A Mechanistic Model of Ehlers-Danlos Syndrome, Mast Cell Activation Syndrome, and Postural Orthostatic Tachycardia Syndrome 

A Vicious Cycle of Mitochondrial Dysfunction and Systemic Dysregulation

Ehlers-Danlos Syndrome (EDS), Mast Cell Activation Syndrome (MCAS), and Postural Orthostatic Tachycardia Syndrome (POTS) frequently present as a clinical triad, suggesting shared pathophysiological mechanisms. This essay proposes a comprehensive model wherein environmental stressors trigger mitochondrial dysfunction, initiating a cascade of interconnected failures involving heme synthesis disruption, exclusion zone (EZ) water depletion, metabolic shifts, collagen breakdown, barrier integrity disruption, immune activation, nervous system hyperactivity, and autonomic dysregulation.

Each mechanism is interconnected, forming a self-reinforcing cycle that perpetuates chronic symptoms of EDS (hypermobility, tissue fragility), MCAS (hypersensitivity, inflammation), and POTS (orthostatic intolerance, fatigue). Quantum biology effects further exacerbate these processes, impacting cellular signaling, electron and proton flow, and tissue stability. Below, each step is detailed to provide clinicians with a mechanistic framework for understanding and potentially addressing these syndromes.

1. Mitochondrial Dysfunction

Environmental stressors, including blue light, non-native electromagnetic frequencies (nnEMF), chemical toxins (e.g., heavy metals, pesticides), lipid nanoparticles (LNPs) from vaccines, and chronic infections (e.g., Epstein-Barr virus, Lyme disease), impair mitochondrial function. These stressors disrupt ATP production by inhibiting the electron transport chain (ETC), particularly cytochrome c oxidase (CCO), a heme-containing enzyme critical for oxidative phosphorylation (Godley et al., 2005). Blue light and nnEMF may degrade CCO, reducing the inner mitochondrial membrane (IMM) electrical potential, which normally maintains a voltage gradient of approximately -140 to -180 mV. This potential is essential for ATP synthase activity and ion transport. Impaired electron flow along the ETC increases reactive oxygen species (ROS) production, further impairing ATP synthesis and creating oxidative stress (Lambert et al., 2010). Concurrently, mitochondrial dysfunction diminishes the formation of structured EZ water, a gel-like water phase hypothesized to stabilize cellular and extracellular structures via electrostatic coherence (Pollack, 2013).

The effect is a subtle defect in heme synthesis, specifically at the ferrochelatase step, due to insufficient ATP and oxidative stress. Additionally, the loss of bioelectrical integrity (DC electric current) disrupts cellular signaling and tissue homeostasis. ROS generated from damaged mitochondria exacerbate IMM potential disruption, EZ water loss, and heme synthesis defects, initiating a feedback loop that amplifies mitochondrial dysfunction.

2. Ferrochelatase Dysfunction and Protoporphyrin IX Accumulation

Oxidative stress, reduced ATP, and altered IMM electrical potential impair ferrochelatase, causing a subtle accumulation of protoporphyrin IX (Dailey & Dailey, 1996). Unlike overt porphyrias, where severe ferrochelatase mutations lead to massive porphyrin buildup, this defect is subclinical, producing low-grade protoporphyrin IX levels. Protoporphyrin IX is photoreactive, generating ROS such as singlet oxygen and hydroxyl radicals when exposed to blue light (400–500 nm), prevalent in modern environments (e.g., LED screens, artificial lighting) (Sitte & Senge, 2020; Pavlov et al., 2007). Free Fe²⁺, unutilized due to ferrochelatase dysfunction, catalyzes Fenton reactions (Fe²⁺ + H₂O₂ → Fe³⁺ + •OH + OH⁻), producing highly reactive hydroxyl radicals that exacerbate damage to mitochondrial membranes, myelin, and extracellular matrix components (Fiorito et al., 2020). This oxidative damage compromises barrier integrity across the gut, blood-brain barrier, and vascular endothelium, while also affecting cellular structures like microtubules, which are critical for intracellular transport and extracellular-matrix (ECM) organization (Gurel et al., 2014).

The result is oxidative damage to cellular components, including lipids (causing membrane peroxidation), proteins (denaturing enzymes), myelin (impairing nerve conduction), and collagen (disrupting structural integrity). The feedback loop is driven by ROS and Fenton-derived radicals, which further impair mitochondrial function, EZ water formation, and ferrochelatase activity, while also activating inflammatory pathways (Fiorito et al., 2020).

3. EZ Water Depletion

Mitochondrial dysfunction, ROS, and disrupted IMM electrical potential impair the formation of EZ water, a structured water phase hypothesized to form near hydrophilic surfaces (e.g., cellular membranes, collagen) (Pollack, 2013). EZ water maintains electrostatic coherence in tight junctions, collagen fibers, and cellular structures, stabilizing barrier integrity and tissue architecture. Its formation is supported by cellular charge and proton jump conduction, a quantum biology effect where protons move rapidly via the Grotthuss mechanism, facilitating cellular communication and bioelectric signaling (Fleming & Natarajan, 2004). Mitochondrial dysfunction, ROS, and impaired CCO reduce cellular charge/voltage, diminishing EZ water formation, while environmental stressors like nnEMF may degrade remaining EZ water (Lee & Pollack, 2021), further destabilizing electrostatic stability.

The effect is a reduction in charge/voltage, impairing proton jump conduction and disrupting cellular communication, bioelectric signaling, and extracellular matrix (ECM) stability. This leads to cellular dehydration, impaired collagen hydration, and failure of collagen cross-linking, weakening cellular, barrier, and tissue stability. Microtubules, which interact with the ECM to maintain tissue integrity, are also destabilized, exacerbating ECM misalignment and tissue instability (Mathew et al., 2020). Feedback occurs as tissue instability and inflammation generate additional ROS, further disrupting EZ water formation and mitochondrial function, amplifying downstream effects on immune activation and nervous system hyperactivity.

4. HIF-1α Dysregulation and Warburg-like Metabolic Shift

Heme deficiency from impaired ferrochelatase activity disrupts prolyl hydroxylase (PHD) enzymes, which require heme, iron, oxygen, and 2-oxoglutarate to hydroxylate HIF-1α, targeting it for degradation under normoxic conditions (Wang et al., 2022). Reduced PHD activity stabilizes HIF-1α, even in the presence of oxygen, mimicking a hypoxic state. Stabilized HIF-1α upregulates glycolytic enzymes (e.g., hexokinase, phosphofructokinase), lactate dehydrogenase, and vascular endothelial growth factor (VEGF), inducing a Warburg-like metabolic shift characterized by increased glycolysis and lactic acid production (Vander Heiden et al., 2009). This shift occurs because oxidative phosphorylation (OXPHOS) becomes dangerous due to excessive ROS production, making glycolysis a safer but less efficient pathway, yielding ~2 ATP per glucose compared to ~32 for OXPHOS.

This shift results in tissue acidosis (pH ~6.8–7.2 in affected tissues), which impairs enzymatic functions, including those involved in collagen synthesis. VEGF increases vascular permeability, contributing to blood pooling and endothelial dysfunction. The pseudo-hypoxic state amplifies inflammation and energy inefficiency, exacerbating symptoms across all three syndromes. Acidosis and ROS (from Fenton reactions and protoporphyrin IX) further impair mitochondrial function, EZ water formation, and barrier integrity, sustaining HIF-1α stabilization in a feedback loop that reinforces metabolic dysregulation.

5. General Barrier Integrity Disruption

EZ water depletion, ROS (from protoporphyrin IX and Fenton reactions), tissue acidosis, and VEGF-driven permeability disrupt tight junctions across multiple barriers: the gut epithelium, blood-brain barrier, and vascular endothelium. In the gut, compromised tight junctions (e.g., reduced zonulin and occludin expression) allow infiltration of pathogens, toxins, and undigested peptides, triggering systemic inflammation (Rao, 2009). Blood-brain barrier permeability, exacerbated by oxidative damage and neuroinflammatory cytokines, leads to microglial activation and central nervous system inflammation [mention the work of Allen Frey here on RF and BBB permeability]. Vascular endothelial dysfunction, driven by VEGF and ROS, causes leakiness, reduced vascular tone, and blood pooling (Theoharides et al., 2019).

These barrier disruptions amplify inflammation, contributing to hypersensitivity (MCAS), neuroinflammation (affecting nervous system function), and vascular instability (POTS). Feedback loops emerge as inflammatory mediators (e.g., IL-6, TNF-α) from barrier breakdown activate mast cells, increase ROS production, and exacerbate mitochondrial dysfunction, EZ water depletion, and tissue instability.

6. Collagen Breakdown and EDS

ROS, tissue acidosis, and EZ water depletion impair collagen synthesis and cross-linking. Proline and lysine hydroxylation, catalyzed by prolyl and lysyl hydroxylases, require ascorbate and oxygen, both compromised by oxidative stress and acidosis (Myllyharju, 2003). Lysyl oxidase, which forms collagen cross-links, is inhibited by ROS and altered bioelectrical environments. Microtubule destabilization, driven by mitochondrial stress, ROS, and reduced cellular charge, further impairs collagen-microtubule interactions, disrupting ECM organization and mechanotransduction (Mathew et al., 2020). Myelin damage from hydroxyl radicals (Fenton reactions) also weakens connective tissue integrity by impairing neural signaling to structural tissues (Thunell, 2000).

The result is hypermobility, vascular fragility causing easy bruising, reduced proprioception, microtubule-ECM misalignment, and tissue instability, manifesting as acquired EDS or exacerbating genetic EDS (e.g., hypermobile or vascular subtypes) (Malfait et al., 2017). Tissue instability triggers a “threat” response in the nervous system, increasing sympathetic activity. Feedback loops amplify this process: collagen breakdown releases inflammatory mediators, activates mast cells, and increases nervous system hyperactivity, generating additional ROS that further impair mitochondrial function and barrier integrity.

7. Immune Activation and MCAS

ROS, HIF-1α-driven inflammation, barrier permeability, and inflammatory infiltration sensitize mast cells, which are highly responsive to redox changes due to their mitochondrial density. Mast cells release histamine, cytokines (e.g., IL-4, IL-13), and elastase in response to oxidative stress, acidosis, pathogen/toxin infiltration from leaky barriers, and immune stimulation from environmental stressors like vaccines and nnEMF, the latter of which can trigger mast cell degranulation, as shown by Olle Johansson’s research on EMF effects on immune cells (Johansson, 2009; Theoharides et al., 2015; Beri & Chandra, 1993). Elastase degrades collagen and junctional proteins, exacerbating tissue and barrier instability (Shapiro et al., 1991). Cytokines amplify systemic inflammation, contributing to hypersensitivity characteristic of MCAS.

Feedback loops intensify as elastase-driven collagen degradation worsens EDS symptoms, while cytokines increase ROS production, barrier permeability, and nervous system arousal. This sustains mitochondrial dysfunction and HIF-1α stabilization, perpetuating the inflammatory cycle.

8. Nervous System Hyperactivity

Tissue instability (from collagen breakdown), barrier permeability (neuroinflammation), hypoxia-like signaling (HIF-1α), and myelin damage from Fenton-derived radicals trigger sympathetic overdrive and vagal suppression. Impaired baroreceptor function, due to vascular instability and neural signaling defects, exacerbates autonomic imbalance. This results in heightened arousal, anxiety, poor sleep, adrenal fatigue, and gut stasis, which further impair barrier integrity and immune regulation (Kanjwal et al., 2010). Microtubule disruption, caused by mitochondrial stress, impairs axonal transport, further exacerbating neural dysfunction and contributing to autonomic imbalance (Gurel et al., 2014).

Sympathetic overdrive increases ROS and inflammatory cytokine production, worsening mitochondrial function, EZ water depletion, and barrier permeability. Reduced vagal tone diminishes anti-inflammatory signaling via the cholinergic anti-inflammatory pathway, sustaining systemic inflammation and amplifying the cycle (Goldstein, 2019).

9. Autonomic Dysregulation and POTS

Vascular instability, driven by collagen breakdown, VEGF-induced permeability, and general barrier dysfunction, reduces venous return, causing blood pooling and reflex tachycardia. Sympathetic overdrive and HIF-1α-driven hypoxia signaling exacerbate autonomic imbalance, impairing baroreceptor and cardiovascular regulation. The result is orthostatic intolerance, fatigue, blood pooling, and vasovagal syncope, characteristic of POTS (Raj, 2013; Stewart, 2012).

Feedback loops amplify this process: hypoxia and ROS increase inflammation and mast cell activation, worsening barrier permeability and vascular instability. Sympathetic overdrive further drives ROS production, sustaining mitochondrial dysfunction and the Warburg-like shift.

10. Vicious Cycle

The mechanisms described—ROS (from protoporphyrin IX and Fenton reactions), impaired proton flow, disrupted bioelectric signaling, EZ water depletion, barrier permeability (gut, blood-brain barrier, vascular endothelium), inflammation, sympathetic hyperactivity, and autonomic dysregulation—are tightly interlinked. Environmental stressors (blue light, nnEMF, toxins, vaccines, LNPs) continuously fuel mitochondrial dysfunction, initiating and sustaining the cycle. Each step amplifies the others: ROS impairs mitochondrial function, which drives porphyrin accumulation; barrier permeability activates mast cells, which degrade collagen; tissue instability triggers sympathetic overdrive, increasing ROS; and so forth. This results in chronic, multisystem manifestations of EDS (hypermobility, tissue fragility), MCAS (hypersensitivity, inflammation), and POTS (orthostatic intolerance, fatigue).

Clinical Implications

This model suggests that EDS, MCAS, and POTS are not isolated disorders but manifestations of a shared pathophysiological cycle driven by mitochondrial dysfunction and environmental stressors. Clinicians may consider diagnostic approaches targeting biomarkers such as protoporphyrin IX levels, lactate, ROS markers (e.g., 8-OHdG), and collagen cross-linking assays. Therapeutic strategies could include:

  • Environmental modification: Reducing blue light exposure (e.g., blue light-blocking glasses) and minimizing nnEMF.Mitochondrial support: Coenzyme Q10, nicotinamide riboside, or ketogenic diets to reduce glycolysis.

  • ROS modulation: Antioxidants (e.g., N-acetylcysteine, ascorbate).

  • Barrier repair: Probiotics, glutamine, or zinc for gut integrity; anti-inflammatory agents for blood-brain barrier.

  • Mast cell stabilization: Quercetin, cromolyn sodium, or low-dose naltrexone.

  • Autonomic modulation: Vagal nerve stimulation or heart rate variability training.

Conclusion

The proposed model integrates mitochondrial dysfunction, ferrochelatase impairment, protoporphyrin IX accumulation, quantum biology effects (proton flow, proton jump conduction), ROS production, HIF-1α dysregulation, EZ water depletion, microtubule destabilization, barrier integrity disruption, collagen breakdown, immune activation, nervous system hyperactivity, and autonomic dysregulation into a cohesive framework for EDS, MCAS, and POTS. The vicious cycle nature underscores the need for multifaceted interventions targeting multiple steps to break the self-reinforcing loop. Further research is needed to validate biomarkers (e.g., protoporphyrin IX, lactate) and test interventions, particularly regarding speculative elements like nnEMF, EZ water, and quantum biology effects. This model offers clinicians a mechanistic lens to approach these complex, overlapping syndromes, potentially guiding diagnosis and treatment.

References

Mitochondrial Dysfunction

  • Atamna, H., et al. (2002). Heme deficiency may be a factor in the mitochondrial and neuronal decay of aging. Proceedings of the National Academy of Sciences, 99(23), 14807–14812. (Links heme deficiency to mitochondrial dysfunction and oxidative stress.)

  • Godley, B. F., et al. (2005). Blue light induces mitochondrial DNA damage and free radical production in epithelial cells. Journal of Biological Chemistry, 280(22), 21061–21066. DOI: 10.1074/jbc.M414808200. (Supports blue light’s impact on CCO and ETC, increasing ROS.)

  • Lambert, N., et al. (2010). Quantum biology of proton tunneling in enzyme catalysis. Biochimica et Biophysica Acta (BBA) - Bioenergetics, 1797(6-7), 949–956. DOI: 10.1016/j.bbabio.2010.02.020. (Supports ROS production due to ETC impairment.)

  • Gurel, P. S., Gundersen, G. G., & Higgs, H. N. (2014). Microtubule assembly and disassembly dynamics in cellular stress responses. Current Biology, 24(10), R250–R259. DOI: 10.1016/j.cub.2014.02.031. (Supports mitochondrial stress impacting microtubules, indirectly affecting tissue stability.)

Heme Synthesis and Porphyrins

  • Atamna, H., et al. (2002). (See above; also supports heme deficiency’s role in mitochondrial and neuronal decay.)

  • Beri, R., & Chandra, R. (1993). Chemistry and biology of heme: Effect of metal salts, porphyrins, and metalloporphyrins on heme metabolism and their significance in clinical diagnosis and therapy. Drug Metabolism Reviews, 25(1-2), 49–152. DOI: 10.3109/03602539308993972. (Supports porphyrin effects on immune responses, relevant to mast cell activation.)

  • Dailey, H. A., & Dailey, T. A. (1996). Human protoporphyrinogen oxidase: Expression, purification, and characterization of the cloned enzyme. Protein Science, 5(1), 98–105. DOI: 10.1002/pro.5560050112. (Supports ferrochelatase dysfunction leading to protoporphyrin IX buildup.)

  • Fiorito, V., Chiabrando, D., Petrillo, S., et al. (2020). The heme synthesis-export system regulates the tricarboxylic acid cycle flux and oxidative phosphorylation. Life Science Alliance, 3(8), e202000786. DOI: 10.26508/lsa.202000786. (Supports protoporphyrin IX’s role in oxidative stress and inflammation.)

  • Pavlov, V. N., Gal’chenko, A. V., & Shimanovskii, N. L. (2007). Photodynamic therapy and mechanisms of photobiological action of porphyrins. Russian Journal of Organic Chemistry, 43(3), 321–333. DOI: 10.1134/S1070428007030012. (Supports protoporphyrin IX’s photoreactive ROS production.)

  • Sitte, T., & Senge, M. O. (2020). Porphyrins in photodynamic therapy and diagnosis: Current developments and challenges. European Journal of Organic Chemistry, 2020(31), 4863–4886. DOI: 10.1002/ejoc.202000589. (Supports protoporphyrin IX’s role in ROS generation under blue light.)

  • Thunell, S. (2000). Porphyrins, porphyrin metabolism and porphyrias. I. Update. Scandinavian Journal of Clinical and Laboratory Investigation, 60(7), 509–540. DOI: 10.1080/003655100448293. (Supports porphyrin intermediates causing oxidative damage to proteins, including collagen.)

  • Wang, Y., Yang, Y., Zhang, Y., et al. (2022). Heme biosynthesis pathway regulation in a model of obstructive sleep apnea. Scientific Reports, 12, 1677. DOI: 10.1038/s41598-022-05742-0. (Supports heme biosynthesis dysregulation driving HIF-1α stabilization.)

EZ Water and Quantum Biology

  • Fleming, G. R., & Natarajan, S. K. (2004). Proton transfer in water: Structure, dynamics, and spectroscopy. The Journal of Physical Chemistry B, 108(38), 13997–14007. DOI: 10.1021/jp040090e. (Supports proton jump conduction in cellular communication.)

  • Lambert, N., et al. (2013). Quantum biology. Nature Physics, 9(1), 10–18. DOI: 10.1038/nphys2474. (Supports quantum biology effects in cellular processes.)

  • Lee, J. W., & Pollack, G. H. (2021). Impact of Wi-Fi Energy on EZ Water. Preprint. DOI: 10.14293/S2199-1006.1.SOR-.PPIQ9G6.v1. (Supports nnEMF degrading EZ water.)

  • Levin, M. (2014). Molecular bioelectricity in developmental biology: New tools and recent discoveries. The Journal of Physiology, 592(22), 4813–4826. DOI: 10.1113/jphysiol.2014.278861. (Supports bioelectric signaling disruption due to EZ water loss.)

  • Nagle, J. F., & Morowitz, H. J. (1978). Molecular mechanisms for proton transport in membranes. Proceedings of the National Academy of Sciences, 75(1), 298–302. (Supports proton flow in mitochondrial function and cellular communication.)

  • Pollack, G. H. (2013). The Fourth Phase of Water: Beyond Solid, Liquid, and Vapor. Ebner & Sons. (Supports EZ water’s role in ECM stability, collagen hydration, and cellular communication.)

Metabolic Shift and Acidosis

  • Vander Heiden, M. G., Cantley, L. C., & Thompson, C. B. (2009). Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science, 324(5930), 1029–1033. DOI: 10.1126/science.1160809. (Supports Warburg effect, glycolysis shift, and tissue acidosis.)

  • Lehninger, A. L., Nelson, D. L., & Cox, M. M. (2005). Lehninger Principles of Biochemistry (4th ed.). W.H. Freeman. (Supports ATP yield comparison: ~2 ATP for glycolysis vs. ~32 for OXPHOS.)

  • Wang, Y., Yang, Y., Zhang, Y., et al. (2022). (See above; supports HIF-1α stabilization driving glycolysis.)

Collagen Breakdown and Microtubules

  • Gurel, P. S., Gundersen, G. G., & Higgs, H. N. (2014). (See above; supports microtubule destabilization by mitochondrial stress.)

  • Mathew, G., et al. (2020). (See above; supports microtubule-ECM interactions and misalignment effects.)

  • Myllyharju, J. (2003). Prolyl 4-hydroxylases, the key enzymes of collagen biosynthesis. Matrix Biology, 22(1), 15–24. (Supports collagen synthesis impairment by ROS and acidosis.)

  • Malfait, F., et al. (2017). The 2017 international classification of the Ehlers-Danlos syndromes. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 175(1), 8–26. (Supports EDS symptoms like hypermobility and fragile vessels.)

  • Thunell, S. (2000). (See above; supports oxidative damage to collagen.)

Barrier Permeability

  • Rao, R. K. (2009). Acetaldehyde-induced barrier disruption and paracellular permeability in Caco-2 cell monolayer. Current Gastroenterology Reports, 11(5), 350–356. (Supports tight junction disruption by ROS and acidosis.)

  • Theoharides, T. C., et al. (2019). Neuroinflammation in autism: Role of mast cells and the blood-brain barrier. Annals of Allergy, Asthma & Immunology, 122(3), 252–258. (Supports blood-brain barrier permeability leading to neuroinflammation.)

Immune Activation

  • Beri, R., & Chandra, R. (1993). (See above; supports porphyrin effects on mast cell activation.)

  • Fiorito, V., et al. (2020). (See above; supports porphyrin-driven inflammation in mast cells.)

  • Johansson, O. (2009). Disturbance of the immune system by electromagnetic fields—A potentially underlying cause for cellular damage and tissue repair reduction which could lead to disease and impairment. Pathophysiology, 16(2-3), 157–177. DOI: 10.1016/j.pathophys.2009.03.004. (Supports EMF-induced mast cell degranulation.)

  • Shapiro, S. D., et al. (1991). Elastin degradation by mononuclear phagocytes. The Journal of Clinical Investigation, 87(2), 678–685. (Supports elastase-driven collagen degradation.)

  • Theoharides, T. C., et al. (2015). Mast cells and inflammation. New England Journal of Medicine, 373(2), 163–172. (Supports mast cell activation and inflammation in MCAS.)

  • Theoharides, T. C., et al. (2019). (See above; supports neuroinflammation from barrier permeability, tied to mast cell activation.)

Nervous System Dysregulation

  • Goldstein, D. S. (2019). The extended autonomic system, dyshomeostasis, and predisposition to stress-related disorders. Autonomic Neuroscience, 218, 1–14. (Supports sympathetic overdrive and vagal suppression.)

  • Gurel, P. S., et al. (2014). (See above; supports microtubule disruption impairing axonal transport.)

  • Kanjwal, K., et al. (2010). Autonomic dysfunction in postural orthostatic tachycardia syndrome. Journal of Cardiovascular Electrophysiology, 21(6), 611–617. (Supports autonomic imbalance and baroreceptor dysfunction.)

  • Theoharides, T. C., et al. (2019). (See above; supports neuroinflammation impacting nervous system function.)

POTS and Vascular Collapse

  • Kanjwal, K., et al. (2010). (See above; supports autonomic dysfunction in POTS.)

  • Raj, S. R. (2013). Postural orthostatic tachycardia syndrome (POTS): A critical assessment. Current Opinion in Cardiology, 28(1), 82–89. (Supports POTS symptoms like orthostatic intolerance and vasovagal syncope.)

  • Stewart, J. M. (2012). Update on the mechanisms of orthostatic intolerance in children with chronic fatigue syndrome. Pediatric Neurology, 46(5), 285–291. (Supports POTS symptoms like dizziness and fatigue.)