One of the most persistent beliefs I encounter in clinical practice is that low energy means something has 'gone wrong' with the mitochondria. People assume that fatigue must reflect a failure of energy production — that the body is no longer capable of generating ATP efficiently, and that the solution is simply to provide more of the right nutrients. This belief fundamentally misunderstands how human biology works.

The body does not passively lose the ability to make energy. It withholds it. And when you understand why, fatigue begins to look far less like a defect — and far more like a deliberate, protective strategy.

Energy Is Not Just Fuel — It Is a Commitment
Every cell in your body is constantly assessing its environment — not just in terms of calories or oxygen, but in terms of safety. Is there inflammation present? Is the immune system activated? Are stress hormones elevated? Is there a threat that requires vigilance rather than repair?
This matters because mitochondrial metabolism is not neutral. The Krebs cycle and electron transport chain generate reactive oxygen species as natural by-products — molecules that, in stable conditions, serve as essential signals coordinating repair and adaptation. But under conditions of threat, excessive mitochondrial activity becomes risky. It increases oxidative load, amplifies inflammatory signalling, and demands metabolic investment that may not be safe to sustain.
So the body does something profoundly intelligent. It downshifts.

Glycolysis - The Ancient Survival Engine
Glucose metabolism begins with glycolysis — an ancient pathway that takes place outside the mitochondria entirely. It evolved billions of years before oxygen-based life and remains the cell's fallback when mitochondrial function is suppressed.
Glycolysis is fast but inefficient: it yields only two ATP molecules per glucose, compared to 30-36 through full oxidative phosphorylation. It produces lactate as an end product. Why would the body ever prefer this route?
Because efficiency is not always the goal. Survival is.
Glycolysis allows the cell to generate energy while keeping mitochondria relatively quiescent — reducing oxidative stress, conserving cofactors needed for defence, and maintaining metabolic readiness without committing to the high-output, high-risk strategy of full mitochondrial engagement. Immune cells use this strategy deliberately when fighting infection, shifting dramatically toward glycolysis to proliferate rapidly and generate the inflammatory mediators needed for immune defence.

Pyruvate Dehydrogenase - The Gatekeeper
The pivotal moment comes at the end of glycolysis, when pyruvate is produced. This represents a metabolic crossroads — perhaps the most important decision point in human bioenergetics.
From here, carbon can be committed to mitochondrial oxidation via conversion to acetyl-CoA, or diverted into lactate, allowing glycolysis to continue without mitochondrial engagement. The enzyme controlling this decision is pyruvate dehydrogenase (PDH) — functionally a permission checkpoint that determines whether the cell commits to full oxidative metabolism or remains in safer, more constrained territory.
PDH is exquisitely sensitive to signals of danger. Inflammatory cytokines such as IL-1β, TNF-α, and IL-6 suppress its activity. Chronic cortisol elevation shifts metabolism away from mitochondrial oxidation. Hypoxia, oxidative stress, heavy metals, and nutrient depletion (particularly thiamine, lipoic acid, and magnesium) all converge on this same enzymatic gate.
The result is not random dysfunction, but regulated inhibition — often mediated by PDH kinases that actively phosphorylate and silence the complex in response to danger signals. From the cell's perspective, this makes perfect sense: when PDH is inhibited, pyruvate is shunted toward lactate, oxidative pressure is reduced, and resources are conserved.
This is not a broken system. It is a system choosing restraint.

The Krebs Cycle as a Signalling Hub
When acetyl-CoA does enter the Krebs cycle, the goal is not ATP itself — the cycle produces only one ATP equivalent per turn. Its true value lies in feeding forward NADH and FADH₂ to power the electron transport chain. But there is another dimension that is clinically crucial: the intermediates of the cycle are not just metabolic stepping stones — they are signalling molecules that directly shape immune behaviour and inflammatory tone.
α-ketoglutarate supports regulatory immune function and promotes epigenetic states associated with repair and tolerance. Succinate, by contrast, accumulates when the Krebs cycle becomes truncated and acts as a potent pro-inflammatory signal, stabilising HIF-1α and driving IL-1β production.
What this means clinically is profound: when mitochondrial flow is impaired, metabolism itself becomes inflammatory. This explains why chronic inflammatory conditions are so often accompanied by fatigue, exercise intolerance, and cognitive symptoms even in the absence of overt pathology. The metabolic terrain has shifted toward defence, and immune signalling follows suit.

Why Supplements Alone So Often Disappoint
This framework explains a common clinical frustration: why targeted mitochondrial supplements frequently fail to deliver lasting change.
CoQ10, B vitamins, magnesium, carnitine — these nutrients are genuinely essential. But they do not override inflammatory signalling. They do not convince PDH to open the gate when the cell still perceives threat. If extracellular and intracellular signals continue to communicate danger, metabolism will remain constrained regardless of cofactor availability.
Worse, trying to force energy production under these conditions can backfire. Pushing substrates through impaired mitochondria increases oxidative stress, activates further inflammatory signalling, and reinforces the very metabolic state the supplements were meant to correct.
The mistake is not in the nutrients themselves — it is in assuming that energy can be commanded rather than permitted.

The Real Work of Restoring Energy
True recovery begins upstream of ATP. It involves identifying and reducing the signals that keep metabolism in defence mode: chronic inflammation from any source, unresolved immune activation, persistent stress responses, nutrient insufficiency at the enzymatic level, and impaired redox balance.
This is why post-exertional malaise — the characteristic worsening that follows exertion in conditions like chronic fatigue syndrome — is such an important clinical signal. It reflects a system that has not yet regained metabolic safety. Pushing before the terrain is ready typically prolongs recovery rather than accelerating it.
When upstream pressures ease, PDH activity can resume, Krebs cycle flow stabilises, and mitochondrial metabolism re-engages organically. Energy returns not because it is pushed, but because the body once again deems it safe.

A Final Reframe
Your cells are not failing you. They are responding precisely to the signals they are receiving.
Fatigue is not a deficiency of effort, discipline, or supplements. It is a reflection of biological intelligence operating under constraint. The body is not broken — it is protecting itself from what it perceives as an unsafe investment.
When the environment changes — internally and externally — energy follows. The mitochondria do not need to be forced back online. They need to be shown that it is safe to return.
The goal is not to override the body's wisdom. It is to create the conditions under which that wisdom chooses a different path.

References

Mitochondrial Function & Reactive Oxygen Species
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Glycolysis & Metabolic Flexibility
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Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324(5930):1029-1033.
Pyruvate Dehydrogenase Regulation
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Immunometabolism & Krebs Cycle Intermediates
Mills EL, Kelly B, O'Neill LAJ. Mitochondria are the powerhouses of immunity. Nature Immunology. 2017;18(5):488-498.
O'Neill LAJ, Kishton RJ, Rathmell J. A guide to immunometabolism for immunologists. Nature Reviews Immunology. 2016;16(9):553-565.
Tannahill GM, Curtis AM, Adamik J, et al. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature. 2013;496(7444):238-242.
Williams NC, O'Neill LAJ. A role for the Krebs cycle intermediate citrate in metabolic reprogramming in innate immunity and inflammation. Frontiers in Immunology. 2018;9:141.
Cell Danger Response
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Inflammation & Mitochondrial Suppression
Picard M, McEwen BS. Psychological stress and mitochondria: a systematic review. Psychosomatic Medicine. 2018;80(2):141-153.
Cherry AD, Bhalla J, Bhalla M, et al. Mitochondrial biogenesis and inflammation in human skeletal muscle. The Journal of Physiology. 2014;592(11):2291-2301.