way to articulate the energetic conditions that must be satisfied for any system to transition from non-living chemistry to organized, self-regulating processes.
All matter contains energy, but what differentiates living systems is their capacity to transform that energy in a controlled manner. All matter holds energy. Matter, in a way, is raw energy crystallized or brough into stillness, in material form. But living systems are defined by their ability to transform that energy into work, structure, and information. What the ERP says is that this transformation is only possible when energy encounters the right biophysical constraints. It must meet a boundary, a surface, or a substrate that shapes its flow and allows the stored potential to become something functional/useful.
Seen from this angle, the emergence of life becomes a question about where early Earth provided the right kinds of energetic gradients and the right kinds of constraints. Environments such as mineral interfaces, hydrothermal vents, and redox-rich surfaces could have supplied both the right energy potential and the resistive structures needed for primitive transformations. While the ERP does not claim to describe this origin, it highlights the importance of temporal and spatial dynamics that are often underemphasized in purely molecular explanations for life’s origin. The way energy moves, is constrained, and transformed across different materials may have created the conditions for simple chemical systems to create information (i.e., patterned energy), encode that information in relatively stable forms (Schrödinger’s “aperiodic crystal,” DNA), grow increasing complexity, and become what we now recognize as life.
MitoWorld: In the same way that Einstein’s mass-energy equation appears to be universal, do you expect that the ERP will be applicable to life that may have arisen and evolved on other worlds?
Picard and Murugan: The ERP is not presented as a universal law, and we do not assume it would apply to life that evolved under very different physical or chemical conditions. Whether life elsewhere would follow the same relationships is unknown because we do not know how the energetics of another environment would shape the constraints that give rise to resistance. Resistance is not a fixed quantity. It emerges from the particular substrates, structures, and boundary conditions available to a given form of life. If the chemistry, temperature, or energy sources of another world were fundamentally different, the pattern of constraints, and therefore the nature of resistance, could also be different.
What does seem fundamental is that for energy to be put to meaningful work, it must be transformed, and transformation requires resistance of some kind. Energy flowing without constraint cannot build structure or sustain function. Think of a photon beaming in outer space, never hitting anything, without any possibility of slowing down—no transformation possible. It is the interaction between energy potential and the resistance imposed by matter that creates the possibility for work, organization, and information. The ERP is one attempt to formalize this relationship for carbon-based, living systems on Earth.
What the ERP does provide is a framework that encourages us to look for measurable links between energy potential, flux, and the constraints imposed by biological structure. If we want to build a truly universal energetic principle for life, we will need to approach it in this way—not just molecularly, but energetically. By identifying patterns, defining their boundaries, and designing experiments that test them. It will take time, more data, and likely several iterations.
Perhaps one day we may arrive at a formulation that is broadly universal, but getting there requires first learning how to describe life energetically and recognizing the kinds of relationships that matter.
MitoWorld: Energy and information are both fundamental to life. Insofar as they are distinct parameters, which do you view as more fundamental to biology?
Picard and Murugan: In our view, energy and information are deeply interdependent in biology. Energy flow creates the conditions that allow living systems to sense, interpret, and respond to their environment. Information is the pattern that emerges from those energetic processes.
When cells adjust their resistance to energy flow, they are not only regulating metabolism but also encoding something about their internal state and the demands placed on them. This gets encoded temporarily as metabolite concentrations, which reflects information (an energy pattern) at a given point in time. If this pattern persists, and the metabolite concentration remains a certain way, that’s meaningful information the (epi)genome has evolved to respond to. So you get changes in gene expression. That’s yet another way to encode information, by changing the levels of mRNAs. Which then become proteins, an even stabler later of information encoding. If you keep going down that path, you get to organelles, cells, and whole organisms. That’s growth, development, and healing—the encoding of information, fundamentally energy patterns, in physical forms. In a way, growth and development are the accretion of matter, shaped by éR that patterns energy into self-enduring biological structures. Quite amazing.
At the level of whole physiology, dynamic adjustments in éR allow the organism to learn from energetic conditions and change its behavior accordingly. So we have molecules like GDF15, which encode an energy pattern—excess energy resistance, in the case of GDF15—released by specific cells into the bloodstream to alert the brain. In that sense, information arises from energy patterning, and the flow of energy is organized through information, making them two expressions of the same underlying energetic process that we are.
In a recent paper in iScience, an inter-institute research team led by Keisuke Kawata and his PhD student, Gage Ellis, examined the effects of repetitive head injuries in athletes with and without attention deficit hyperactivity disorder (ADHD). They found baseline levels of tricarboxylic acid (TCA) cycle metabolites were elevated in the ADHD group. After head injuries, both groups had lower levels, but the ADHD group had greater decreases. Thus, ADHD is associated with elevated baseline levels, but all athletes experience mitochondrial dysfunction after head injuries.
Athletes often suffer head injuries, and heading the ball is a common activity in soccer. The research team sought to determine the effects of subconcussive impacts of a normal soccer ball on mitochondrial function. They used a machine to launch a soccer ball at a specific speed to be headed by the player. Each player completed 10 headers. The researchers examined 25 players with and 25 players without ADHD by determined levels of TCA metabolites (e.g., oxaloacetate, citrate, isocitrate, pyruvate, alpha-ketoglutarate, and fumerate) in the blood before and after the head injuries.
Interestingly, they found that athletes with ADHD had elevated levels of citrate, isocitrate, malate, and oxaloacetate before the experiment. After the headers, both groups of athletes had lower levels, but the ADHD athletes had lower levels than the non-ADHD athletes. The ball impacts, although common in soccer players, had a significant effect on mitochondrial function.
These findings provide important insights into two key areas. While concussions have received a lot of attention in the last few years, players of other sports, such as soccer and basketball, are at risk for head injuries. Soccer is an extremely popular sport among young athletes these days. ADHD has become more common. Lower levels of citrate and oxaloacetate are assumed to indicate reduced energy production, and higher levels of the metabolites indicate increased energy demand. This study links mitochondrial dysfunction to both of these conditions and, in so doing, points to potential strategies to prevent or treat those injuries.
Discussion with Dr. Kawata and Mr. Ellis
MitoWorld: [Kawata] These findings are very relevant to the prevalence of ADHD and soccer among young people these days. Can you give us an indication of what direction your research might go in to advance these findings?
You’re absolutely right. Our findings have broad relevance beyond just soccer. Many athletes in contact sports experience repetitive head impacts, and brain energy metabolism is a key marker of healthy brain maturation and aging. Regarding ADHD, one important next step is to understand how psychostimulant medications might modulate the brain’s response to subconcussive impacts. We’re also very interested in exploring potential countermeasures for these head impacts, since we still don’t have an effective prophylactic agent that can truly enhance brain resilience against repetitive trauma.
MitoWorld: [Kawata] The injury model used in the experiment was much more mild than the injuries incurred in many contact sports. Do you have any plans to look at patients after more serious injuries?
I think the real novelty of our work lies in studying these more subtle impacts rather than the obvious, severe injuries. Cellular responses to major brain trauma have been explored for decades, but what’s fascinating is that even something as mild as 10 soccer headers can trigger dramatic changes in TCA cycle metabolites. That’s a completely new insight. So rather than moving toward more serious injuries, we plan to keep focusing on this subconcussive spectrum of brain trauma. It likely carries broader implications for athletes and everyday populations.
MitoWorld: [Ellis] Can you speculate on how ADHD might be linked to enhanced levels of mitochondrial activity as evidenced by the higher levels of those compounds?
The athletes with ADHD that participated this study were all ingesting prescribed ADHD medication. There are several different types of ADHD medication, the most common of which are stimulants. Psychostimulant ADHD medication functions by altering dopaminergic and adrenergic pathways, specifically at the postsynaptic cleft. By binding to dopamine and norepinephrine receptors, neurotransmitters released by the presynaptic cleft are then reabsorbed. It is possible that the extracellular level of neurotransmitters and increased binding of synaptic receptors could alter the ionic state of the cell, upregulating ATP demand and then in turn increasing metabolic demand prior to exposure to head impacts. Another potential link to increased energy metabolite levels at baseline would be ADHD stimulant medication’s role as an immunomodulator, in which it has been reported to increase brain-derived neurotrophic factor, as well as suppress inflammatory interleukins such as interleukin-1 beta and tumor necrosis factor-alpha. In addition to modulation of pro and anti-inflammatory proteins, stimulant medication has shown to modulate oxidative stress as well, with evidence of both increasing and suppressing reactive oxygen species (ROS). While it is unclear the direction of modulation for ROS, it is notable that ADHD medication does play a role in oxidative stress and therefore could be the source of the enhanced mitochondrial activity denoted in this study.
MitoWorld: [Ellis] Can you envision a therapy for ADHD or head injuries that might involve treating mitochondria?
There are several different possible therapies for ADHD and for head injuries that include modulating mitochondrial function. One potential intervention would be pretreating with omega-3 fatty acids such as eicosapentaenoic and docosahexaenoic acid, which reduce oxidative stress and reinforce cell membrane structural integrity. Another potential therapy for head injuries, as well as ADHD, that also affect the mitochondria would be graded aerobic exercise. Currently, graded incline treadmill walking is a common protocol to treat concussions by reducing symptoms and improving return to play in athletes. Exercise improves ADHD symptom expression in children and adolescents, as well as reduces pro-inflammatory interleukins in individuals who engage in regular exercise. In addition to treating head injuries and improving ADHD symptom outcomes, aerobic exercise helps to regulate glycolytic pathways and improve metabolism.
In spite of all of this, the type of exercise, the intensity, and therefore the dosage for improving ADHD symptoms has not been defined and therefore is unknown. In addition to this, the graded incline treadmill walking to improve concussion outcomes is also extremely heterogenous per the individual.
MitoWorld: [Ellis] Did you have enough ADHD athletes in your study to see increase risk with those with more severe ADHD?
For this study, although we had 25 individuals with ADHD participate in the study, we did not see an increased risk correlated with ADHD severity. However, given the ADHD participants were all using medication, it is possible that ADHD severity and symptom expression was dampened, therefore making it improbable that ADHD severity would be correlated with mitochondrial outcomes.
MitoWorld: [Kawata] How did you come to be interested in mitochondria in the first place?
My interest in mitochondria actually goes back to my master’s program, when I worked in a lab focused on mitochondrial biology. I studied brain mitochondrial biogenesis and mitophagy, which really sparked my fascination with how these processes sustain neural health. More recently, I was part of a study (Vike et al., 2022, iScience 25(1):103483) that found potential links between head impacts and mitochondrial energy deficiencies in American football players. However, the causal relationship was still unclear because human studies at the time weren’t well controlled. That’s what motivated us to use a metabolomics approach in a rigorously controlled trial, to better understand how mitochondria respond to subtle head impacts.
Reference
Ellis G, Nowak MK, Kronenberger WG, Recht GO, Ogbeide O, Klemsz LM, Quinn PD, Wilson L, Berryhill T, Barnes S, Newman SD, and Kawata K (2025) Alterations in mitochondrial energy metabolites following acute subconcussive head impacts among athletes with and without ADHD. iScience 28(6).
All of us need sleep, but the reasons for that need are poorly understood. Scientists have previously reported changes that occur in the brains of animals that have remained awake for long periods. However, it wasn’t clear if these changes are causes or results, and the physical basis of the need for sleep is still unknown.
In a recent paper published in Nature, researchers at Oxford University, led by Gero Miesenböck, argued that the only way to sort out this issue was to look at specialist neurons with known roles in inducing and maintaining sleep. To gain insights into what makes us sleepy, the Oxford scientists studied the fruit fly Drosophila and compared the genes turned on or off in sleep-promoting neurons of rested and tired flies. Interestingly, almost all the upregulated genes encoded proteins involved in mitochondrial respiration and ATP synthesis. Other effects of sleep loss included mitochondrial fragmentation, mitophagy, and more contacts between mitochondria and the endoplasmic reticulum. After sleep, all of these were reversed, and nearly everything returned to normal.
The Miesenböck team speculate that the reason why animals need sleep is their power-hungry nervous systems, whose energy demands can only be met by stripping electrons from foodstuffs and transferring them to oxygen. Oxygen, however, is a double-edged molecule because its chemical nature invites missteps in mitochondrial electron trades; electrons leak from the respiratory chain and form damaging reactive oxygen species. This, they suggest, is the root cause of sleep.
The authors also note that neurons regulating sleep and energy balance work through similar mechanisms. These mechanisms involve cycles of mitochondrial fission and fusion. Fusion increases weight gain and fat deposition and also sleep. Hindering fusion does the opposite.
They conclude that sleep, like aging, may be an inescapable consequence of aerobic metabolism. Their findings enhance the understanding of how sleep is controlled and why we need sleep. The deeper understanding of sleep might also eventually point to potential new strategies for helping patients with sleep challenges.
A Conversation with Dr. Miesenböck
MitoWorld: What do you see as the next steps in your research?
There are two obvious follow-up steps. The first is to ask whether mitochondrial respiration also regulates mammalian sleep, or whether this is a fly thing. I definitely think it is not, but it still needs to be proven formally. The second question relates to the function of sleep. We may have put our finger on the cause—electrons spilling from mitochondria—but how sleep prevents or repairs the resulting damage remains unexplained.
MitoWorld: Multiple theories try to explain the need for sleep. Your work adds real observations to the idea of sleep as an ancient metabolic need for energy-consuming brains. Is this likely to be enough to tip the scales in favor of mitochondria?
Maybe there are no scales to be tipped because sleep has many functions and most theories will turn out to be correct. In our view, sleep originally evolved because neurons consume a lot of oxygen to support their energy needs. Once mitochondria had forced rest periods on animals, other functions were likely added, such as the downscaling of synapses strengthened during waking or memory consolidation.
MitoWorld: You described how you deprived the flies of sleep in your methods section, but I can imagine that readers might be wondering how you keep flies from sleeping. Could you briefly summarize that process and also how you induced sleep in the flies?
We deprived the flies of sleep just like we would deprive you: by poking them every 10 seconds or so. Fortunately, we have a machine that does that.
MitoWorld: You note a connection between sleep and eating and the need to maintain a balance for each of these key physiological processes. Can you elaborate on that?
Both sleeping and eating are, to use an old-fashioned term, drives: basic needs regulated by feedback. The less you sleep, the more tired you are; the less you eat, the more hungry you are. We now know that the neuronal controllers of sleep and hunger are similar in that they both depend on cycles of mitochondrial fission and fusion.
MitoWorld: This study features some very nice technical work (e.g., selection of an organism with cells known to be involved in sleep, a key fluorescent marker for selection, single-cell transcriptomes). Can you comment on those?
Thank you. My favorite of the many clever experiments Raffaele Sarnataro did draws on the concept of optogenetics, which we originated a quarter of a century ago. Raffaele put a light-driven proton pump into the mitochondria of sleep-promoting neurons and powered ATP synthesis with photons rather than electrons. This made electrons redundant and put flies to sleep.
MitoWorld: Could you speculate on whether your findings can be extrapolated to humans?
There are some hints. For example, an overwhelming sense of tiredness is a common symptom of human mitochondrial disease, despite normal ATP levels and no muscle fatigue.
MitoWorld: How did you come to be interested in mitochondria in the first place?
A previous study from my lab (Kempf et al., Nature 2019) provided the first clue that mitochondria are involved in the regulation of sleep. We discovered that sleep loss increases reactive oxygen species (ROS) in sleep-control neurons and that curbing electron leakage in their mitochondria (which fuels ROS production) reduces the pressure to sleep. In the present study, we played dumb and pretended we knew nothing about how sleep-control neurons sense the need for sleep. And voilà, when we looked at gene expression changes with a completely open mind, mitochondria popped up again.
Reference
Sarnataro R, Velasco CD, Monaco N, et al. (2025) Mitochondrial origins of the pressure to sleep. Nature 645: 722–728. https://doi.org/10.1038/s41586-025-09261-y
In a paper published in Science,1 Samir M. Parikh and an inter-institute research team explored the relationships among mitochondrial DNA (mtDNA) mutations, acute injuries, and chronic damage to the kidney. They found that the injuries result in mutations that hinder the mitochondria’s key activities and leave the organ more susceptible to future damage. Importantly, they found that this damage was amenable to metabolic treatment.
Mutations to mtDNA have been implicated as a driver of aging. The mitochondrial genome is much smaller than the nuclear genome. However, each cell contains hundreds to a thousand or more mitochondria, and each mitochondrion contains two to 10 copies of the mtDNA. Interestingly, mutations to mtDNA accumulate with aging, and that accumulation accelerates after age 70. The mutations to some but not all copies of the mtDNA in each mitochondrion result in differences in those genomes. This is called heteroplasmy.
The team used a mouse model for acute and chronic injuries to kidneys to examine the effects of mtDNA mutations. They found that the mutations accumulate and that they reduce gene expression, oxidative metabolism, and resistance to oxidative injury. Exogenous supplies of adenosine, but not other nucleosides, improved the function of the injured kidneys. Further studies identified loss of the key enzyme adenylate kinase 4, encoded in the nuclear genome, as the reason for the loss of ATP and the ability of adenosine to improve outcomes.
When they examined a large human cohort of 370,000 individuals from the UK biobank, they found that mtDNA mutations represented a risk factor for future acute injury and associated with the severity of chronic kidney disease. These results confirmed the association between mtDNA mutation burden and kidney injury.
These findings also confirm the kidney as an excellent model for the study of aging. Finally, they suggest that injuries to other organs, such as stroke and myocardial infarction, might be influenced by the effects of accumulating mtDNA mutations.
Conversation with Dr. Parikh and first author Dr. Huihui Haung
MitoWorld: What is the next likely goal in your research to follow up on this work?
SMP and HH: There are so many different directions to take this work, and they’re all interesting! On the translational side, does the relationship between mtDNA mutation burden and kidney disease hold in other human cohorts? More fundamentally, what mechanisms does a cell employ to monitor the fidelity of its mtDNA? Is it just overall oxidative function, or something more specific? Do cells in other organs composed of long-lived cells endowed with a high mitochondrial content also exhibit time and injury-dependent mtDNA mutations?
MitoWorld: There are so many copies of the mtDNA in each cell that it seems hard to understand how mutations to some of them can cause trouble. Do you have any speculation on what the threshold is for those mutations to be a problem?
SMP and HH: There are a few possibilities. First, the heteroplasmic single-nucleotide variants that are a focus of the manuscript represent one kind of mtDNA damage. Other assays largely relegated to the supplementary materials accompanying the paper demonstrate the rapid appearance and persistence of more profound changes to the mtDNA, such as indels. Second, we found that artificially introducing heteroplasmic mtDNA mutations by compromising the 3-5′ exonuclease activity of POLG sufficed to reduce oxidative function in renal tubular epithelial cells. Whether these changes affect tRNA function or subunits of the electron transport chain, or both, remains to be determined. Finally, in the cellular and mouse model data, we analyzed heteroplasmy without a threshold, but because the human data have so many orders of magnitude higher replicates per group, we were able to employ a more stringent variant allele frequency cutoff of 5%.
MitoWorld: Interestingly, the damage in your model was to a nuclear gene. How do you see the mtDNA mutations related to that enzyme?
SMP and HH: We do not yet have direct evidence that the enzyme AK4 regulates mtDNA mutations. However, we know that communication between the mitochondrial and nuclear genomes is essential to maintain mtDNA heteroplasmy within a safe threshold. AK4 is a nuclear-encoded mitochondrial protein and a key enzyme that regulates cellular ATP levels. Its expression is highly responsive to mitochondrial DNA damage. We speculate that AK4 may serve as a bridge or sensor that transmits deleterious mitochondrial signals to the nucleus, coordinating energy balance and mitochondrial fate. Further studies are needed to test this hypothesis.
MitoWorld: Damaged mitochondria have been implicated in aging and your current work also suggests that. What mechanisms might be involved? Is it just the slow deterioration of energy production or another mechanism?
SMP and HH: This is a really interesting question. Recent exciting work also conducted in the UK Biobank resource suggests that the nucleus has an important role in determining the burden of mtDNA mutations over a lifetime.2 The nuclear genes they implicated through a GWAS analysis were either the same or highly related to the ones we arrived at experimentally. The notion of a cell’s battery running down with age is intuitive and appealing. It is also possible that there is gain of toxic function as the mitochondrial code degrades. More work is needed to dissect among these possibilities.
MitoWorld: Can you envision how reducing mtDNA heteroplasmy might slow the processes of aging?
SMP and HH: Restoring the mitochondrial code may itself improve the oxidative function of the cell’s organelle. One could also imagine that the cellular processes involved in balancing the cell’s complement of mitochondria—namely the balance between mitochondrial biogenesis and mitochondrial clearance through mitophagy and the lysosome—wind up having multiple beneficial effects on overall cellular function.
MitoWorld: What about mitochondria interested you in the first place?
SMP and HH: As your readers appreciate, mitochondria are weird in many wonderful ways. Their membranes are composed of different lipids, their proteins start with a uniquely modified N-terminal amino acid, and the mtDNA genome lacks introns and the code to generate the vast majority of proteins that make up mitochondria, but exists in variable and polyploid amounts. The generation and dissolution of mitochondrial mass can be uncoupled entirely from cellular replication, and even the physical structure and networked appearance of mitochondria within cells are highly dynamic. Our bodies’ reliance on these weird organelles is clear from genetic experiments of nature.
The human data on monogenic mitochondrial syndromes are clear that kidney health is frequently impaired. It’s very easy to visualize mechanical work, such as skeletal or cardiac muscle contraction, requiring lots of ATP. But the tubular epithelium in the kidney is doing an enormous amount of chemical work. It might surprise the readers to know that, in humans, this specialized epithelium is responsible for the active transport of more than one pound of sodium back into the body every single day, atom-by-atom, against powerful electrochemical gradients. That’s more than 10e25 cations being pushed “uphill” back into the body from the crude filtrate every day. This apparatus is so exquisitely tuned that even a reduction to 10e24 sodium atoms would be lethal in a matter of minutes.
References
1 Huang H, Wang Y, Zsengeller ZK, Gorham JM, Vemireddy V, Clark AJ, Pan H, Dreyfuss JM, Jotwani V, Shlipak MG, Sarnak MJ, Parikh CR, Thiessen-Philbrook H, Katz R, Waikar SS, Lake NJ, Lek M, Shi W, Puiu D, Hong YS, Seidman JG, Arking DE, Parikh SM (2025) Reversible compromise of physiological resilience by accumulation of heteroplasmic mtDNA mutations. Science 390: 164–172.
2 Gupta R, Kanai M, Durham TJ, Tsuo K, McCoy JG, Kotrys AV, Zhou W, Chinnery PF, Karczewski KJ, Calvo SE, Neale BM (2023) Nuclear genetic control of mtDNA copy number and heteroplasmy in humans. Nature 620: 839–848.
Stealth BioTherapeutics, Inc, (Stealth) has received FDA approval for its drug FORZINITY™ (Elamipretide Injection). The drug is used to improve muscle strength in adult and pediatric patients over 30 kg with Barth syndrome, a rare and life-limiting disease. FORZINITY is the very first mitochondrial-targeting therapy approval.
“FDA approval culminates more than a decade of clinical development,” said Reenie McCarthy, Stealth CEO. “We were inspired by patient advocacy to start our development journey and patients remained our north star along the way, strengthening our resolve through every challenge.”
Barth syndrome is a life-limiting pediatric disease that affects only about 150 people in the United States. The disease is caused by a mutation in the TAFAZZIN (TAZ) gene that results in the loss of tetralinoleoyl-cardiolipin, a key lipid for mitochondria. It is an x-linked disease, which means that females can be carriers, but typically only males are affected. Patients suffer from exercise intolerance, muscle weakness, debilitating fatigue, heart failure, recurrent infections, and delayed growth. The greatest risk of death occurs before age 5.
Mitochondria are tiny cell organelles primarily known for producing energy within the cell, but they also have many other important activities. Each cell contains hundreds to thousands of mitochondria. Mitochondria are also unique in that they contain their own DNA. They are increasingly implicated in many diseases, but, to date, there have been no successful drug interventions of the mitochondria themselves.
“We are grateful for and applaud this incredible step that was reached expeditiously by the FDA after Stealth’s most recent new drug application and after years of circuitous challenges,” said Emily Milligan, MPH, executive director of Barth Syndrome Foundation (BSF). “We have worked tirelessly to support this outcome, and today is a day to celebrate, although much work remains.”
Elamipretide is reported to show improvement in mitochondrial structure and function in a cardiolipin-dependent manner, resulting in improved heart and skeletal muscle function 2-5. It readily enters mitochondria and migrates to the mitochondrial inner membrane 2,6. Once there, it specifically binds to cardiolipin to improve membrane stability, enhance ATP synthesis, and reduce the production of reactive oxygen species.
Simona Lobasso, PhD, an expert on lipidomics and cardiolipin role at the University of Bari, Italy, recently reported 4 that Elamipretide treatment improves ultrastructural morphology (i.e., inner membrane and cristae) and function in isolated cardiac mitochondria by restoring their ability to recycle themselves within the heart cells in a mouse model of Barth syndrome.
She added, “In a previous study,4 we found that in vivo treatment of TAZ-deficient mice with Elamipretide promoted respiratory “supercomplex” organization in cardiac mitochondria. We hypothesize that it exerts its beneficial effect by entering mitochondria and influencing the function of the respiratory chain. By improving mitochondrial structure, respiratory capacity and dynamics, Elamipretide can also improve overall heart and skeletal muscle functions in treated mice.”
Michael Murphy, PhD, a noted mitochondrial expert at the University of Cambridge who is not associated with Elamipretide or its approval process, but familiar with clinical trials and FDA drug approval offered, “The approval of Elamipretide for Barth syndrome patients arose from an open label 168-week trial of 10 patients with eight completing the trial with functional improvements being reported.” He added, “This is a potentially good step for this group of patients who have few treatment options. While this outcome cannot be compared with a long-term placebo-controlled double-blind study, the small number of patients and their prognosis make this challenging.”
Such breakthroughs are critical for the support foundations. “BSF will continue its efforts to advocate for label expansion to include individuals under 66 pounds and monitor Stealth’s progress on meeting post-approval requirements and coordinating with our international affiliates to expand access internationally.” said Lindsay Marjoram, PhD, BSF director of research.
“While we are thrilled to have achieved this milestone, we are keenly aware that our work is not done,” said Jim Carr, Stealth chief clinical development officer. “We took the weekend after the approval to celebrate and then leaned right back in to initiate activities for our post-marketing trial, which will enroll 48 subjects, age 5 and older, at sites in Europe and Australia. We also plan to meet with the FDA in the next few months to align on a pathway toward expanding the label to include younger children.”
Stealth plans to continue working on elamipretide for additional indications, including children less than 30 kg with Barth syndrome and dry age-related macular degeneration and primary mitochondrial myopathy. In addition, they are developing bevemipretide for ophthalmic and neurological disease indications.
Questions for about the approval process and the prospects for the disease:
MitoWorld: FDA approval of elamipretide is a landmark achievement. Do you think this will encourage other pharm and biotech companies to pursue therapies for these rare diseases?
Lindsay T. Marjoram (LTM): It is our hope that this approval will help kickstart future investments into both mitochondrial and ultra-rare diseases. I think this approval helps to demonstrate that the FDA is more committed to using the accelerated approval pathway in ultra-rare drug submissions. To spur future investment, though, it will be critical for Congress to reauthorize the Pediatric Priority Review Voucher Program, which gives companies, such as Stealth, the financial incentive to invest in diseases that may not be profitable.
MitoWorld: Can you elaborate on the molecular mechanism of elamipretide?
LTM: Elamipretide is a mitochondrial cardiolipin binder that localizes to the inner mitochondrial membrane and improves mitochondrial morphology and function. In Barth syndrome, lack of TAFAZZIN activity leads to a build-up of immature (monolyso-) cardiolipin and alters the structure of the inner membrane. The impaired structure leads to decreased energy production.
MitoWorld: Barth syndrome is a rare disease. How hard was it to identify study a sufficient number of subjects to obtain significant results?
LTM: BSF was a partner in ensuring that the trial was enrolled. I believe it took less than a year to fully enroll. There were a lot of learnings from this process since it was the very first trial to be run in our community. One thing we learned from this trial was that it needed to run longer than anticipated.
MitoWorld: Are you looking at other drug candidates for mitochondrial diseases?
David Brown, PhD, Stealth senior vice president of discovery: Our next generation clinical stage compound, bevemipretide, is in early clinical trials, and we have a deep pipeline of mitochondrial targeted therapeutics in early stage development.
LTM: BSF has funded >$7M in research, which has resulted in >$41M in follow-on funding from agencies, such as NIH. The Foundation continues to support research into the basic mechanistic underpinnings of Barth syndrome and development of potential therapeutics, including enzyme replacement therapy, AAV-mediated gene therapy, anti-sense oligonucleotide therapy, and small-molecule development.
References
1 U.S. Prescribing Information:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/215244s000lbl.pdf
2 Szeto HH (2014) First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergetics. Br. J. Pharmacol. 171: 2029–2050.
3 Chatfield KC, et al. (2019) Elamipretide improves mitochondrial function in the failing human heart. JACC: Basic Transl. Sci. 4: 147–157.
4 Russo S, De Rasmo D, Rossi R, Signorile A, Lobasso S (2024) SS-31 treatment ameliorates cardiac mitochondrial morphology and defective mitophagy in a murine model of Barth syndrome. Sci. Rep. 14: 13655.
5 Russo S, De Rasmo D, Signorile A, Corcelli A, Lobasso S (2022) Beneficial effects of SS-31 peptide on cardiac mitochondrial dysfunction in Tafazzin knockdown mice. Sci Rep. 12: 19847.
6 Sabbah HN, Alder NN, Sparagna GC, Bruce JE, Stauffer BL, Chao LH, Pitceathly RDS, Maack C, Marcinek DJ (2025) Contemporary insights into elamipretide’s mitochondrial mechanism of action and therapeutic effects. Biomedicine & Pharmacotherapy 187: 118056.
Mitochondria Fight Pathogens by Starving Cells of Folate
In a recent paper in Science, a research team led by Lena Pernas of UCLA showed that cells infected with a pathogen activate their mitochondria to gobble up the available folate.
Mitochondria are deeply involved in cellular metabolism and use many of the nutrients that a pathogen need. Is this competition for resources simply a coincidence, or is it a strategy to protect against pathogens? The Pernas group focused on the replication of mitochondrial DNA (mtDNA), which requires the materials for nucleotide biosynthesis. For a model pathogen, they used the protozoan parasite Toxoplasma gondii. For the parasite, folate is essential to make thymidine for DNA synthesis and proliferation.
Interestingly, the researchers found that the parasite caused the cells to begin making new mtDNA, which depended on the integrated stress response and its key effector, the activating transcription factor 4 (ATF4). They found that ATF4 turns on one-carbon metabolism, which requires folate, to increase mtDNA. They also noted that disrupting mitochondrial one-carbon metabolism resulted in increased parasite replication.
T. gondii needs folate to make thymidine and new DNA, but ATF4 activation short-circuits that synthetic pathway by depriving the pathogen of folate. They concluded that the cells actually use mitochondrial metabolism as a weapon against pathogens.
A Conversation with Dr. Pernas
MitoWorld: This is an interesting paper about how cells use mitochondria indirectly to defend against a pathogen. Can this phenomenon be generalized to other pathogens or other nutrients?
LP: I think so—especially for pathogens that depend on host nutrient that can be sequestered or consumed by host mitochondria.
MitoWorld: What might be the next steps in your research into this action?
LP: Our immediate next steps are to understand if we can pharmacologically enhance mito1C during infection to restrict parasite growth, and to define other ways mitochondria limit pathogen replication.
MitoWorld: Are there any harmful side-effects of using up a portion of the folate in the cell? LP: This is such an exciting question! Another way to think of it is: can mitochondria become ‘selfish,’ and limit critical nutrients for the cell? That’s a concept that Dr. Tania Medeiros (the first author) will explore in her lab. I don’t think transient activation of mito-1C has harmful side-effects. However, in cases of mitochondrial disease where mito-1C enzymes are chronically activated, this may harm the host cell by restricting folate needed for other processes—analogous to the limiting of dTTP by dysfunctional mitochondria from nuclear genome replication, as Anu Suomalainen-Wartiovaara (U. of Helsinki) has shown.
MitoWorld: Is the mtDNA made in response to the pathogen simply degraded?
LP: We don’t have any evidence for degradation. One puzzling result is that, although mtDNA levels increase, we don’t see a corresponding increase in mtRNA or mtDNA-encoded proteins. One possibility is that the parasite produces an effector that inhibits the translation of mtDNA-encoded proteins.
MitoWorld: Can you speculate on whether this phenomenon might be used therapeutically? LP: It might be difficult since folate is a critical vitamin for multiple processes. I can speculate that increasing folate concentrations may not be beneficial during infection. In fact, elevated serum folate has been associated with increased malaria parasitemia in humans. Plasmodium, the causative agent of malaria, is another parasite that relies on folate for dTMP synthesis. Rather, we should consider how to specifically enhance mito1C, or mitochondrial use of folate. Another point is that the inhibition of the ISR has been explored in different disease contexts, but if this blocks mito1C, it may be important to first test individuals for pathogen burden.
MitoWorld: How did you become interested in mitochondria in the first place?
LP: When I started graduate school, my PhD advisor (John Boothroyd, Stanford U) showed me an electron micrograph of a monocyte isolated from a mouse infected with Toxoplasma. I couldn’t stop thinking about why all the mitochondria of that cell were surrounding the parasite. I’ve been working on this question ever since!
Reference
Medeiros TC, Ovciarikova J, Li X, Krueger P, Bartsch T, Reato S, Crow JC, Tellez Sutterlin M, Martins Garcia B, Rais I, Allmeroth K, Hartman MD, Denzel Ms, Purrio M, Mesaros A, Leung K-Y, Greene NE, Sheiner L, Giavalisco P, Pernas L (2025) Mitochondria protect against an intracellular pathogen by restricting access to folate. Science 389(6761): eadr6326.
In a paper published in Nature Metabolism, a multi-institute research team, led by Timothy A. Ryan of Weill Cornell Medicine, found that the balance of lipid droplet (LD) metabolism and catabolism is critical to the transmission of nerve impulses at the synapse.
For some time, the brain has been assumed to use glucose almost exclusively as an energy source. Triglycerides were not considered to have a role in energy production as the stored form of these fat molecules, LDs, are rarely seen in healthy neurons. The discovery of a neuron-specific TG lipase, DDHD2, caused a closer look at TG metabolism in the brain. Loss of DDHD2 activity results in a buildup of LDs in neurons and cognitive impairments in a variant of a condition called hereditary spastic paraplegias in humans.
They found that blocking DDHD2 or of the mitochondrial lipid transporter CPT1 led to torpor in mice. Furthermore, they found that blocking DDHD2 in dissociated neurons causes LDs to accumulate in neurons, particularly at nerve terminals.
They suggest a complex model in which LDs at the synapse are in a careful balance. They found that fatty acids could provide sufficient energy for synaptic vesicle recycling, even in the absence of glucose. They also note the Randal cycle, in which the use of fatty acids and glucose for energy in energy-requiring tissues are tightly regulated and speculate that a similar system might exist in brain. They speculate that fatty acids to fuel neurons may be transported from non-neuronal cells in the brain by lipoproteins that contain apolipoprotein E, which is known to be associated with Alzheimer’s disease and sent to mitochondria to be used in ATP production. These findings add additional evidence for the involvement of DDHD2 mutations in various diseases.
A Conversation with Dr. Ryan
MitoWorld: You suggest in the Discussion that this process might be more important in aged individuals. Do you have any data on that or plans to follow up on that?
There are several published studies providing evidence that in humans, LDs accumulate in the diseased, aged brain. At present though, getting more mechanistic detail of what is going on is difficult, as the aging process is not easy to model in simpler organisms with complex nervous systems.
MitoWorld: Excess fatty acids are consigned to use to produce energy in the mitochondria. Is that the primary use of those fatty acids, or are they used in membrane repair in the synapse and the leftovers go to the mitochondria?
This remains an open and very interesting question. The brain is mostly made of lipid. Neurons have both very elaborate architectures that extend huge distances, all requiring a plasma membrane made of lipids. Additionally, within neurons another organelle, the endoplasmic reticulum, also extents over the entire extent of the cell. This too is made of lipid. An open and underexplored are is where these lipids are synthesized. Are they all imported and if some from where? If not where is the biosynthetic machinery to make fatty acids located. Many non-neuronal cells also have elaborate fatty acid demands for their architecture (e.g. Schwann cells).
MitoWorld: Can you speculate how these results might be used in a therapeutic strategy?
The existence of DDHD2 suggests in neurons and the dramatic impact of perturbing it acutely or chronically (as in HSP54) all point to the likelihood that b-oxidation in neurons is always happening and, therefore, always participating in making ATP to fuel neuron function. Our brains are also famously intolerant of interrupting the fuel supply, as if your plasma glucose drops by a mere factor of 2, most people begin to manifest neurological symptoms. There has been exciting progress in developing potential therapeutic strategies to boost glycolysis. Understanding that this might be supplementing a background level of b-oxdation might clarify the potential variability of boosting glycolysis in different people.
MitoWorld: Other recent papers have commented on the junctions of mitochondria and the endoplasmic reticulum for transfer of materials. Might something like that be involved in the transfer of fatty acids to the mitochondria?
There has been exciting progress in identifying proteins that are responsible for exchanging fatty acids between the endoplasmic reticulum and various organelles. For example, VPS13 is an excellent example of a class of proteins that do this, and mutations in one of the four variants in humans each lead to a different disease. VPS13A is currently considered to be at the interface of the ER, mitochondria and LDs and is therefore a candidate to facilitate the transfer of fatty acids between these organelles.
MitoWorld: This fascinating finding injects fatty acid metabolism into the energy environment of neurons. Do you have any idea of the relative amounts of energy from fatty acids vs glucose?
Classic biochemistry predicts that for every two carbons of a fatty acid you generate one molecule of acetyl-coA in the mitochondria. For each acetyl-coA, you would produce ~ 30-36 ATP molecules. Glycolysis of a single glucose molecule produces only one acetyl-coA molecule (as well as two net ATP even without mitochondria). So on a per molecule basis fatty acids provide a lot more ATP.
Reference
Kumar M, Wu Y, Knapp J, Pontius CL, Park D, Witte RE, McAllister R, Gupta K, Rajagopalan KN, De Camilli P, Ryan TA (2025) Triglycerides are an important fuel reserve for synapse function in the brain. Nature Metabolism 7: 1392–1403.