Seabridge Bioenergetics

In this article we shall look at how high levels of Co2 from glucose metabolism acts as the main vasodilator preventing the over baseline use of nitric oxide as an emergency vasodilator, how nitric oxide inhibits respiration on cytochrome c oxidase in the electron transport chain and how co2 competes with nitric oxide protecting against nitric oxide inhibition of cytochrome c oxidase. Thereby, I shall argue that Co2 enhances not only oxygen delivery to the tissue by the bohr effect, but also enhances cellular respiration by stabilising proteins, and securing electron flowing freely to the final electron acceptor oxygen. Lastly, we shall discuss how staying at altitude and eating a high carb diet are prime ways of retaining high carbondioxide levels in the system.

Mainstream medicine and people in general often think of carbondioxide as nothing more than a wasteproduct that needs to be washed out and excreted from the lungs.
I recently had two extremely exciting patient cases, where it showcased the metabolic and energetic effects of Carbondioxide.

One patient hyperventilated to such an extent that he fainted several times—likely due to CO2 washout and the subsequent vasoconstriction in the brain, leading to low blood flow to the brain, causing the patient to faint, probably due a form of pseudo hypoxia – A very high partial pressure of oxygen in the blood and a very high saturation of oxygen in hemoglobin, but an inability to deliver and use the oxygen, leading to fainting.

The other patient case had some unrecognized issue that caused her to have a very low oxygen saturation in the blood and a very low partial pressure of oxygen in the blood (pCO2). So modern medicine would think she is severely hypoxic based on very low oxygen saturations. However, the patient had a very high level of CO2, which we know is protective against hypoxia, among other things through the Bohr effect, which has been described here on the blog before. Clinically, the patient did not have a significantly increased respiratory rate or breathing difficulty. The patient was severely cachexic, meaning there is not a lot of muscle tissue, and thereby, not a high oxygen need. No cyanosis either centrally or peripherally. The patient’s lactate level was on the low side, indicating that she did not have an oxygenation problem in the cells, as the electron flow could freely flow through the krebs cycle and the electron transport chain and finally reduce oxygen to water. The electrons freely flowing and the NADH and FADH2 easily oxidised, meaning that no anaerobic glycolysis had to be activated.
This is a classic example of CO2’s protective effect against hypoxia, it has the effect of lowering the need for oxygen coming in through the lungs.

We shall now look at why it might be protective of respiration:

CO2 is produced to a much greater extent during carbohydrate metabolism than during fatty acid metabolism in a ratio of 1/0.7. Two-thirds of the CO2 comes from the Krebs cycle, where one-third comes from glycolysis.
So when glucose metabolism is reduced, and the body uses higher than baseline lipolysis either from imparied glucolse metabolism or lack of glucose, that means lower levels of Co2

If the Krebs cycle, glycolysis or the link between the two is inhibited, or if there is no sufficient supply of glucose, it leads to a metabolic shift towards lipolysis, which leads to a reduced production of CO2.
CO2 is the primary endogenous vasodilator in the body, and when the CO2 level drops, leading to lower blood flow because of the bohr effect, and hypoxia (https://pubmed.ncbi.nlm.nih.gov/16919605/), the body’s “emergency vasodilator” is activated, where Inducible Nitric Oxide Synthase (iNOS) is activated, leading to a systemic increase in nitric oxide because increased blood flow is needed.

Here we see the 3 wheels of energy in terms of optimal cellular energy production – glycolysis, Krebs cycle and electron transport chain. When there’s a shift towards lipolysis, CO2 levels drop, and nitric oxide is used as an emergency vasodilator

It is an increase in iNOS activity that is likely the causative factor in the blood pressure drop seen in septic shock, where endotoxin activates iNOS, causing vasodilation to a degree that is dangerous. (https://pubmed.ncbi.nlm.nih.gov/12721155/).
As another example, it is known that hypocapnia/low CO2 causes significant vasoconstriction in the brain, while hypercapnia/high CO2 causes increased blood flow through significant vasodilation in the brain (https://www.ncbi.nlm.nih.gov/books/NBK53082/).

An increase in nitric oxide can be a problem because nitric oxide makes covalent bonds with metals in the electron transport chain’s complex IV, aka cytochrome c oxidase, and this has an inhibitory effect on cytochrome c oxidase/complex 4 in the electron transport chain, which normally has to accept electrons from cytochrome c and use them to reduce oxygen to H2O (https://www.sciencedirect.com/science/article/pii/S000527281100212X) (https://www.sciencedirect.com/science/article/abs/pii/S0891584902013266).

A blockage of electrons in the electron transport chain is a problem because the electron flow stops, oxygen accumulates and cannot be reduced, leading to free radical havoc, an accumulation of NADH and FADH2 aka reductive stress, and reduced ATP production. Thus, nitric oxide inhibits oxidative phosphorylation in the electron transport chain, also known as mitochondrial respiration, while co2 protects it. Oxygen accumulates and cannot be used. More oxygen supply can never solve this problem—only by breaking the covalent bond of NO in cytochrome c oxidase can the electron flow be restored. This is actually the same principle as with cyanide poisoning, inhibiting cytochrome c and mitochondrial respiration, leading to a quick death in the right amounts (https://en.wikipedia.org/wiki/Cyanide).

It turns out that CO2 protects cytochrome c oxidase against these reactions and bindings with, among others, nitric oxide, by reducing the reactivity in the binuclear center in cytochrome c oxidase without negatively affecting the electron flow (https://pubmed.ncbi.nlm.nih.gov/7945208/). It is somewhat the same principle in hemoglobin, which also uses heme in the protein structure, where CO2 reduces the binding of oxygen, so the oxygen can be delivered where metabolism is most active, and CO2 production is ongoing.

Conclusion:

Insufficient CO2 increases the amount of nitric oxide, which reversibly inhibits the electron transport chain’s complex 4 and inhibits oxidative phosphorylation, and thus ATP/energy production in the mitochondria. But CO2 inhibits the binding of nitric oxide to cytochrome c oxidase by reducing reactivity without preventing electron flow. Therefore, CO2 is protective of respiration right down to oxidative phosphorylation in the mitochondria and not just through the Bohr effect as previously assumed on this blog.

When the electron flow is not inhibited in the electrontransport chain, there is a protection from a more reductive state in terms of the redox balance on NAD+/NADH – the electrons flow freely to oxygen, and therefor, there is no need to activate the anaerobic glycolysis, where pyruvate is converted to lactate.
Thus, it can be said that co2 protects oxidative phosphorylation and thereby, indirectly also protects against the formation of lactic acid.

It is of utmost importance, to have a well functioning flow of electrons in terms of creating ATP.
A high sugar, low fat diet, is a good way to start in terms of keeping Co2 production high, but one could speculate that breathing patterns, not breathing to much, could be a good way to conserve high levels of Co2.
Staying at high altitude is another way of increasing Co2 levels, although initially, Co2 may fall due to a compensatory hyperventilation, it generally will rise after altitude adaptation. We know from the Haldane effect, that when partial pressure of oxygen rises, it causes a dissociation of Co2, and Co2 is more easily washed out – but at altitude, when the partial pressure of oxygen is lower, the hemoglobin has a higher tendency to retain the Co2 on the heme group.
One could speculate, that maybe this is one of the main reasons why people who live at altitide lives longer than the baseline population despite increased risks from higher radiation.
On another day, we shall look more into how co2 might stabilize other enzymes than cytochrome c oxidase/complex 4 and how the increased Co2 levels might be one of the factors that makes altitude training so popular among athletes.

Regarding the patient cases described at the beginning, it is unfortunate that modern medicine considers CO2 as a waste product that must be removed at all costs, but one could hope that collective eyes will one day open to a potential therapeutic use of CO2 or a higher use of carbonic anhydrase inhibitors (carbonic anhydrase converts Co2 to bicarbonate) to save lives in septic conditions or (pseudo)hypoxic conditions. Perhaps it is all the political drama around CO2 in the atmosphere that makes CO2 laden with negativity in the collective consciousness.