The energy resistance principle: a new framework for understanding life

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).

It’s time for a science of health, and a good look at the science behind the healing process. It looks likely that mitochondria play a central role in our ability to heal and be resilient. – Martin Picard, Columbia University

Martin Picard, PhD, runs the Mitochondrial Psychobiology Lab at the Columbia University Irving Medical Center. He and his students and colleagues, including Caroline Trumpff, a clinical psychologist and epidemiologist by training—now a mitochondrial psychobiologist—have deeply phenotyped healthy individuals and people with mitochondrial diseases. Picard, Trumpff, and the MiSBIE team devoted themselves to conducting psychological, stress and other biological investigations that are not strictly in the category of diseases, mutational consequences, or medical conditions. This has led to a rich body of investigations, studies and findings, including being part of a team that mapped mitochondrial distribution across all brain structures for the first time. Some of these investigations of energetics and stress do relate to underlying issues in medicine.

With NIH funding the Picard Lab assembled and led MiSBIE, a five year set of investigations and papers that will be reported out at the upcoming MiSBIE Symposium at Columbia University, and online, on December 12. The details are below, after MitoWorld’s interview with Dr. Picard.

MitoWorld: Martin, tell us about MiSBIE, how it came about, what it is.

Picard: MiSBIE is the Mitochondrial Stress, Brain Imaging, and Epigenetics Study. It was born in 2016, and it ran between 2018 to 2023. I put most of my startup funds into it—the most important study I thought my lab should focus on for the years to come. It was also the human translation of a 2015 preclinical study that showed that mitochondria regulate stress responses in mice. Now we’re 10 years later and we’ve learned a lot, which we’ll discuss at the Symposium on December 12^th.

MitoWorld: Who should attend the 2025 MiSBIE Symposium?

Picard: Anyone interested in learning about mitochondria, stress, and health should find something of value at the symposium. Researchers in mitochondrial psychobiology and related fields may find details of the latest work in this area of interest. There will be relevant data and findings for clinicians who care for patients with primary mitochondrial diseases. And Mito patients may appreciate seeing the team unearthing new principles and findings that may eventually affect their care and empower them to achieve their full health potential. Entrepreneurs may also see opportunities in new mind-mitochondria connections discovered through MiSBIE. Finally, funders and philanthropists may find valuable lessons from the success of this deeply interdisciplinary study.

MitoWorld: Who is presenting and can you provide some URLs on what will be discussed, background papers?

Picard: Symposium presentations will be by scientists and students who have directly contributed parts of the MiSBIE study. You’ll hear directly from the team that conducted the study, and who are now performing analyses to understand the mind-mitochondria connection. The best background paper is the MiSBIE Mother Paper. Other MiSBIE data papers on the effects of mental stress on the metabokines FGF21 and GDF15, and on cell-free mtDNA, immune cell mitochondrial biology and symptoms, immune cell stimulation, and neuroimaging signatures have been published in final form or as preprints. All PDF are freely available on our website www.PicardLab.org/Publications

MitoWorld: What do you hope the outcome to be? What is the take away? And what do you hope to stimulate?

Picard: I hope people leave the MiSBIE Symposium inspired, with a new sense of the energetic processes underlying stress responses, brain processes, immune regulation, and the energetic cost of life. The key take away is that the energetic and molecular state of our mitochondria is linked to our experiences. More research is needed to bring energy into medicine, and to develop a more holistic model of what human health actually is. Most of biomedicine is about diseases—it’s time for a science of health, and a good look at the science behind the healing process. It looks likely that mitochondria play a central role in our ability to heal and to be resilient.

MitoWorld: Where can people register?

Picard: People can attend on Zoom or in person, and register at www.PicardLab.org/MiSBIE. We expect 400-500 people—there is room for everyone!

Details on the upcoming December 12 Symposium

The Mitochondrial Stress, Brain Imaging, and Epigenetics (MiSBIE) study was developed to understand the role of mitochondria and energy more generally in mind-body processes, as well as their potential relevance to people with mitochondrial diseases. At this Symposium, MiSBIE investigators and the international team of collaborators will share findings addressing some of the hypotheses we originally set out to test, plus some unexpected discoveries made along the way. The dataset and analyses conducted to date have linked mitochondria to immune, neuroimaging, endocrine, metabolic, psychosocial, and clinical outcomes relevant to the mind-mitochondria connection. We welcome you and your team to learn, discuss, question, and ideate to develop new collaborations.

The symposium will close with:

• Discussion around opportunities and future directions with the MiSBIE dataset.
• A poster sessionfor MiSBIE investigators and attendees wishing to present mitochondrial psychobiology-relevant research.
• A celebratory receptionwith mito-friendly food and drinks to commemorate MiSBIE’ success.

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.

A Divided Community

In a September 2025 Viewpoint published in Nature Metabolism entitled “Mitochondria Transfer,” the editors noted, “. . . the topic continues to be met with skepticism.” As a result, the journal asked nine mitochondrial biologists to share their personal views on intercellular mitochondria transfer. There was little new here.

Their responses amounted to yes, no, and maybe. Many questions loom for otherwise promising results. What are the mechanisms and consequences of this process? If mitochondria do move between cells endogenously, when they arrive in another cell, do they resume their normal functions? Does the transfer of a relatively small number of mitochondria have the power to rescue a cell that is under bioenergetic stress?

At MitoWorld, we know most of the Viewpoint respondents, and we know the gulf between them. By kicking off debate, Nature Metabolism has started a process that we hope can mature from rhetoric to a more evidence-based picture of the efficacy of mitochondrial transfer and transplantation. Across the globe, investigations are underway in both categories. Given the limited mechanistic understanding of this process, it is surprising that mitochondrial transplantation is now a not uncommon medical intervention and remains a tantalizing subject of research and development in a variety of biotech companies.

First Step: Nomenclature

In all of this, there is a blurring of terminology. In January, Jon Brestoff and Keshav Singh, et al. published “Recommendations for mitochondria transfer and transplantation nomenclature and characterization,” also in Nature Metabolism. What is clear in their paper’s title is the notion of i) transfer being endogenous, part of an intrinsic biological mechanism and ii) transplantation, the act of deliberately introducing mitochondria into organs, tissues, and cells being exogenous. Over 30 researchers participated in what was a laudable effort to explore agreed-upon naming, processes, and explanatory conventions. While the consensus statement and an agreement for an International Committee on Mitochondria Transfer and Transplantation Nomenclature (ICMTTN) represents an important step forward, notable disagreements persist. Foremost among the complications related to mitochondrial transfer and transplantation relates to the unknown fate of any mtDNA harbored by incoming organelles.

Second Step: Conference

MitoWorld found itself in the middle of this controversy when it was asked to help with the first Mitochondrial Transplantation Conference. Held in April at Hofstra University, the event was organized by Northwell Health and led by Lance Becker. It featured a mix of compelling medical intervention talks and video for failing hearts (James McCully), treatment for stroke victims (Melanie Walker), and other resuscitation experiments with animals (Lance Becker). MitoWorld assisted in having endogenous transfer represented (Jonathan Brestoff). In all of this, there was excitement but also apprehension that parents of children and adults with mitochondrial genetic diseases will be given false hope for near-term treatments. Several drug developers were present, as were patient groups. It is likely some form of transplantation organization will emerge from that meeting.

Deeper Dive—Transfer and Transplantation

Given the lack of evidence-based dialogue, MitoWorld reached out to the Viewpoint respondents who are actively doing work in both categories. Yasemin Sancak, The Sancak Lab, University of Washington Pharmacology, and Rubén Quintana-Cabrera, Neurometabolism and Mitochondrial Dynamics Lab, Instituto Cajal, CSIC responded to MitoWorld.

MitoWorld: Why do you think there is such a controversy about mitochondria transfer and transplant? 

Sancak: Transfer of mitochondria between cells is shown in different organisms and systems, and although this is relatively novel finding, it is widely accepted in the field. However, mitochondria transplantation attracts skepticism. In my opinion, the controversy stems from the expectation that, for mitochondrial transplantation to work as intended, the transplanted mitochondria should successfully incorporate into the host tissue in large numbers and maybe survive there for a long time, integrate into the donor tissue, and restore mitochondrial function and tissue health. Currently, the evidence of this happening is limited, and mechanisms of mitochondrial entry and survival are not well understood. But we also cannot ignore the exciting data that show the utility of mitochondrial transplantation in the clinic. Until we understand the molecular details and mechanisms of this process, the controversy is likely to continue. The field needs more preclinical and clinical research to understand mechanisms of therapeutic benefit and to establish clinical guidelines.

Quintana-Cabrera: These are quite novel concepts, now widely accepted by the scientific community after solid data in different cells and tissues. My perception is that both general and even specialized audiences are mostly focused on the incorporation of healthy mitochondria from neighboring cells or tissues to enhance mitochondrial activity in the compromised recipient cell. However, we should not overlook the transfer of damaged mitochondria, which may also benefit a cell by enabling their elimination through surrogate degradation in neighboring cells. Regarding transplants, the apparent controversy mainly concerns the injection of isolated mitochondria. Transplants using donor cells, such as mesenchymal stem cells or mitochondria encapsulated in vesicles or artificial membranes are viewed as able to better withstand the extracellular environment and the journey through the body to the target tissue. However, those advocating for transplants of isolated mitochondria need to standardize the approaches and to clarify how mitochondria survive outside the cell, influence inflammation, and integrate into recipient cells, or if they can take over native mitochondrial function in the long term.

MitoWorld: What may convince you that transfer happens naturally and/or that transplantation has effects? 

Sancak: Many animal and cell culture studies show that mitochondrial transfer happens naturally, and this process is likely to serve different functions. Mitochondrial transplantation research in a pre-clinical setting mostly shows positive outcomes, but the long-term benefits of mitochondrial transplantation are not addressed. A small number of human studies show clinical benefit, but these are mostly feasibility and safety studies that were conducted with a small number of patients. One promising common finding from human studies so far is that mitochondrial transplantation does not seem to have any adverse effects and is generally considered to be safe. I think this is very promising and should open the door to bigger clinical trials. Ultimately, well-controlled clinical trials are needed to determine if mitochondrial transplantation will work for a disease of interest and what long term effects will be.

Quintana-Cabrera: A growing body of evidence demonstrates the natural occurrence of different types of transfer, mediated by tunneling nanotubes, microvesicles, or naked mitochondria, across various tissues and both in physiology and pathology. This is leading the scientific community to accept mitochondrial transfer as a naturally occurring event.

Of course, this is still a young field, and existing gaps need to be addressed by thoroughly evaluating the various dimensions of mitochondrial transfer. For example, further progress is needed in the assessment of intercellular communication mechanisms, such as tunneling nanotubes, which contribute to mitochondrial transfer but are technically challenging to study in vivo. Transplantation can produce meaningful effects, at least in the short term, depending on the delivery method, dosage, and source of mitochondria. Additional manipulations may enhance mitochondrial integration, modulate immune responses, or improve targeting to the appropriate tissue. However, it remains essential to understand how transplanted mitochondria interact with a much larger population of resident ones and to characterize both the short- and long-term effects of transplantation. This knowledge will help determine which strategies are truly beneficial. Such benefits may arise from whole mitochondria, their components, or even from transient cellular responses triggered by the presence of exogenous mitochondria.

MitoWorld: What do you say to those who contend that transplantation, at best, is a reaction to the presence of transplanted mitochondria, not that transplanted mitochondria are functionally integrated into recipient cells?

Sancak: This is an important question that highlights the significance of understanding what happens at the molecular level once the external mitochondria are delivered to the recipient cells. Most animal experiments show that the transplanted mitochondria must be functional to provide a positive outcome in the recipient cells. This suggests that the recipient cells’ reaction to presence of transplanted mitochondria is not the whole story, and transplanted mitochondria function is important. I think it is more likely that both mechanisms will play a role, and depending on the disease, transplantation method, and recipient cell, one mechanism may play a more prominent role than the other.

Quintana: This is a critical question that indeed needs clarification. Are transplanted mitochondria directly restoring function, or are they instead exerting indirect effects that still benefit the recipient cell or tissue? The latter could involve activation of stress-response pathways that partially restore homeostasis. Again, the source or method to deliver mitochondria may be key to what response is engaged, and the functional integration of mitochondria may not always be necessary to explain beneficial outcomes. Depending on the kind of transfer, whole mitochondria, or at least mitochondrial DNA, may escape degradation and integrate into the acceptor cell. Even in this scenario, we still need to assess whether and how their contribution reconfigures the native mitochondrial content, and what other events may occur in parallel.

MitoWorld: What does your research from actual cases tell you about what the transplanted mitochondria are actually doing? 

Sancak: The transplantation studies I was involved in were focused on safety, and no clinical outcomes other than safety were monitored rigorously. What I can say is that mitochondrial transplantation appears safe in every system tested, which makes it more appealing to pursue as a potential therapeutic intervention. We still need to systematically investigate which mitochondrial functions are the most important.

Quintana: We observe spontaneous mitochondrial transfer in the nervous system, particularly at neuron-glia connections, in both healthy tissue and in pathological contexts, such as glioblastoma. The latter represents another dimension of transfer, where cancer-neural connectivity and mitochondrial exchange are emerging as key factors in cancer progression. We see that, in physiological contexts, transfer occurs spontaneously and is regulated by specific molecular players involved in intercellular communication and dynamics. Notably, we observe that different ways of transfer or mitochondrial acquisition serve to reconfigure the mitochondrial signature and metabolism in the nervous system and glioblastomas, with the potential to modulate their physiology and offer new venues for therapeutic interventions.

Recommendation

Having been involved in this topic for some time, MitoWorld has discussed a simple step toward moving from debate to a methodology to review what is being discovered in mitochondrial transfer (endogenous) and what is being performed in mitochondrial transplantation (exogenous). Here are the suggestions and more are welcome from the community.

1. Establish a working group to track developments

As Brestoff, Keshav, et al. did with nomenclature, MitoWorld suggests the establishment of an agreed-upon tracking system for transfer and transplantation activity. This could be a formal registry, an inventory, or catalog. It will include common terminology and naming of activity, methods, collection, evidence, results, conclusions, and recommendations. We are asking a number of researchers to help in this process.

2. AI review of literature and associated data

MitoWorld has a relationship with Heureka Labs, developed in part by mitochondrial and metabolic researcher and AI specialist Matthew Hirschey, PhD (Duke University School of Medicine). Heureka will develop an initial approach to use AI to index past research for categories of activity and to develop data standards for analyzing and synthesizing data and processes.

3. Basic science and the phenomenology of mitochondria

There is still much to learn about our endosymbionts, the mitochondria, along with their DNA, and the complex mitonuclear system. Mitochondria have suffered years of obscurity in many forms of research and medicine. They have been typecast as the powerhouse of the cell. mtDNA is just beginning to be a larger topic, with the first conference on the subject having been held this summer in Nashville, Mechanisms of Mitochondrial DNA Mutation and Repair. We would like to see the still poorly understood mechanisms of mitochondrial biology become more central to funding agencies around the world, as it is increasingly apparent that mitochondria, as the hubs of metabolism, are central to the health of our cells.

A collective effort across the mitochondrial research and clinical communities has sought to play down the “powerhouse of the cell” phrase as the sole description of mitochondria and, instead, to elevate the amazing multiplicity of mitochondrial functions. Top among those functions is mitochondrial signaling. The leaders in the signaling field will be gathering at the Keystone “Mitochondria Signaling in Physiology and Disease Symposium,” Feb 09–12, 2026, at the Keystone Resort, Keystone, Colorado in the U.S, whose keynote speaker is Anu Suomalainen Wartiovaara, University of Helsinki, presenting “Lessons Learned from Patients with Mitochondria Mutations for Physiology and Diseases.” [Conference Flyer]

Scientific organizers, Navdeep Chandel, Northwestern University Feinberg School of Medicine, and Aleksandra Trifunovic (video), Institute for Mitochondrial Diseases and Aging, University of Cologne, among the most published on the topic, have brought together a very strong group of international speakers to present findings and stimulate dialog.  Among them is José Antonio (Tonio) Enríquez, Professor and Group Leader of the “Functional Genetics of the Oxidative Phosphorylation System (GENOXPHOS)” Laboratory at the Spanish National Center for Cardiovascular Research (CNIC) in Madrid, Spain.

Because of Tonio’s expertise in mitochondrial bioenergetics, oxidative phosphorylation (OXPHOS) and mitochondrial signaling and communication, MitoWorld asked him to answer a few questions about mitochondrial signaling and its significance to build the platform for understanding mitochondria more completely.

MitoWorld: What is the significance of this conference in terms of content, collaborations and the field of mitochondrial signaling?

Enríquez: This Keystone conference represents a pivotal moment in mitochondrial research, marking the formal recognition of mitochondria as central signaling hubs rather than mere energy factories. The conference, organized by Navdeep Chandel and Aleksandra Trifunovic, brings together field leaders who have fundamentally reshaped our understanding of mitochondrial biology over the past 25 years.

MitoWorld: Why is the conference important to do you individually? Can you introduce your area that relates to signaling?

Enríquez: My research area directly relates to signaling through the study of metabolic channeling and respiratory supercomplex assembly. These structures are not merely efficient ATP production units. They represent sophisticated signaling platforms that regulate ROS production, metabolite flux, and cellular stress responses. The spatial organization of respiratory complexes influences how electrons flow through the chain, affecting both energy production and generation of signaling molecules, such as superoxide and hydrogen peroxide. Furthermore, my work on aging mechanisms connects directly to mitochondrial retrograde signaling pathways that communicate cellular stress to the nucleus, triggering adaptive responses or, when dysregulated, contributing to age-related pathologies.

MitoWorld: It seems that “signaling” always must be added to any mitochondrial discussion to get beyond the APT/powerhouse conversations. Talk about how we should see mitochondria and mtDNA as part of the signaling functions in cells with the nucleus and beyond.

Enríquez: The persistent need to add “signaling” to mitochondrial discussions reflects decades of reductionist thinking that portrayed mitochondria solely as cellular powerhouses. This ATP-centric view, while historically important, has become a conceptual limitation that obscures the true complexity of mitochondrial function. Mitochondria and mtDNA function as integrated signaling networks with multiple mechanisms.

• Metabolite signaling: Mitochondria produce signaling metabolites (e.g., α-ketoglutarate, succinate, acetyl-CoA, and citrate) that directly regulate nuclear gene expression through epigenetic modifications. These metabolites serve as cofactors for chromatin-modifying enzymes, linking mitochondrial metabolism to nuclear transcriptional programs.
• ROS as signal transducers: Rather than just being toxic byproducts, mitochondrial ROS function as essential signaling molecules that activate stress-responsive pathways, regulate hypoxia responses, and control cellular fate decisions. The spatial and temporal regulation of ROS production allows mitochondria to communicate specific information about cellular energetic and redox status.
• Retrograde signaling pathways: Mitochondria communicate their functional status to the nucleus through calcium-calcineurin signaling, AMPK activation, and transcription factor regulation. These pathways allow cellular adaptation to mitochondrial dysfunction and coordinate nuclear gene expression with mitochondrial needs.
• mtDNA as an inflammatory signal: Cytoplasmic release of mitochondrial DNA activates innate immune pathways through cGAS-STING signaling, linking mitochondrial damage to inflammatory responses. This represents a fundamental immune surveillance mechanism that monitors mitochondrial integrity.

MitoWorld: List and discuss the various types of signaling and the ones you personally are interested in.

Enríquez: The diversity of mitochondrial signaling mechanisms reflects the evolutionary origin and cellular integration of these organelles.

• Metabolite-mediated signaling: This includes one-carbon metabolism products (SAM, formate), TCA cycle intermediates (α-KG, succinate, fumarate), and lipid signaling molecules (cardiolipin, ceramide). These metabolites regulate epigenetic modifications, transcriptional programs, and enzymatic activities throughout the cell.
• ROS Signaling: Different mitochondrial sites produce distinct ROS species with specific signaling functions. Complexes I and III generate superoxide with different submitochondrial localizations, affecting cytoplasmic versus matrix signaling pathways. H₂O₂ serves as a diffusible signaling molecule that modifies cysteine residues on target proteins.
• Calcium signaling: Mitochondria function as calcium buffers and signal processors, with calcium uptake and release coordinating with cellular calcium oscillations to regulate gene expression, enzyme activities, and cellular excitability.
• Mitokine secretion: Mitochondrial stress triggers the release of signaling proteins, such as FGF21, GDF15, MOTS-c, and Humanin, that act in autocrine, paracrine, and endocrine manners to coordinate tissue responses. These represent a new class of stress-responsive hormones.
• Intercellular mitochondria or mitochondrial components transfer: Direct transfer of mitochondria or mitochondrial components between cells represents a mechanism for intercellular signaling that can modify recipient cell function.
• Epigenetic regulation: Mitochondrial function directly influences nuclear chromatin structure through metabolite availability, NAD+/NADH ratios, and histone modification enzyme activities. This creates a direct link between mitochondrial metabolism and gene expression programs.

Personally, I am most interested in ROS signaling mechanisms and metabolite-mediated epigenetic regulation, as these directly relate to my research on respiratory complex assembly and aging mechanisms.

MitoWorld: If we are to re-define mitochondria how important is signaling and what might the inclusive definition include?

Enríquez: Signaling is critically important because it represents the mechanism by which mitochondria integrate their traditional functions with cellular and organismal physiology. Without signaling, mitochondria would be isolated organelles incapable of coordinating their activities with cellular needs or communicating their status to other cellular compartments. The new paradigm recognizes mitochondria as “cellular command centers” that process information, make decisions, and coordinate responses rather than simply executing metabolic programs

MitoWorld: For newcomers to the field, what would you tell them in terms of the importance of signaling in general and mitochondrial signaling in particular?

Enríquez: For students and PhD candidates entering the field, I would emphasize several key points.

• Understanding signaling as fundamental biology: Every cellular process, from development to disease, involves signaling networks. Students should approach mitochondria as integrated systems rather than isolated organelles.
• Interdisciplinary perspective is essential: Modern mitochondrial research requires integration of biochemistry, cell biology, physiology, bioinformatics, and clinical medicine. Students should develop broad competencies and collaborative skills to address complex mitochondrial questions.
• Technical diversity: The field requires expertise in diverse methodologies—from single-cell analyses and live imaging to omics approaches and animal models. Students should gain experience with multiple technical approaches to study mitochondrial function.
• Clinical relevance: Mitochondrial signaling dysfunction underlies numerous diseases, including cancer, neurodegeneration, metabolic disorders, and aging. Understanding the translational potential of basic research enhances both scientific impact and career opportunities.

Students must understand that signaling represents the mechanism by which mitochondria exert their biological effects beyond energy production. Dysregulated signaling, not simply energy deficiency, underlies most mitochondrial contributions to disease pathology.

We invite you to read our new article, “Welcome to the Mitoverse,” featured in the October 2025 issue of STEM Magazine—a widely read online publication reaching K–12 STEM teachers, college instructors, and faculty across the United States and beyond.

We’re thrilled to bring the world of mitochondria to a broader educational audience as part of www.MitoWorld.org’s mission to expand understanding of cellular dynamics, the mitochondrial genome, and the crucial mito-nuclear axis.

Why We Wrote “Welcome to the Mitoverse”

As we developed the article—written as an FAQ on MitoWorld—we realized how few straightforward, accurate, and well-referenced explanations exist for what mitochondria really are: their origins, their roles in health and disease, and their central place in modern biology and medicine.

We also recognized a deeper challenge. While genetics and the microbiome have each had their revolutions, the mitochondrial revolution is only beginning. Raising awareness must start early—in schools—where students’ natural curiosity can be fostered with accurate, up-to-date narratives about how life works.

Help Us Build a Mito-STEM Curriculum

This publication represents an opportunity to start a new effort we call MITO-STEM— partnerships connecting K–12 teachers, college instructors, and mitochondrial researchers. Our hope is to engage educators who want to introduce students to the remarkable world of mitochondria: their dynamic structure, their unique DNA, and their continuous dialogue with the nucleus and the rest of the cell.

In most biology classrooms, cells are still depicted as static spheres with a few scattered mitochondria—an image that bears little resemblance to reality. Yet understanding how mitochondria actually function, and how they dynamically coordinate and communicate with the nucleus, is essential to understanding life itself.

If you are interested in participating, please contact info@mitoworld.org

Mainstreaming Mitochondria

At MitoWorld, our mission is to mainstream mitochondria—to make their importance visible in both public understanding and medical research. Greater awareness will help drive funding for conditions ranging from rare mitochondrial diseases at birth to neurodegenerative disorders in later life.

By connecting scientists and educators through MITO-STEM, we hope to reshape how biology is taught and understood—inspiring students to see the living cell as a vibrant, interconnected system and mitochondria as its central players.

We invite teachers, researchers, and institutions to join us in this effort. Read “Welcome to the Mitoverse” in STEM Magazine’s October 2025 issue, and explore how you can get involved at www.MitoWorld.org.

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.