Beyond Mitochondrial Dysfunction: Micronutrient Permissiveness and the Next Evolution of Bioenergetic Health

Why can two people face similar physiological stress yet recover so differently?

One may experience temporary fatigue, adapt, recover, and return to baseline. Another may remain exhausted for days, become increasingly intolerant of exertion, develop pain or cognitive symptoms, and gradually lose resilience.

We often explain this difference by looking for a disease, a mitochondrial defect, or a nutrient deficiency.

But there may be another way to think about it:

What if health depends not only on how much energy-producing machinery we have, but on how permissive the biological environment is for energy to move through that machinery?

A new narrative review published in Nutrients provides an interesting starting point for this question. Abanades and colleagues examine micronutrition as a strategy for mitochondrial dysfunction in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia. Their review brings together mitochondrial bioenergetics, oxidative and nitrosative stress, immune regulation, NAD⁺ metabolism, glutathione, and a range of nutrients involved in cellular energy metabolism.

On its own, the review makes an important case for looking beyond single nutrients.

Placed alongside Bruce Ames's micronutrient triage theory—and extended through the framework of bioenergetic impedance—it points toward something broader:

Micronutrients may be important not simply because deficiencies cause disease, but because they help determine whether physiological systems remain permissive enough to meet changing energetic demands.

That distinction could influence how we think about fatigue, resilience, chronic disease, healthy aging, and eventually personalized preventive medicine.

Mitochondria Are Not Just ATP Factories

The Nutrients review begins from an increasingly familiar observation: mitochondrial abnormalities have been reported in both ME/CFS and fibromyalgia.

Studies in ME/CFS have described alterations in oxidative phosphorylation, respiratory capacity, membrane potential, ATP-related metabolism, and other aspects of cellular bioenergetics. In fibromyalgia, investigators have reported reduced bioenergetic health in peripheral blood mononuclear cells, structural mitochondrial abnormalities, and experimental evidence of impaired mitochondrial biogenesis and quality control.

But the authors are appropriately cautious.

There is no single mitochondrial defect that explains every patient. Findings vary according to cell type, methodology, patient selection, and disease phenotype. Mitochondrial dysfunction may be part of the pathology without necessarily being its original cause.

This is an important distinction.

The authors therefore describe a broader redox–immune–mitochondrial triangle.

Mitochondria influence redox regulation and immune signaling. Immune activation can increase oxidative and nitrosative stress. Oxidative stress can damage mitochondrial proteins, membranes, and DNA. Mitochondrial stress can then further influence inflammation and cellular signaling.

The result may be a self-reinforcing network rather than a single broken component.

That is already a significant improvement over the simplistic idea that chronic fatigue means that mitochondria simply "cannot make enough ATP."

But we can take the model further.

Micronutrients: More Than Deficiency Versus Sufficiency

Mitochondrial energy metabolism depends on many micronutrients simultaneously.

B vitamins participate in glycolysis, the TCA cycle, and electron transfer. Magnesium is essential for ATP-dependent processes. Coenzyme Q10 participates directly in electron transport. NAD⁺ metabolism links redox reactions with metabolic regulation and cellular stress responses. Glutathione depends upon adequate precursor availability. Carnitine supports fatty-acid transport. Other nutrients participate in antioxidant defense, mitochondrial structure, enzyme activity, and signaling.

The review therefore argues for a systems-based micronutritional approach, rather than expecting a single nutrient to correct a complex multisystem disorder.

But one observation in the review may be even more important.

The authors note that subclinical micronutrient insufficiencies—or increased micronutrient requirements during chronic inflammation and metabolic stress—may create metabolic bottlenecks even in the absence of overt nutritional deficiency.

This takes us directly back to the work of Bruce Ames.

Bruce Ames and the Micronutrient Triage Principle

In 2006, Bruce Ames proposed what became known as the triage theory of micronutrients.

His argument was evolutionary.

When micronutrients are scarce, biological systems cannot necessarily support every function equally. Natural selection would favor preserving processes essential for immediate survival and reproduction, while functions whose consequences become important years or decades later may receive lower priority.

Moderate micronutrient insufficiency might therefore leave essential short-term functions relatively intact while gradually compromising genomic maintenance, antioxidant protection, mitochondrial health, and other long-term protective processes.

Ames subsequently described modest micronutrient deficiencies as potentially accelerating molecular aging, including mitochondrial decay.

This is profoundly different from the classic deficiency model.

Classical nutrition often asks:

Is the person deficient or not?

Ames instead directs us toward another question:

When resources become marginal, which functions continue to receive support—and which functions are quietly sacrificed?

The person may remain alive and apparently functional while accumulating a long-term biological cost.

This concept can now be extended further.

From Micronutrient Sufficiency to Micronutrient Permissiveness

A useful term for the next step may be micronutrient permissiveness.

Micronutrient permissiveness can be conceptualized as:

the degree to which micronutrient availability permits metabolic pathways to achieve the throughput required by the current physiological demand.

This is not a term proposed by Abanades and colleagues or by Ames. It is an extension of their observations through the bioenergetic impedance framework.

And the distinction matters.

Micronutrient status describes what is available.

Micronutrient permissiveness asks whether what is available is enough to permit the

metabolic work currently required.

A nutrient concentration that is adequate during rest may become functionally limiting during infection, heavy exercise, tissue repair, persistent inflammation, oxidative stress, environmental exposure, pregnancy, psychological stress, or another state of increased physiological demand.

In other words, adequacy is partly demand-dependent.

This means moderate insufficiency may first appear not as complete pathway failure but as a loss of reserve.

At low demand, everything appears normal.

As demand rises, the system reaches its metabolic ceiling earlier.

That is where micronutrition begins to intersect with bioenergetic impedance.

Bioenergetic Impedance: From Capacity to Flow

The bioenergetic impedance framework approaches physiology from the perspective of flow.

Having mitochondria is not enough.

Having nutrients is not enough.

Having fuel is not enough.

Energy must move through a coordinated sequence of processes:

substrate delivery → transport → glycolysis/β-oxidation → TCA-cycle processing → reducing-equivalent transfer → electron transport → proton gradient → ATP synthesis → ATP utilization → recovery and repair

Every stage has finite capacity.

If one part becomes restrictive, adding more substrate upstream does not necessarily produce more useful energy downstream.

Instead, pressure can accumulate.

This is the essence of bioenergetic impedance: resistance encountered as physiological demand attempts to generate energetic flow through a system of finite and changing capacity.

Micronutrients become important because they help establish the biochemical environment through which this flow must occur.

Moderate insufficiency may reduce enzyme activity or reserve without completely stopping a pathway.

Under increasing demand:

lower micronutrient permissiveness→ earlier throughput limitation→ higher bioenergetic impedance

The problem is therefore not necessarily a deficiency severe enough to produce a classical nutritional disease.

It may be an inability to support the required flux at the required time.

When Throughput Becomes Limited, Congestion Matters

This also changes how we interpret oxidative stress and altered metabolism.

If downstream oxidative metabolism cannot accommodate incoming substrate and reducing equivalents, upstream processes do not simply disappear.

Metabolic traffic begins to accumulate.

Conceptually:

demand rises→ downstream throughput becomes limiting→ NADH/FADH₂ reoxidation becomes constrained→ local redox pressure increases→ dehydrogenase flux may slow→ intermediates accumulate→ carbon is rerouted→ alternative pathways help preserve immediate function

This is bioenergetic congestion.

Some rerouting may be highly adaptive.

Increasing glycolysis, producing lactate, changing substrate preference, mobilizing stored fuels, modifying inflammatory signaling, or altering endocrine and autonomic output can all help an organism survive a temporary challenge.

The problem is not adaptation itself.

The problem begins when the system cannot completely recover afterward.

Recovery Is More Than Restoring ATP

This may be one of the most important consequences of introducing permissiveness into the model.

Recovery cannot simply mean replenishing ATP.

True recovery requires the biological environment to become permissive again.

That may require restoration of:

• micronutrient availability,

• redox balance,

• NAD⁺/NADH handling,

• substrate balance,

• mitochondrial quality control,

• inflammatory resolution,

• autonomic and neuroendocrine regulation,

• tissue cooperation,

• and sufficient reserve for the next challenge.

The sequence becomes:

Respond → Adapt → Recover

When recovery is complete, impedance falls again and the system returns toward baseline.

But repeated stress combined with inadequate permissiveness may produce:

Respond → Adapt → incomplete recovery

The next challenge then begins from a less favorable starting point.

Over time:

repeated demand→ repeated throughput limitation→ congestion and compensatory rerouting→ incomplete recovery→ progressively reduced permissiveness→ higher baseline impedance

Eventually, adaptation itself may become stabilized.

This is what we describe as bioenergetic lock-in.

Lock-In May Help Explain Chronicity

The review discusses mitochondrial-to-nuclear retrograde signaling: changes in ATP, ROS, calcium, NAD⁺ metabolism, and mitochondrial proteostasis can alter nuclear transcription and influence mitochondrial biogenesis, antioxidant responses, inflammation, and cellular stress adaptation.

This provides an important mechanism through which transient metabolic disturbances might produce more persistent cellular states.

The impedance framework extends that idea across time and across biological scales.

Repeated compensation may progressively reshape:

mitochondrial behavior, cellular signaling, substrate preference, inflammatory tone, autonomic regulation, tissue interactions, behavior, sleep, and resource allocation.

Eventually, what originally helped the organism survive the stress may itself become part of the environment that limits subsequent recovery.

That is lock-in.

And it offers another way to think about chronic fatigue and other chronic conditions without requiring one permanently defective molecule to explain everything.

Why This Changes the Micronutrient Conversation

The lesson is emphatically not that people with fatigue should take increasingly large combinations of mitochondrial supplements.

The clinical evidence summarized in the review shows why that conclusion would be premature.

CoQ10 combined with NADH has shown encouraging signals in ME/CFS. Magnesium has produced some improvements in fibromyalgia but not consistently in fatigue or quality of life. Alpha-lipoic acid has strong biochemical plausibility but disappointing disease-specific trial results. GlyNAC has interesting human evidence largely outside ME/CFS and fibromyalgia. Creatine can improve muscle phosphocreatine and strength without necessarily improving the broader symptom complex.

These apparently inconsistent findings actually make sense from an impedance perspective.

A nutrient can only relieve a bottleneck if that nutrient-dependent process is contributing materially to the bottleneck.

Adding an upstream cofactor when downstream electron transfer remains constrained may accomplish little.

Increasing substrate availability when the system is already congested may not improve throughput.

Improving one mitochondrial parameter may not restore tissue or network-level recovery.

This changes the therapeutic question from:

“Which supplement improves mitochondrial function?”

to:

“What is currently limiting permitted bioenergetic throughput in this person?”

That is a very different form of precision medicine.

A Future Research Agenda: Measure Recovery, Not Just Deficiency

This combined perspective suggests several directions for future research.

Rather than categorizing people simply according to diagnosis, studies could begin stratifying them according to bioenergetic phenotype.

Future investigations could combine nutritional status with measures of redox balance, metabolic intermediates, respiratory reserve, inflammation, body composition, autonomic regulation, environmental exposures, symptoms, and functional capacity.

Even more importantly, measurements should become dynamic.

A resting biomarker tells us where the system is now.

A

controlled challenge followed by repeated measurements may tell us whether it can

respond, adapt, clear the perturbation, and recover.

T

he future phenotype may therefore be less:

normal versus abnormal

and more:

How much demand can the system accommodate before throughput becomes constrained, and how quickly does it restore permissiveness afterward?

That could be particularly useful in fatigue syndromes, metabolic disease, aging, exercise physiology, and preventive medicine.

From Micronutrient Permissiveness to Tissue Permissiveness

Micronutrients may ultimately represent only the first layer.

The same principle can operate hierarchically:

Micronutrient permissiveness determines whether biochemical reactions have adequate cofactors.

Metabolic and redox permissiveness determine whether substrate oxidation and electron transfer can proceed efficiently.

Mitochondrial permissiveness determines whether existing mitochondrial machinery can express its energetic capacity.

Cellular permissiveness includes transport, signaling, proteostasis, redox control, and mitochondrial quality.

Tissue permissiveness incorporates vascular supply, extracellular conditions, inflammation, structural integrity, innervation, and cooperation among different cell types.

Network permissiveness determines whether organs can coordinate resource allocation and recovery across the whole organism.

A stressor therefore does not possess a fixed biological cost.

Its cost depends partly on the system encountering it.

The same exercise, infection, sleep loss, environmental exposure, or psychological challenge may be readily absorbed by a highly permissive system and profoundly disruptive to another operating close to its throughput ceiling.

Toward a Different Definition of Resilience

This leads to a broader interpretation of health.

Health is not simply possessing adequate ATP.

It is not simply possessing enough nutrients.

And it is not merely the absence of mitochondrial dysfunction.

Resilience may depend on maintaining sufficient biological permissiveness for energetic throughput to rise when demand rises—and then restoring that permissiveness after the challenge has passed.

Bruce Ames helped show that moderate micronutrient insufficiency may quietly force biological triage long before classical deficiency disease appears.

Abanades and colleagues bring mitochondrial bioenergetics, redox regulation, immune signaling, and micronutrition together and emphasize the importance of metabolic bottlenecks and coordinated nutritional support.

Bioenergetic impedance adds the dynamics of flow, constraint, congestion, recovery, and time.

Together, they suggest a progression:

Permissiveness→ determines achievable throughput→ throughput relative to demand determines impedance→ sustained impedance creates congestion and rerouting→ recovery restores permissiveness→ repeated incomplete recovery progressively reduces permissiveness→ persistent adaptation becomes lock-in

This may be a useful next step for bioenergetic medicine.

The future may not be about trying to make mitochondria work harder.

It may be about understanding what allows them—and the tissues and networks surrounding them—to work freely enough when they are needed, and to recover completely afterward.

References

Abanades, S., Fernández, I., Capdevila, N., & Cardona, F. (2026). Micronutrition as a therapeutic strategy for mitochondrial dysfunction in myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia: A narrative review. Nutrients, 18, 2702. https://doi.org/10.3390/nu18162702

Ames, B. N. (2006). Low micronutrient intake may accelerate the degenerative diseases of aging through allocation of scarce micronutrients by triage. Proceedings of the National Academy of Sciences of the United States of America, 103(47), 17589–17594. https://doi.org/10.1073/pnas.0608757103

Ames, B. N. (2018). Prolonging healthy aging: Longevity vitamins and proteins. Proceedings of the National Academy of Sciences of the United States of America, 115(43), 10836–10844.