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.