oxidative shielding – 50 years of misinterpreted research – mitochondrial diseases are actually physiological as a cell danger response

It is currently completely unknown that there are 3 types of mitochondria that lead to completely different phenotypes of cells. Decades-old knowledge about antioxidation, inflammation and treatment approaches is incorrect or incomplete.

This article is the first in a planned series to explain the cell danger response system and the treatment of (post-viral) “fatigue“.

Summary

Pro-inflammatory M1 mitochondria do not generate free radicals because they have been damaged, as we have been told for decades, but intentionally to protect the cell from further infection. This is called “oxidative shielding” and this M1 function is part of the innate immune defense (Naviaux 2012 / FullText) and is a monotonous and automated cell response to both external oxidative and reductive stress.

The cells intentionally produce superoxides and hydrogen peroxides and stiffen their cell membranes to make them less permeable and vulnerable to external attacks.

The free radicals are therefore not the cause of a disease, but the reaction to it, and instead of treating the free radicals with antioxidants, one should concentrate on the metabolic basis of this cellular defense response.

This affects, for example, diseases such as autism, type 1 and type 2 diabetes, cancer, heart disease, schizophrenia, Parkinson’s and Alzheimer’s disease.

In these diseases, the cause of “oxidative shielding” is a natural reaction to damaging stimuli such as infection or toxins and is wrongly interpreted as a contributory cause of carbohydrates and – wrongly – seen as the target of therapeutic efforts. We have to eliminate the trigger of this cell danger response and help the cells to return to a normal metabolic situation from this reaction, then these chronic diseases can also be cured.

The aim of this series of articles is to understand this and to develop appropriate tools or to bring them to us from the Naviaux laboratories. We are following the research of Prof. Naviaux and his clinical partners, such as Dr. Neil Nathan et al.

Prof. Naviaux – innovative research

this article is based on the article cited above and other work by Prof. Robert K Naviaux, scientist at the Univ. California in beautiful San Diego.

So let’s get into this review to follow Prof. Naviaux’s research that ultimately led him to the discovery of the Cell Danger Response System.

I became aware of this new, innovative scientific concept through a Podcast #121 by Dr. Neil Nathan on Scott Foresgren – Betterhealthguy

evolution was anaerobic to begin with

3.5 billion years ago, the entire metabolic machinery developed in a strictly oxygen-free so-called anaerobic environment on earth (e.g. citric acid cycle, Krebs cycle, respiratory chain, pentose phosphate cycle, fatty acid metabolism, glutathione-StW, heme synthesis, pyruvate dehydrogenase etc. etc. Tang 2010). Oxygen was a highly toxic molecule at the time.

It was only 2.4 billion years ago that cyanobacteria came along and produced oxygen through photosynthesis, so that around 1.1-1.7 billion years ago there was enough oxygen available.was (0.1%) to allow mitochondria to develop for the first time, which can use oxygen. This oxygen concentration is still the optimal amount for mitochondria, the current atmospheric oxygen of 21% is 150x higher than that present in the cells and is still toxic to cells. The evolutionary changes in metabolism since the cyanobacteria serve primarily to tame the toxic oxygen.

Intracellular mitochondria initially served to defend against the abundant viruses and intracellular predatory bacteria in our evolutionary past, no cell survives without appropriate defense.

Normal concentrations of intracellular nutrients allow mitochondria to live a normal life, any deficiency in certain nutrients has been interpreted as an indication of intracellular parasites and leads to mitochondria becoming active as a defense mechanism.

All mitochondrial enzymes are regulated in their enzymatic activity by the concentrations of the various reaction partners, so that when concentrations change, exactly the amount of substrate that is needed is synthesized.

If metabolically important source substrates are missing (e.g. because they are eaten away by parasitic bacteria), the mitochondria stop working normally, the oxygen in the cell increases and is diverted to the production of peroxides, creating so-called pro-oxidative M1 mitochondria.

This reaction is called oxidative shielding

Because the M0 mitochondria consume huge amounts of oxygen, but the M1 mitochondria no longer consume it, the oxygen pressure in the cell increases dramatically.

Cytosolic proteins and ultimately membranes are oxidatively modified, which then serve to protect the cell membranes and DNA.

These include the signaling molecules we know well, such as NFkB, sirtuins, KEAP1 / Nrf2, NOX, all with the intention of preventing cells from replicating and stabilizing the membrane so that enemies cannot get in or out.

This oxidative shielding is therefore to be viewed in a completely different way to the current theory of oxidative stress, which we have brought to the center of our understanding of disease:

free radicals are created as a product of disease, which destroy and damage everything, so we must fight and prevent the free radicals with antioxidants and that is how we treat the disease

But:

• ROS … is the result and reaction to danger, stress and intoxication of cells
• ROS … are produced in a targeted and deliberate manner in the mitochondria and cytosol
• ROS … are intended to kill enemies – or the cell itself – in order to prevent any toxic or harmful changes from being passed on to neighboring cells
• ROS … disappear on their own when the toxic or harmful environment of the cell can be neutralized or eliminated

The conventional view so far is: ROS are the main triggers of disease and must be combated by antioxidants.

If this thesis is correct, we should experience great successes in practice:

current view and treatment regimes based on it fail in practice

VitE could not improve diabetes, VitC administered routinely doubles the cancer risk, VitE+beta-carotene increases lung cancer and prostate cancer by 1.6 times as well as the new onset of diabetes

This information comes from the original article by Prof. Naviaux, where the references are also provided. I am still a bit shocked by this and have to accept these statements without checking them, because this would imply that standard orthomolecular applications are not very helpful!

Naviaux continues: if free radicals are so bad and cause and maintain diseases, then why do strategies that reduce free radicals only have a moderate – or – no – or – even paradoxically bad effect?!!

Oxidative shielding is universally widespread

all aerobic cells and organisms protect themselves from attacks and stress with oxidative shielding, even bacteria show this behavior.

Metabolic “fever” is the response to stressors

If a cell is stressed or there is a shortage of nutrients, the mitos are blocked, the intracellular oxygen partial pressure increases, which generates ROS: the counterpart to fever at the cellular level.

If oxidative stress is the cellular response, treating it would weaken the cell in the long term

If ROS is the response to noxious substances such as viruses, bacteria, Toxines, treatment with antioxidants would weaken the cellular defenses and longer treatment is harmful.

Cell culture experiments often misleading

Due to these oxygen issues, cell culture studies often cannot be transferred to the organism, since the oxido-reductive conditions are not controlled as well as the pH value of the nutrient solutions and the enormous oxidative stress in the cell culture means that the cells react anything but “normally”.

Experiments with damage to cells that lead to cell death in cell culture (and are therefore interpreted as detrimental, e.g. the withdrawal of antioxidants vs. the supply of antioxidants) must be reinterpreted from the perspective of the organism:

a cell that voluntarily dies when it is infected (apoptosis) is doing the right thing in the context of the entire organism, it sacrifices itself to protect the body.

Prof. Greilberger also always says that “all cell culture experiments have to be stopped” because the nutrient solutions contain too many antioxidants and at the same time the oxygen partial pressure of the nutrient solution environment is much too high.

Prof. Naviaux also makes this clear when he says that increasing the oxygen content of the cell culture dishes by at least ten times activates the entire antioxidant defense of cells and produces results that do not match in vivo experiments.

Cells in cell culture double in size every day. This is why the main work of the mitochondria is directed towards the growth and synthesis of biomass, while in resting tissues the mitos mainly serve the conventional energy production for cell work.

The combination of these factors: too much oxygen and mitos that mainly produce mass instead of cell work, do not allow us to observe and measure redox systems in cell culture in practice and has led us down the wrong path.

Originally, I was made aware of this fact by Graz University biochemist and doctor Prof. Greilberger. He thinks that practically all cell culture experiments can be “punched” because the results are completely unphysiological, produced in a massively oxidative atmosphere and only reproduce cell danger responses, not physiological reactions.

Epigenetic adaptation in tissues

Oxygen gradients can also be found within organs and tissues. For example, the cells in the liver lobule near an artery have a different metabolic polarity (especially ornithine transcarbaomylase) than near a vein (especially ornithine aminotransferase).

There is a high degree of cooperation within tissues, quite different from that in a cell culture. The dirt/waste from one cell serves as building material or fuel for other cells.

The corresponding unused genes are silenced by methylation so as not to cause interference. This means that the environment controls gene expression almost completely, not the other way around as we always thought: that DNA controls the appearance of the cell —> this is wrong.

Metabolites are also extracellular signal molecules

Many chemical substances that have a certain metabolic significance within the cell are used outside of cells as information transmitters.

For example, ATP is an energy-transferring molecule within the cell, but outside a cell ATP becomes a “danger” signal and warns neighboring cells that danger is imminent and that they must prepare themselves. The neighboring cells then switch to oxidative M1 metabolism and reduce their mitochondrial oxygen combustion, increase the warning level and defense within the cell and switch to fermentation metabolism.

Succinate is also a fuel/building material in the citric acid cycle, outside the cell it regulates blood clotting,

Citric acid within the cell is an important component of the citric acid cycle, outside the cell it becomes a nutrient signal and informs the cells that there is plenty of food available.

There are corresponding receptors on the surface of cells for all of these “signal molecules”. If the citrate receptor is blocked, the cell reacts in the same way as with “calorie restriction” and then lives much longer.

The most important statement here is certainly: Extracellular ATP switches the cells into cell danger response mode, in which they lower all blinds, isolate themselves, stop energy production, massively reduce protein biosynthesis and reduce glutathione metabolism.

Crabtree – Effect and oxygen utilization and mito-respiration

As early as 1929, Dr. Crabtree discovered that an increased supply of glucose reduces mitochondrial oxygen consumption by up to 50% and that glucose is not burned to water but fermented because the combustion machinery is blocked.

Especially in diabetes, cells are constantly presented with a high glucose level.

The now heated glucose fermentation in the cytosol converts ADP into ATP, which strongly inhibits mitochondrial ATP production through feedback, whereby the energy generated in the mitos backs up and is discharged in the form of peroxides, which the cells release to the outside.

Because this also reduces the oxygen consumption of the cells, this can also be measured as a reduction in the oxygen consumption between arteries and veins in the organism.

If less oxygen is needed, this leads to a reduction in capillary density in the long term and thus the hypoxia is fixed as supply hypoxia and ultimately also damages the tissue functions.

We see this, for example, in chronic neurodegenerative diseases.

An analogous example of over-fertilized water

The same thing happens in over-fertilized water: the algae overgrow everything and eventually rot, creating an oxygen-poor, hostile environment, the over-fertilized water is “tipped” and dies. Just like with diabetes, an oversupply of food ultimately leads to the death of life.

Intracellular oxygen gradient

Outside the cell, the oxygen pressure is 30 Torr, in the mitochondria it is 0.2 Torr. In other organelles such as the endoplasmic reticulum, the Golgi or the lysosomes, there is a different, very specific partial oxygen pressure.

The organelles migrate to where they find their optimal oxygen pressure in the cell. By burning the oxygen, the mitos become corresponding oxygen sinks and therefore build up this gradient. This gradient also determines whether a cell “works” and differentiates or “multiplies” and proliferates.

“metabolic memory”

short-term changes in the oxygen demand of mitochondria lead to a cascade of downstream redox protein changes, which can last for a relatively long time.

This is the reason why long-lasting improvements in metabolism are often seen in diabetics after short periods of strict dietary restriction (low carb).

short-term physical exertion increases the basal metabolic rate for many hours, and this can still be measured even after days.

Repeated training leads to an improvement in muscle that lasts for months and can reverse age-related deterioration.

All of this requires oxidative stress, which is produced by exercise.

Training is inhibited by antioxidants

If VitC and VitE are taken regularly, this positive effect of long-term training on the muscles and insulin sensitivity is blocked.

Hormesis is the adaptation to negative external stimuli – so we always need phases of free radicals that strengthen and strengthen us.

If you take antioxidants (VitC, VitE) during training, muscle performance is reduced by up to 25%, as is muscle blood flow.

Phytotherapeutics are mostly oxidants

These great plant aids help animals that help with seed dispersal live better and longer. Interestingly, most of these flavonoids and other particularly healthy plant substances are actually oxidants, which “strengthen” the cell through their short-term pro-oxidative effect, as they briefly simulate an infestation with a parasite, which increases the cell’s defenses, similar to the hardening effect of a short ice-cold shower. Quercetin, curcumin, green tea EGCG, sulphuraphane, etc., strongly increase the glutathione concentration, express stress proteins and upregulate cytokines.

Conclusiong and summary

What we previously interpreted as disease triggers and damaging noxious substances: free radicals and peroxides – are by no means the factors that determine the disease, but are the cell’s reaction to a disturbance or illness. We call this “oxidative shielding”.

Temporary increase in free radicals through muscle training, plant substances are important adaptation aids for the development and growth of mitochondria.

The carbonylation of proteins (oxidation), lipid peroxidation, fibrosis and hundreds more oxidative changes are not the disease but part of the cell reaction and defense. Both oxidative and reductive stressors lead monotonously to this “oxidative shielding”, which is an innate, very basic form of cell immunity against parasites and enemies and takes place in bacteria, plants and animal cells. This also increases the stiffness of the cells’ membranes and inhibits cell division.

This stimulus response can be modulated by fasting or overfeeding.

If the stress is accompanied by overfeeding (with glucose), the cell switches to Crabtree metabolism, switches off mitochondria and thus reduces the oxygen requirement, resulting in chronic inflammation and Warburg metabolism.

Treating chronic diseases with antioxidants is like reducing fever with aspirin for pneumonia. Of course aspirin helps and is “clinically proven in studies” for pneumonia, but untreated pneumonia can still kill the patient; it would be better to treat the pneumonia with antibiotics rather than just the fever.

Nitro-tyrosine is like fever, such oxidized proteins are only the symptom, not the disease, and antioxidants can lower nitro-tyrosine, but not necessarily cure the disease.

Only with personalized individual cause search and treatment can complex diseases such as autoimmune diseases, autism, Parkinson’s, diabetes, cancer and other diseases be eliminated, that is what the future will bring.

It will be exciting to follow Prof. Naviaux on his journey of discovery. We are in this review in 2012, and in the meantime the Naviaux Lab has found very differentiated causes and answers for many chronic diseases. Let’s see what the next article brings.

If you want to “read aloud”, here is the next paper that I want to summarize:

Metabolic Features of the Cell Danger Response

as well as Dr. Naviaux’s friend and co-author, Dr. Neil Nathan

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• Neil Nathan (Author) - Adam Fedyk, Neil Nathan (Narrators)

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