The Mitochondrial Nutrient Missing From Every Supplement

It's the respiratory chain component you never learned about in school.

I searched “mitochondrial” on Amazon and accepted its suggested search of “mitochondrial support,” then looked at the first 50 supplements that came up and examined their labels to see if any had MK-4. One had MK-7 at a very modest dose of 100 micrograms, and none had any MK-4.

There was an awful lot of CoQ10, which humans can synthesize. The entire point of taking CoQ10, of course, is that you may have a genetic impairment in synthesizing it, you may be taking a a statin for your cholesterol or a bisphosphonate for your osteoporosis, which prevent you from synthesizing it, or you may have trouble getting it into your cells and need to ram it through with very high doses.

MK-4 is in every way the same. Humans synthesize it from all other forms of vitamin K, but you could have impaired synthesis, you could be impairing your own synthesis by taking a statin or a bisphosphonate, you could have trouble absorbing the precursors (other K vitamins) from food, or you could have trouble getting it into your cells.

CoQ10 and MK-4 have very similar structures. They are both fat-soluble quinones with long-tails, though CoQ10 is almost twice the size with a much longer tail. They follow the same pathways of absorption and uptake from the gut, through the lymph, and into cells.

The main drugs that inhibit their synthesis are the same. The problems you would have getting them into your cells are the same. The only difference is the genetic impairments impacting their synthesis are different.

Lo and behold, they both accumulate in the inner mitochondrial membrane, where the respiratory chain is.

Lo and behold, they have similar redox potentials, which measures their electron-transferring properties. MK-4 in a lipid monolayer is negative 63 millivolts. According to Molecular Biology of the Cell, CoQ10 has a redox potential of positive 30 millivolts. These are standard redox potentials and the actual values differ from context to context based on factors such as the relative concentrations of the substances involved, but they serve for approximate comparisons. Electrons move from more negative to more positive redox potentials:

If complexes I is around -320 mV, complex II is less than -200 mV, and complex III is roughly +100 mV, then both CoQ10 (+30 mV) and MK-4 (-63 mV) would be similarly capable of moving electrons from complexes I and II to complex III, at least in principle.

However, this would not actually happen this way in practice because respiratory chain complexes are not floating around randomly but are rather built into “supercomplexes.” For example, this is the complex I-III-IV “supercomplex” from bovine heart mitochondria depicted in Molecular Biology of the Cell:

The CoQ10, designated Q, is deeply attached into the inside of this architecture, and unless MK-4 is also deeply bound in the same spots, it isn’t going to traverse the same pathway.

However, the evidence is that CoQ10 and MK-4 play distinct roles in the respiratory chain:

• When fruit flies have their MK-4 synthesis shut off by knocking out the UBIAD1 gene, they develop a respiratory chain disorder that cannot be rescued with CoQ10, but can be rescued with MK-4.

• On the other hand, in yeast and human cells with defects of CoQ10 synthesis, MK-4 cannot fix the problem.

• In two human case reports (here and here), menadione, a relatively toxic precursor to MK-4, had some utility in treating a complex III disorder. The authors proposed that MK-4 was taking electrons from vitamin C and delivering them to cytochrome C.

As I covered in Vitamin C, Whole Food Vs. Synthetic: Does It Matter?, this is a known role of vitamin C in plants: to supply electrons to the respiratory chain under conditions of stress when other sources of electrons are limiting.

Yes, that means vitamin C has calories.

Anyway, MK-4 has a much shorter tail than CoQ10, which means the following:

• It won’t fit in exactly the same places if there is specificity to the CoQ10-binding site of respiratory chain complexes.

• CoQ10 will stay on the inside of the membrane, because that part of the membrane is fattier and its longer tail makes it more fat-soluble.

• MK-4 will stay toward the outside of the membrane, because the outside is more watery and MK-4’s shorter tail makes it more water-soluble.

• CoQ10 will move more slowly through the membrane, while MK-4 will move much more rapidly through the membrane.

All of this makes MK-4 very well suited to take electrons from anything with a more negative redox potential within proximity to the inner mitochondrial membrane and donate them to cytochrome C, which is also mobile within the membrane.

Thus, MK-4 likely serves an essential-to-life role as a “release valve” and “reserve carrier” to the canonical pathway of the supercomplexes. The supercomplexes run the bulk of electron transfer, but then the precise balance of flow needed in any given instant is fine-tuned with MK-4’s more diverse and mobile properties.

The ideal way to optimize mitochondrial health is to use the Comprehensive Screening for Energy Metabolism, and the philosophical approach outlined in How I Found My Health “Super Unlock” After 20 Years of Research and 20,000 Genes Tested.

The middle of the road path to using MK-4 for mitochondrial health would be to use the Comprehensive Nutritional Screening and use MK-4 dosing to bring up intracellular vitamin K2 concentrations at least into the normal range and preferably to the top half of that range.

The simple thing to do: mitochondrial support supplements that are meant as blunt tools to try to paper over the hundreds of different problems bucketed as “mitochondrial dysfunction” should all have about one microgram of MK-4 for every one milligram of CoQ10.

The dosing rationale is that standard doses of CoQ10 are around 100 milligrams, whereas 100 micrograms of K2 seems to gain most of the benefit for the average person. By contrast, in conditions of stress requiring higher doses, such as to combat severe kidney calcification, it looks like the optimal dose is somewhere around 3000-4000 micrograms, and 3500 milligrams is around the upper dose of CoQ10 used in genetic disorders of CoQ10 synthesis. I outlined dosing rationales for vitamin K2 in The Ultimate Vitamin K2 Resource.

Like your mitochondria? You should love MK-4.