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The Cell Danger Response and Its Role in Autoregulation

Aric D. Cox, DC


Much is known on the importance of mitochondria in optimal cellular function, but our enlightenment on its biochemical and energetic dynamics is only beginning. Referring to mitochondria just as the powerhouse for cellular energy is like calling the heart just a pump or saying the brain is not plastic. It turns out mitochondria have a seat right in the middle of our body’s security system to invading threats, called the cell danger response.

Like a quarterback calling an audible to snuff out a blitz. Or like how a weighted golden idol can set off a number of booby traps to stop an invading Indiana Jones, the mitochondria set off a cascade of changes in order to preserve cellular integrity. Here the action of cellular biology and autonomic function are married together.


But once the traps are set off to stop the intrusion, then what? Once the cell danger response is triggered, the system cannot complete the healing cycle because the “all clear” signal has not been given. Instead, the body remains on alert.


In chronic illness the original triggering event is often remote and may no longer be present.” Naviaux, Antipurinergic Therapy for Autism, 2017


Despite our best attempts to initiate and support healing when dealing with the mire of chronic illness, progress can be slow. Obstacles may appear in the way of self-regulation at some point during treatment. This is especially present in cases of chronic fatigue syndrome, mold illness,

fibromyalgia, Lyme disease, chronic viral infections, or neurodegenerative and autoimmune conditions.

Dr. Robert Naviaux’s work helps to bring more clarity to what exactly the self-regulatory capacity is trying to do in response to the initial threat (toxin, infection, stress) to its homeostasis. Once the initial stress has tripped a breaker in the circuits of the body, the cell danger response (CDR) persists until the proper conditions reset the breaker.


Our cells quickly adapt to threats by communicating with each other through purinergic signaling (i.e., ATP, ADP). This means ATP and ADP are not just for powering metabolic machinery, but are deeply involved in self-regulation.1,2


Extracellular ATP is a major factor in the inflammatory process. The binding of extracellular ATP to many types of purinergic receptors can incite potent inflammatory mechanisms. For example, in the brain and neural tissues, this signaling is involved with NF-κ beta and T-cell activation from microglial cells.


Damage (i.e., broken or lysed) to our cells from invading viruses, heavy metals, infectious microbes, or significant mental/emotional trauma releases ATP and ADP into the extracellular space. Dr. Naviaux refers this release as the chemical “flare” to warn nearby cells. This then sets into motion several functional changes in the cell, including cellular structure, physiology, metabolism, and gene expression.


Initially, the CDR starts off as adaptive but will turn maladaptive if the threat persists. What started with normal, almost predictable stressors of famines and feasting or fighting and fleeing has been thrown into overdrive by modern stressors.


Summer vs Winter metabolism


Because our ancient metabolic roots went through times of soaking up plentiful food and times of withering during food scarcity, our metabolism has two different modes. Summer metabolism refers to when food is readily available and requires more physical activity to gather or harvest. Winter metabolism is triggered by less available food and the body is more focused on repairing and maintaining what it already has.


Since mitochondria are the center of CDR activity, this tale of two metabolic fates may also be described by how the mitochondrial function changes. There exists anti-inflammatory M2 mitochondria, which function to meet the needs of cells not under duress. Contrast this with pro inflammatory M1 mitochondria, which are activated in the CDR. M1 mitochondria consume less oxygen in order to keep it available to protect the cell via oxidative shielding. Thus, M2 mitochondria are associated with winter metabolism and M1 mitochondria with summer metabolism.3


Biochemically, these two sides to our metabolism have different signaling modulators: mTOR for summer or AMPK for winter. mTOR (mammalian target of rapamycin) senses fuel abundance and stokes the metabolic fires to synthesize new proteins for rapid growth without inflammation.4 AMPK (AMP-activated protein kinase) takes over when fuel is decreased and is forced to recycle cellular components for maintenance and repair.5


As it would appear, we should naturally cycle back and forth between summer and winter metabolism just as nature does. However, given the signals that our modern environment sends to our cells, we often get stuck in summer metabolism. This is the result of persistent stressors and leads into mTOR overdrive.

Factors that influence imbalances in summer metabolism:


• Stealth pathogens

• Mold toxicity

• Microbial/viral infections

• Heavy metal toxicity

• Calorie excess and/or infrequent calorie restriction

• Xenobiotics

• Psychological trauma

• Physical trauma


Unhealthy summer metabolism causes accumulation of old and damaged proteins, fans the flames of chronic inflammation, and adds to the degradation into chronic diseases. Conversely, AMPK-driven winter metabolism favors more anti-inflammatory pathways.

Metabolism of the CDR


There are 21 documented metabolic features of the cell danger response. Depending on the conditions the cell is operating under, the fate of each metabolite will tip towards health or disease.


Metabolites of the CDR:


1. Mitochondria

2. Oxygen

3. ATP

4. Cysteine/sulfur

5. Vitamin D

6. Folate

7. S-adenosyl methionine

8. Ornithine

9. Histidine

10. Arginine

11. Heme

12. Phospholipids

13. Tryptophan

14. Lysine

15. Cholesterol

16. Vitamin B6

17. Arachidonate

18. Sphingosine

19. Ceramide

20. Heavy metals

21. Gut microbiome


For the purposes of this article, I will highlight the more interesting and important metabolites.


Mitochondria – While they are a key sensor and central in coordinating the CDR, the price to pay is mitochondrial fragmentation, mitophagy, and autophagy.6 This occurs in the sacrificial effort to remove infected/toxic cells and their intracellular pathogens/toxins.

ATP – Stressed cells release ATP, which activates the NLRP3 inflammasome via purinergic signaling.7 This causes the release of cortisol in the absence of ACTH. This is a particularly nasty shift as it involves the double hit of inflammation and cortisol.

Cysteine/sulfur – These two metabolites shift away from glutathione production in order to prioritize detoxification.8 The rub here is depleted glutathione (due to used up reserves and lack of substrate) and impaired methylation.

Folate – The oxidizing conditions of the CDR creates less available methyl tetrahydrofolate in order to produce more purines for purine signaling and perpetuating the CDR. This means less is available for methylation pathways.

Vitamin D – During the CDR, 24-alpha hydroxylase is activated which decreases the concentration of active vitamin D.9 Lowered vitamin D levels increase inflammation and the risk of autoimmunity.

Heavy metals – When redox conditions favor reducing, more metals are excreted than are accumulated. However, under the oxidizing conditions of the CDR, sequestration is

more favored. Beyond the known neurotoxic effects of heavy metals, oxidizing conditions of the CDR favor sequestration and accumulation of metals.

Gut microbiome – When the host is sick, its microbes are sick too. The CDR changes the physical habitat of the gut, reduces the availability of dietary nutrients, and alters the monitoring of the enteric and central nervous systems. While a 5R Gut program can be effective, complete gut healing and resetting comes by resolving the CDR.


Resolving the CDR


All the metabolic features of the CDR respond well to diet and activity changes, supplementation, and adaptogens.10 However, the complete metabolomic picture of the cell danger response has yet to come into full view. What happens with entrenched chronic issues when therapeutic lifestyle changes are not enough to right the ship?


From experience, it is not enough just to address nutrient deficiencies and remove toxic burdens to facilitate healing. While mitochondria are still broadcasting the CDR signal supplementation and detoxification aren’t enough to bring resolution.


If Dr. Naviaux’s studies found that chronic disease begins when the CDR fails to resolve, then what resolves the CDR and resets cellular metabolism?


Since a key initiator of the cell danger response lies in purinergic signaling, anti-purinergic therapy shows promise. Through understanding and targeting the 19 known classes of purinergic receptors, normal cellular healing function can be restored. Here are a few documented compounds found to reset the cell danger response:


Suramin – From parasites and viruses to autoimmune diseases and autism, this compound from pine needles has a long history of healing with research showing it to be a competitive antagonist of ATP signaling.11

Baicalin – A component of the herb Chinese skullcap, baicalin has been shown to reduce extracellular ATP.12

Kaempferol – Found in cruciferous vegetables, this bioflavonoid has shown to be a purinergic receptor agonist.13


Under normal conditions the mitochondrial-autonomic connection should turn off the CDR and cellular life return to normal. Only through the combination of removing the initial threat and turning off the CDR can there be restoration of healthy cellular function. Given our current allostatic load, normal conditions are hard to come by. There is a complicated knot of interwoven stressors and responses built up over time that have all triggered the CDR.


Resolving the CDR is not always as easy as the “one pill for one ill” approach. Even if maximum effort is applied to healing, time is still a factor. The body, mind, and spirit need time to lick their wounds despite having everything they need to heal, repair and renew.


While researchers strive to understand the complexity of the stress response, we cannot forget the bigger picture. Connections and relationships nourish just as much as any phytochemical. Light, sound, and movement illicit stronger and longer lasting responses in the body than

anything synthesized in a lab. The therapy of a healthy, safe, and open partnership between patient and practitioner can be a signal to the cells that help and hope are waxing and danger is waning. When the needs of the body, mind, and spirit are addressed on the macro level, our cellular components on the micro level respond in kind.











Aric D. Cox, DC

Institute of Restorative Health


References:

1. Ferrari, D et al. “Extracellular ATP activates transcription factor NF-kappaB through the P2Z purinoreceptor by selectively targeting NF-kappaB p65.” The Journal of cell biology vol. 139,7 (1997): 1635-43. doi:10.1083/jcb.139.7.1635

2. Ferrari, D et al. “P2X7/P2Z purinoreceptor-mediated activation of transcription factor NFAT in microglial cells.” The Journal of biological chemistry vol. 274,19 (1999): 13205-10. doi:10.1074/jbc.274.19.13205

3. Naviaux, Robert K. “Antipurinergic therapy for autism-An in-depth

review.” Mitochondrion vol. 43 (2018): 1-15. doi:10.1016/j.mito.2017.12.007 4. Yang, Z, and X-F Ming. “mTOR signalling: the molecular interface connecting metabolic stress, aging and cardiovascular diseases.” Obesity reviews : an official journal of the International Association for the Study of Obesity vol. 13 Suppl 2 (2012): 58-68. doi:10.1111/j.1467-789X.2012.01038.x

5. Salminen, Antero, and Kai Kaarniranta. “AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network.” Ageing research reviews vol. 11,2 (2012): 230-41. doi:10.1016/j.arr.2011.12.005

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7. Xia, Jingsheng et al. “Neurons respond directly to mechanical deformation with pannexin-mediated ATP release and autostimulation of P2X7 receptors.” The Journal of physiology vol. 590,10 (2012): 2285-304. doi:10.1113/jphysiol.2012.227983

8. McLain, Aaron L et al. “Glutathionylation of α-ketoglutarate dehydrogenase: the chemical nature andrelative susceptibility of the cofactor lipoic acid to

modification.” Free radical biology & medicine vol. 61 (2013): 161-9.

doi:10.1016/j.freeradbiomed.2013.03.020

9. Shanmugasundaram, R, and R K Selvaraj. “Vitamin D-1α-hydroxylase and vitamin D 24-hydroxylase mRNA studies in chickens.” Poultry science vol. 91,8 (2012): 1819-24. doi:10.3382/ps.2011-02129

10. Panossian, Alexander, and Georg Wikman. “Evidence-based efficacy of adaptogens in fatigue, and molecular mechanisms related to their stress-protective activity.” Current clinical pharmacology vol. 4,3 (2009): 198-219. doi:10.2174/157488409789375311 11. http://naviauxlab.ucsd.edu/science-item/suramin/

12. Zhang, Jun et al. “Study of baicalin on sympathoexcitation induced by myocardial ischemia via P2X3 receptor in superior cervical ganglia.” Autonomic neuroscience : basic & clinical vol. 189 (2015): 8-15. doi:10.1016/j.autneu.2014.12.001

13. Séror, Claire et al. “Extracellular ATP acts on P2Y2 purinergic receptors to facilitate HIV-1 infection.” The Journal of experimental medicine vol. 208,9 (2011): 1823-34. doi:10.1084/jem.20101805