From calorie to energy: the cofactors nothing runs without

You have eaten. Properly, not just coffee standing up. You have slept. At your last check the values were fine. And still you sit there at four in the afternoon feeling as though somebody pulled the plug.

In my consultations I hear almost the same sentence every week: I do not get it, I really do eat enough.

I believe you. Your body simply does not calculate in calories. It calculates in ATP. Between the two lie five stations, and at each one sits a micronutrient.

A calorie is a calculation. Energy is a performance.

Do you know the feeling that your body does not translate food into drive? A calorie is not a substance. It is a measurement from a device in which food was burned and the heat was recorded. It simply does not describe what happens inside your cells.

Your cells do not burn. They break down, in a controlled way, across dozens of enzyme reactions. At the end stands ATP. That is the form of energy a muscle fibre can spend right away. And every enzyme along this route needs a helper part, a cofactor.

This is not a fringe opinion. In 2010 EFSA stated that a cause and effect relationship between thiamine intake and normal energy-yielding metabolism is considered established [Regulatory Document].

And now you understand why the calorie count misses the point in some situations.

From bite to ATP: the route in five stations

Picture an assembly line. At the start a piece of bread, at the end the ATP. In between five work stations, each with its own toolbox. If the tool is missing at one station, the line backs up.

A research group around Depeint wrote down exactly this mapping systematically in 2006 [Mechanism Review].

And now you know why we talk about single nutrients without playing them off against each other.

Thiamine: the narrowest bottleneck in metabolism

If I had to pick one cofactor that makes the principle visible, it would be thiamine. Vitamin B1, converted in the body into thiamine diphosphate. This molecule sits at three key enzymes: pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase and transketolase. If thiamine is missing, more pyruvate can end up as lactate. The sugar is there, the gate is jammed.

In humans we have known the extreme form for more than a hundred years: beriberi and Wernicke encephalopathy. A clinical review from 2021 notes [Systematic Review] that thiamine deficiency affects metabolism, nerves, the cardiovascular system and digestion at the same time and is therefore often overlooked. There is no specific test that reliably rules it out. And it contains one sentence that gets under my skin every time: even in severe cases, clinical improvement can set in within hours to days.

Why your thiamine requirement grows with what you eat

Here comes the point that turns calorie logic around. EFSA states the thiamine requirement not per kilogram of body weight but per megajoule of energy intake [Regulatory Document]: 0.072 milligrams per megajoule on average, 0.1 as the reference intake. That works out at roughly 0.3 and 0.4 milligrams per 1000 kilocalories. Whoever eats more needs more thiamine, purely to be able to use what was eaten.

At this point one could suspect thiamine deficiency everywhere. That is exactly where it gets dishonest. At the Mayo Clinic the prevalence in outpatient heart failure was below 11.6 percent [Cohort, n=30], although earlier work had reported up to 50 percent. A Canadian study found the same rate of 6 percent in patients and controls [Cohort, n=150].

And now you know why I am enthusiastic and cautious about this topic at the same time.

B2, B3, B5 and biotin: the carriers without a headline

When B vitamins come up, it is almost always about B12. The rest of the family works in the background. Yet it is precisely these four that carry the route from calorie to ATP.

A review from 2021 reports that an inherited limitation of riboflavin uptake and utilisation is said to be present in about 10 to 15 percent of the world population [Review]. That is a figure from a narrative review, not an established population number. Still, it opens a door: not everyone makes the same amount of FAD out of the same amount of riboflavin.

Niacin deserves a second look. NAD is not a store that simply sits there. It is used up constantly, among other things during DNA repair [Mechanism Review]. A reduced ratio of NAD to NADH is associated with ageing processes. Associated explicitly does not mean caused.

And now you know why the question about the one most important vitamin for energy is a question metabolism does not answer.

Magnesium: ATP without magnesium is not really ATP

Maybe you have taken magnesium before, for calf cramps or for sleep. And wondered why this substance of all things turns up everywhere.

When textbooks draw ATP, a single molecule appears. In the cell the three phosphate groups carry negative charge, and that charge is shielded by a magnesium ion. For most enzymes the substrate is therefore not free ATP but the complex of ATP and magnesium. Without magnesium the energy currency is present but does not fit the lock.

A large physiological review from 2015 assigns magnesium to more than 600 enzymatic reactions [Mechanism Review]. The popular figure of 300, which haunts guidebooks and labels, is therefore outdated.

For me this is the cleanest human demonstration of the argument. No extreme case. Just a cofactor that became scarcer, and a more expensive metabolism.

The cofactor view does not stop at the plate. A review from 2016 names proton pump inhibitors and diuretics explicitly as causes of hypomagnesaemia [Review]. A review on sport describes increased losses through urine and sweat during intense exertion and estimates the extra requirement at 10 to 20 percent [Review].

Which form makes sense is covered in Which magnesium is the best. And now you know why a single serum value is only part of the story here.

Iron and copper: the metals in the respiratory chain

You know iron as the substance that makes blood red. That is simply not the role we are dealing with here.

In the respiratory chain iron sits in two designs. First in iron-sulfur clusters: tiny metal lattices that pass electrons along like a chain of hands. Complex I carries a particularly large number of them. Second as haem iron in the cytochromes of complexes III and IV. Reviews describe how elaborate the assembly of these clusters is [Mechanism Review]. Between iron in the blood and iron in its place lie many steps.

Right at the end waits copper. Cytochrome c oxidase works with haem a, haem a3 and two copper centres. How this centre is assembled is not fully clarified even after 70 years of research [Mechanism Review].

Why iron deficiency can cost energy before anaemia appears

And the counter-check: a Zurich study gave 90 women with ferritin up to 50 nanograms per millilitre intravenous iron or placebo [RCT, n=90]. In the whole group the difference just missed significance (p=0.07), and only at a baseline ferritin up to 15 did it become clear (p=0.005). The emptier the store, the clearer the effect.

Going deeper: Iron and inflammation explains the hepcidin brake, Improving iron absorption covers the food side, and Functional iron deficiency takes on normal values despite exhaustion. And now you know why iron shows up here as a metal inside an enzyme.

Coenzyme Q10 and carnitine: shuttle and ferry, placed honestly

Now come the two substances written about most and differentiated least.

Coenzyme Q, often sold as Q10, is a fat-loving, redox-active lipid and commutes electrons between complexes I and II and complex III. A review from 2023 describes it more aptly: coenzyme Q is the collection point where electrons from many metabolic pathways feed in [Mechanism Review]. The same authors note that important questions about its biosynthesis and transport remain open.

Carnitine: the ferry for fatty acids

Fat cannot cross the inner mitochondrial membrane by itself. It needs a ferry, and that ferry is called carnitine. Carnitine palmitoyltransferase 1 converts an acyl-CoA ester into an acyl-carnitine ester on the outside, a translocase brings it in, and carnitine palmitoyltransferase 2 converts it back so that beta-oxidation can begin [Mechanism Review].

For fatty acids to become energy, more than two dozen enzymes and transport proteins are needed [Mechanism Review]. A fat calorie is therefore not a credit balance but a promise that is only redeemed by two dozen proteins.

One boundary marker to finish, because mitochondria have become a marketing word. When complex I fails because of a genetic defect, the result is not a diffuse feeling of tiredness but Leigh syndrome, an often fatal encephalopathy [Mechanism Review]. Everyday tiredness is not a mild form of that.

And now you know why I like talking about mechanisms here and dislike talking about promises.

When calories without cofactors become dangerous

There is one situation in which the core argument of this article does not appear as theory but as an emergency.

Think of a person who has eaten too little for a long time. The cellular stores for phosphate, magnesium and thiamine are low, even if the blood values look unremarkable. And now food arrives, above all carbohydrates. Insulin rises, metabolism starts up, and the cells pull in exactly what was already scarce. That is refeeding syndrome.

A German-language review from 2018 names the initial measurement of thiamine and electrolytes and a slow increase in food intake as the central measures [Review]. The cofactor perspective has therefore been standard in clinical nutritional medicine for decades. It has simply barely arrived in the public calorie debate.

The quiet end of the same question

Between the intensive care unit and the afternoon slump lie worlds. It is the same axis, just at the other end.

More on this in Unprocessed food and satiety and in The calorie myth: quality over quantity. And now you know why an emergency protocol from the clinic and the question about your breakfast belong to the same story.

How you might notice this, and what belongs in a medical work-up

That leaves the question that probably interests you most: how is anyone supposed to notice something like this?

The honest answer first: not from a single symptom. Exhaustion is one of the least specific signs in medicine. It can come from lack of sleep, from the thyroid, from depression, from medication, from anaemia or from too little movement. That is why the first step is never a supplement but a proper work-up.

For several cofactors, laboratory diagnostics run into a limit here, and that deserves to be said openly. For thiamine, according to a clinical review, there is no specific test. For magnesium, the serum value reflects the tissue store only to a limited degree. That is not an argument against laboratory work, but an argument for treating values as building blocks rather than verdicts.

What I observe in my consultations I say as an observation and not as proof: people whose exhaustion is not explained after a careful basic work-up often have several small building sites at once rather than one big one. An experience, not a body of data.

If you would like to do more than read and sort this out for your own situation: below this article you will find the option to book an appointment.

And now you know why the most interesting question is not which supplement, but at which station your assembly line is stalling.

Common questions about micronutrients and energy metabolism

Cofactors in the bigger picture

The question of whether food turns into usable energy comes up again in many areas: in training, in exhaustion, in single minerals. From here several routes lead onward.

And because topics touch without being the same: micronutrients in interplay with adaptogens and the stress axis are covered in Micronutrients and adaptogens in burnout. Redox and detoxification in Glutathione as master antioxidant. And if exhaustion with an iron angle is on your mind: Iron deficiency, tiredness and exhaustion.