Having Fuel Is Not the Same as Producing Energy

What David Nicholls’ commentary teaches us about mitochondrial function—and how it connects with bioenergetic impedance

When we talk about cellular energy, we often focus on what is available: glucose, fat, nutrients, oxygen, or ATP. But availability answers only part of the question. We also need to understand how effectively these resources move through the processes that sustain biological work.

A commentary by established mitochondrial bioenergeticist David G. Nicholls brings this distinction into focus. Published in BBA – Bioenergetics in 2025, his article asks a provocative question: Why do many cell biology papers contain fundamental bioenergetic errors?

Nicholls, coauthor of the textbook Bioenergetics, argues that even sophisticated studies can misinterpret mitochondrial function when they overlook the physical principles governing energy transformation.

His message provides a useful foundation for discussing bioenergetic impedance: how constraints on energetic throughput and recovery may shape physiological responses to stress.

Mitochondria operate through driving forces and fluxes

Nicholls begins with the fundamentals. The mitochondrial electron transport chain uses energy from electron transfer to pump protons across the inner membrane. This establishes an electrochemical driving force—the protonmotive force—that enables ATP synthase to produce ATP.

He explains these relationships using an electrical-circuit analogy:

• Voltage corresponds to protonmotive force.

• Current corresponds to proton flux, linked to respiration.

• Conductance describes how readily protons move through available return pathways.

This perspective directs attention to relationships: the force driving a process, the pathways permitting it, and the flow actually achieved.

Measuring one component cannot reveal everything about the functioning system.

A concentration is not a rate

One of Nicholls’ clearest examples concerns ATP measurements.

A difference in ATP concentration may reflect a difference in the size of the nucleotide pool. It does not automatically establish a corresponding difference in cellular energetic status. Nicholls emphasizes the importance of the ATP/ADP relationship and the separation of mitochondrial and cytoplasmic compartments.

This illustrates a distinction that is easy to miss: how much is present and how quickly it turns over are different questions.

A reservoir offers a simple analogy. Its water level tells us how much water it contains at a particular moment. It does not tell us how rapidly water enters, leaves, or passes through a turbine. A high level could accompany vigorous flow—or restricted outflow.

The same reasoning helps explain why substrate availability should not be equated with substrate turnover.

Available fuel does not establish effective throughput

Extending Nicholls’ distinction between pools and fluxes, an abundant substrate pool does not by itself demonstrate that the substrate is being effectively processed.

A measured concentration reflects the balance between entry and removal over time. An elevated pool could therefore arise from increased delivery, reduced utilization, or both. Concentration alone cannot distinguish these possibilities.

This substrate argument is an interpretation extending the commentary’s reasoning; Nicholls does not develop it as a separate framework in this article.

Nevertheless, it changes the question we ask. Alongside “Is enough fuel available?” we should ask:

What determines the rate at which available fuel can be processed into useful biological work?

Where this aligns with bioenergetic impedance

In our published perspective, bioenergetic impedance describes a proposed, time-dependent constraint arising when energetic demands exceed available throughput and recovery capacity. Its emphasis is on the relationship between demand, processing capability, and subsequent restoration.

Nicholls’ commentary aligns with the mechanistic foundation of this thinking: driving forces, conductance, and achieved flux must be considered together.

However, the two contributions operate at different scales. Nicholls focuses on mitochondrial principles and experimental interpretation. Our perspective extends the question to interacting physiological systems and asks whether constraints resolve after a challenge or persist into subsequent challenges.

That extension remains a proposed framework. Its terminology is inspired by physics; it does not imply that the body has one electrical-equivalent impedance value or that a single biomarker can diagnose it.

Better explanations require better measurements

Nicholls also warns about common experimental shortcuts. Fluorescent probes described as mitochondrial membrane-potential indicators can produce signals influenced by plasma-membrane potential, probe concentration, and fluorescence quenching. Oxygen-consumption measurements require careful consideration of the processes controlling respiration.

Even genetic manipulation does not remove the need to demonstrate that a proposed mechanism is consistent with bioenergetic principles.

These cautions are particularly relevant when connecting cellular findings to broader explanations of health. A plausible story must remain distinguishable from a demonstrated mechanism.

For bioenergetic impedance, the challenge is therefore to measure demand and functional capacity, then follow recovery over time. Evidence supporting its individual biological mechanisms does not, by itself, validate the whole framework.

Nicholls’ commentary encourages a more precise understanding of cellular energy: what is present, what is flowing, what controls that flow, and what the measurements actually establish. Those distinctions provide a disciplined starting point for investigating how energetic constraints affect adaptation and recovery.

References

Nicholls, D. G. (2025). Commentary: Why do many cell biology papers contain fundamental bioenergetic errors? BBA – Bioenergetics, 1866, 149541. https://doi.org/10.1016/j.bbabio.2025.149541

Tippairote, T., & Hoonkaew, P. (2026). Bioenergetic impedance: A network physiology framework for stress adaptation, maladaptation, and recovery. Frontiers in Network Physiology, 6, 1967461. https://doi.org/10.3389/fnetp.2026.1967461