The spike protein, ACE-2, cysteine content and redox shifts - Part II

Oxidative stress, cellular respiration, mitochondrial damage, Warburg effect and more

Let’s now talk about oxidative stress and the Warburg effect and what we can do to minimize them.

Oxidative stress can lead to cell damage (including sperm DNA fragmentation guys) and manifests when an abundance of reactive intermediates of oxygen metabolism accumulate due to insufficient of antioxidant activity. The damages can lead to a multitude of disease states including cancer, Parkinson's disease, Lafora disease, Alzheimer's disease, atherosclerosis, heart failure, myocardial infarction, attention deficit hyperactivity disorder, fragile X syndrome, sickle cell disease, lichen planus, vitiligo, autism, infection, chronic fatigue syndrome, depression, enhancement of inflammatory disorders¹ and fibrotic pathways.

In the paper we discussed in Part I, the authors state that in the context of COVID-19, a metabolic rewiring takes place whereby cells rely on glycolysis for ATP supply. Cancer cells undergo this kind of rewiring.

Before we continue, please watch Dr. Eric Berg’s video about oxidative stress and viral infections. I must say it is excellent and covers a lot described in the paper originally intended for review. The one thing that Dr. Berg doesn’t cover are the effects of the COVID-19 shots.

As a side note, the authors of the article do address this briefly in Section 4:

Although the newly developed Covid-19 vaccines are supposed to have established a safe profile, some individuals experience adverse effects.²³ Most of them are benign, such as dizziness, vomiting or transient pyrexia. Other side effects are viral reactivation in varicella-zoster virus⁴ or hepatitis⁵, coagulopathy and resulting stroke and myocarditis following both DNA-based vaccines⁶ and RNA-based vaccines.⁷

So Dr. Berg helps us to understand better what antioxidants are in the context of reductive and oxidative states induced by pathogen presence. We will need to understand the concept of anabolism, to understand the hypothesis proposed in the paper which goes like this:

Covid-19's short- and long-term complications are a result of a similar redox shift and anabolism, due to the reduced cell environment originally caused by the spike protein of the virus.

So, the authors state that the spike protein causes a reduced cell environment that leads to redox shift (decline of the thiol/disulfide equilibrium) and anabolism. Anabolism is biosynthesis → construction of biomolecules including DNA. It is powered by catabolism (breakdown of biomolecules) and requires a lot of energy. To better understand this in the context of COVID-19, spike, hyper-inflammation, cancer, etc…, we need to get into what is known as the Warburg effect and talk about mitochondrial damage.⁸⁹¹⁰

On the Warburg Effect

In contrast to normal differentiated cells, which rely primarily on mitochondrial oxidative phosphorylation to generate the energy needed for cellular processes, most cancer cells instead rely on aerobic glycolysis, a phenomenon termed “the Warburg effect.”¹¹

The Warburg Effect is best summarized as a rewiring of normal cells such that they metabolize glucose via fermentation to promote proliferation and eternal life. This can occur in the presence of normal mitochondrial function, or not. It’s a weird thing to get your head around actually, since one would think that cell proliferation would be synonymous to maximizing ATP access and use. But ‘tis not the case here.

The metabolism of glucose, the central macronutrient, allows for energy to be harnessed in the form of ATP through the oxidation of its carbon bonds. This process is essential for sustaining all mammalian life. In mammals, the end product can be lactate or, upon full oxidation of glucose via respiration in the mitochondria, CO₂. In tumors and other proliferating or developing cells, the rate of glucose uptake dramatically increases and lactate is produced, even in the presence of oxygen and fully functioning mitochondria.¹²

I realize that there are many words and concepts in that paragraph describing what the Warburg Effect is, so here’s a crash course in some of the words.

I highly recommend watching Professor Fink’s lecture (not to be confused with Professor Frink) on Physiology and Cellular Respiration. It is long, but he’s a great teacher - if you don’t mind sudden loud hand slaps every time he talks about carbons being ripped apart.

The two key concepts to understand are mitochondrial oxidative phosphorylation and aerobic glycolysis. Briefly, mitochondria are the power stations in eukaryotic cells (mammalian cells, for example). Oxidative means oxygen involvement. Phosphorylation means a phosphate group is added to some molecule. Aerobic means oxygen. Glycolysis means sugar deconstructed. All of these words are connected by cellular respiration. This is the thing that the mitochondria do to produce our famous energy molecule called adenosine triphosphate (ATP).

On cellular respiration

Cellular respiration occurs via a series of biochemical reactions called anaerobic and aerobic respiration reactions. The former proceeds in the absence of oxygen and the latter proceeds in the presence of oxygen. As part of cellular respiration, sugars need to be broken down - a process called glycolysis.

Glycolysis is just splitting sugars into component parts and these components are called pyruvates. So the first step in cellular respiration is the anaerobic respiration reaction whereby glucose is broken down into component parts for use in the production of 2 ATPs. In the process, hydrogens are removed to be picked up by Nicotinamide adenine dinucleotide (NAD) coenzymes to ultimately transfer these hydrogens to oxygens to form water.

In the absence of oxygen, aerobic reactions will not occur in the mitochondria. In this case, pyruvate undergoes fermentation where it is turned into lactic acid in the cytoplasm. The NADs can’t transfer the hydrogens on to oxygens (because there aren’t any) so they transfer them back to pyruvates to produce lactic acid. This is a reversible reaction. A build-up of lactic acid (oxygen debt) in your muscles can cause cramping and fatigue and is attributed to a deficiency of oxygen. The cramping is the result of an increase in acidity (lactic acid) and protein denaturation in the muscle tissue.

*Technically, it seems to me that you could use breathing exercises to reduce lactic acid levels without increasing your heart rate too much.

As a side note, aerobic glycolysis is glycolysis that occurs in the presence of oxygen. This is the form of ATP production that cancer cells are thought to use.¹³

Another part of cellular respiration is called aerobic respiration whereby the pyruvates are converted into carbon dioxide (complete) in the presence of oxygen. This occurs in the mitochondria. The pyruvates enter the mitochondria where they enter a transition reaction where they become acetyl-co-enzyme A (COA) sugars. The terminal carbons from the anaerobic reaction are stripped (decarboxylated) to form carbon dioxides and acetyl-COA coenzymes. This leads to the Krebs Cycle, whereby 4 additional carbon dioxides are formed as a by-product of the sugars that were broken down. In addition, more free hydrogens are picked up by the NADs and also by Flavin Adenine Dinucleotide (FAD)s. These ‘hot potato’ hydrogens become very important to the next step.

Finally, in the final step of cellular respiration, as part of the electron transport chain, the final 34 ATPs are produced. The electron transport chain is basically a chain of coenzymes that pass the NADs and the FADs to each other to release energy from the hydrogens that is used to phosphorylate ADP into ATP. The end product will be the production of 34 ATPs from a single glucose molecule. This, is called oxidative phosphorylation. Getting rid of hydrogens = oxidation → formation of water.

To summarize, we breathe oxygen for the purpose of accepting hydrogen atoms that are ripped off sugar molecules as they are broken apart to produce ATP. Simple, right?

Oxygen is a hydrogen acceptor. Sugars (glucose) are oxidized to carbon dioxide and oxygen is reduced to water during these processes. Anaerobic respiration yields 2 ATPs and 2 pyruvate sugars, while complete cellular aerobic respiration yields 38 ATPs, 6 carbon dioxides and 6 waters. That’s 36 more ATPs per sugar molecule for use by the body!

By RegisFrey - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=4389845

Think of it this way: anaerobic respiration is the old-school low-oxygen rich environment prokaryotic way to get energy in the form of ATP. When oxygen became more available, respiration evolved to include aerobic respiration whereby the number of ATP molecules was increased to accommodate higher energy needs. Interestingly, the speed at which ATP is produced via anaerobic glycolysis is about 100 times that of oxidative phosphorylation.¹⁴ Now, let’s go back to Warburg and cancer.

Reiteration

In contrast to normal differentiated cells, which rely primarily on mitochondrial oxidative phosphorylation to generate the energy needed for cellular processes, most cancer cells instead rely on aerobic glycolysis, a phenomenon termed “the Warburg effect.”

So now we know that this means that cancer cells prefer to get their ATPs from the low-yield ATP methodology: ‘aerobic’ glycolysis (glycolysis despite the presence of oxygen). But wait now, why would cancer cells - cells that just love to proliferate - rely on the ATP methodology that yields 36 fewer molecules? Wouldn’t cells that need to reproduce (all that they are) require a lot of energy to do so? What’s up with that?

The answer could lie in the fact there are metabolic requirements for proliferation beyond ATP, “including nucleotide synthesis linked to the pentose phosphate pathway (PPP), generation of amino acids for protein synthesis, and production of lipids for membrane formation”.¹⁵ I leave my readers to read reference 15 if you are interested and will leave the details out of this particular article. Safe to say, cancer cells are special and apparently, they have evolved mechanisms to optimize proliferative abilities and survival techniques in the context of low energy requirements in the form of ATP.

Tying it all together

The authors write:

In Covid-19, like any inflammation, there is a metabolic rewiring where cells rely on glycolysis.

This means, that glycolysis becomes the primary source of ATP, even in the presence of oxygen. And this has to do with biosynthesis requirements. Think: anabolism. Think repairing DNA damage. Think requirements for cell proliferation. Cancer and COVID-19 pathologies and hyper-inflamed states all have this feature of altered cellular metabolism derived from redox modulation that can result in alterations in cellular dynamics and varying degrees of DNA, RNA, protein, and lipid damage.¹⁶ It all links back to imbalance.

So what about the spike:ACE-2 interface thing we were talking about in Part I? Isn’t this oxidative stress simply due to the presence of the virus and the immune (over)reactions? Yes, but in addition, the binding event itself attenuates mitochondrial function and induces glycolysis and induces a reduced cell environment that in turn, leads to redox shift and anabolism.¹⁷

ACE-2 signal transduction plays a role in several pathophysiological features, including inflammation, metabolic dysfunction, and aging. [15]¹⁸ The paper I reference in 15 has 1284 references - I have never seen anything like it. That’s more references that amino acids in the spike protein. When ACE-2 is bound, the intercellular signaling cascade (elusive as it is) leads to nitric oxide (NO) production, among other things, that allows for vasodilatation. The thing about that is, the synergistic effects of ROS and NO is DNA and mitochondrial damage.

Spike induces mitochondrial damage.¹⁹²⁰ “Endothelial cells incubated with S1 protein had attenuated mitochondrial function but increased glycolysis, when compared with control cells”. (See reference 18.) Interesting. This mitochondrial damage must play a role in the metabolic rewiring. And I mean, they did notice increased glycolysis in the face of mitochondrial ‘attenuation’. I wonder if an hypoxic environment exacerbates/prolongs this alteration? I have so many more questions and I am sure I have not answered so many more pertaining to this article but, for all intents and purposes, I think that their findings can be boiled down to one key concept:

The spike protein (via its interaction with ACE-2) leads to an age-accelerated pathophysiological profile due to a shift to anabolism (biosynthesis) that is characterized by mitochondrial attenuation and down-regulation of DNA repair that can be measured as reduced serum protein thiols.

What can we do about it? Antioxidants, organosulfur compounds like alpha-lipoic acid, exercise and sleep, of course By the way, you can get alpha-lipoic acid from leafy greens, beef liver, whole brown rice, yams and potatoes! Yum.

All of this science is awesome. But ultimately, we always have to tie what we learn in science back, and into, the physical world and the day-to-day lives that we are all experiencing. I am going to be writing an article next (after my ‘Politics as the WFF’ article) about how simplicity and simple things have been lost and how even the word simple itself has been given bad connotation in our mad world. But simplicity, and all of the things that accommodate it, is truly the way back (and I do mean back) to joy, in my mind.

Breathing. Moving. Eating. Pooping. Petting a kitty. Simple things. I often say that ‘God is in a cat’, and I cannot express the truth that I feel resides in this phrase. El Gato Malo will love this upcoming article.

So go out there and breath deeply and aerobicize ‘til your heart gets big and strong and eat to live, not to appease. Talk to animals. Talk to your loved ones who have passed. Cry. Laugh. Farm. Try not to just enjoy the moments, but to create more of them. It’s almost as if we have to expend energy in order not to. How ironic. I don’t run in the rat-race: it’s a meaningless circle and it rarely leads anywhere of value. There is absolutely no shame in doing ‘nothing’, by the way. Breaks and rest are absolutely essential to productivity, no matter how ad agencies would love to convince that you are just ‘lazy’. Don’t forget that sugary drinks, engineered ‘models’ and drugs are all ‘sponsored by Pfizer’.

Just to tickle your noodles for another upcoming article, the authors of the original article also state the following:

Creutzfeldt-Jakob, the emergence of prions (mis-folded proteins) which damage the neurons, appears to be a redox phenomenon.²¹²²

I don’t doubt that it is. Also: metals.

I hope this two part series has brought some interesting conversations to light in some of your worlds. I will leave it at this for now - I might improve on it as time passes. The next article is going to be a commentary on politics. Should make for a good laugh.

1. https://en.wikipedia.org/wiki/Oxidative_stress

2. J.H. Kim, F. Marks, J.D. Clemens. Looking beyond COVID-19 vaccine phase 3 trials. Nat. Med., 27 (2) (2021), pp. 205-211.

3. T.T. Shimabukuro. COVID-19 Vaccine Safety Updates. (2021).

4. K. Katsikas Triantafyllidis, P. Giannos, I.T. Mian, G. Kyrtsonis, K.S. Kechagias. Varicella zoster virus reactivation following COVID-19 vaccination: a systematic review of case reports. Vaccines, 9 (9) (2021).

5. R. Lensen, M.G. Netea, F.R. Rosendaal. Hepatitis C virus reactivation following COVID-19 vaccination - a case report. Int. Med. Case Rep. J., 14 (2021), pp. 573-576.

6. S. Aghabaklou, S.M. Razavi, P. Mohammadi, S. Gholamin, A. Mowla. Cerebral coagulation complications following COVID-19 adenoviral vector vaccines: a systematic review. J. Neurol. Res., 11 (5) (2021), pp. 69-76.

7. M. De Michele, J. Kahan, I. Berto, O.G. Schiavo, M. Iacobucci, D. Toni, A.E. Merkler. Cerebrovascular complications of COVID-19 and COVID-19 vaccination. Circ. Res., 130 (8) (2022), pp. 1187-1203.

8. P. Icard, H. Lincet, Z. Wu, A. Coquerel, P. Forgez, M. Alifano, L. Fournel. The key role of Warburg effect in SARS-CoV-2 replication and associated inflammatory response. Biochimie, 180 (2021), pp. 169-177

9. L. Szarpak, K. Ruetzler, K. Safiejko, M. Hampel, M. Pruc, L. Kanczuga-Koda, K.J. Filipiak, M.J. Jaguszewski. Lactate dehydrogenase level as a COVID-19 severity marker. Am. J. Emerg. Med., 45 (2021), pp. 638-639.

10. A. Thirupathi, Y. Gu, Z. Radak, R.A. Pinho. Redox status is the mainstay of SARS-CoV-2 and host for producing therapeutic opportunities. Antioxidants, 11 (10) (2022)

11. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009 May 22;324(5930):1029-33. doi: 10.1126/science.1160809. PMID: 19460998; PMCID: PMC2849637.

12. Liberti MV, Locasale JW. The Warburg Effect: How Does it Benefit Cancer Cells? Trends Biochem Sci. 2016 Mar;41(3):211-218. doi: 10.1016/j.tibs.2015.12.001. Epub 2016 Jan 5. Erratum in: Trends Biochem Sci. 2016 Mar;41(3):287. Erratum in: Trends Biochem Sci. 2016 Mar;41(3):287. PMID: 26778478; PMCID: PMC4783224.

13. https://en.wikipedia.org//wiki/Anaerobic_glycolysis

14. Jones W and Bianchi K (2015) Aerobic glycolysis: beyond proliferation. Front. Immunol. 6:227. doi: 10.3389/fimmu.2015.00227.

15. Forrester SJ, Booz GW, Sigmund CD, Coffman TM, Kawai T, Rizzo V, Scalia R, Eguchi S. Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology. Physiol Rev. 2018 Jul 1;98(3):1627-1738. doi: 10.1152/physrev.00038.2017. PMID: 29873596; PMCID: PMC6335102.

16. Erik A. Fraunberger, Gustavo Scola, Victoria L. M. Laliberté, Angela Duong, Ana C. Andreazza, "Redox Modulations, Antioxidants, and Neuropsychiatric Disorders", Oxidative Medicine and Cellular Longevity, vol. 2016, Article ID 4729192, 14 pages, 2016. https://doi.org/10.1155/2016/4729192

17. Thirupathi A, Gu Y, Radak Z, Pinho RA. Redox Status Is the Mainstay of SARS-CoV-2 and Host for Producing Therapeutic Opportunities. Antioxidants. 2022; 11(10):2061. https://doi.org/10.3390/antiox11102061.

18. Lei Y, Zhang J, Schiavon CR, He M, Chen L, Shen H, Zhang Y, Yin Q, Cho Y, Andrade L, Shadel GS, Hepokoski M, Lei T, Wang H, Zhang J, Yuan JX, Malhotra A, Manor U, Wang S, Yuan ZY, Shyy JY. SARS-CoV-2 Spike Protein Impairs Endothelial Function via Downregulation of ACE 2. Circ Res. 2021 Apr 30;128(9):1323-1326. doi: 10.1161/CIRCRESAHA.121.318902. Epub 2021 Mar 31. PMID: 33784827; PMCID: PMC8091897.

19. Huynh TV, Rethi L, Lee T-W, Higa S, Kao Y-H, Chen Y-J. Spike Protein Impairs Mitochondrial Function in Human Cardiomyocytes: Mechanisms Underlying Cardiac Injury in COVID-19. Cells. 2023; 12(6):877. https://doi.org/10.3390/cells12060877.

20. J. Saleh, C. Peyssonnaux, K.K. Singh, M. Edeas. Mitochondria and microbiota dysfunction in COVID-19 pathogenesis. Mitochondrion, 54 (2020), pp. 1-7

21. S. Serine, H. Sungurtekin. Creutzfeldt-Jakob Disease after the COVID-19 Vaccination. (2020).

22. N. Singh, A. Singh, D. Das, M.L. Mohan. Redox control of prion and disease pathogenesis. Antioxidants Redox Signal., 12 (11) (2010), pp. 1271-1294.