A Mechanistic Model - Chronic Stress and Trauma as Environmental Stessors

Chronic Stress and Trauma as Environmental Stressors

This addendum elaborates on chronic stress and trauma as environmental stressors in the mechanistic model of Ehlers-Danlos Syndrome (EDS), Mast Cell Activa- tion Syndrome (MCAS), and Postural Orthostatic Tachycardia Syndrome (POTS), emphasizing their role in mitochondrial dysfunction and related systemic ef- fects. Chronic stress and trauma, encompassing prolonged psychological, emo- tional, or physical strain, disrupt cellular and systemic processes, amplifying symptoms across these syndromes through interconnected mechanisms.

Mitochondrial Dysfunction

Chronic stress and trauma impair mitochondrial function, exacerbating fatigue, tissue instability, and inflammation in EDS, MCAS, and POTS:

  • HPAAxisOveractivation:Chronicstressdysregulatesthehypothalamic-pituitary- adrenal (HPA) axis, elevating glucocorticoids (e.g., cortisol), which inhibit mito- chondrial oxidative phosphorylation by downregulating cytochrome c oxidase (CCO), reducing ATP production and inner mitochondrial membrane potential (-140 to -180 mV) (7; 10).

  • ReactiveOxygenSpecies(ROS)Overproduction:Elevatedcortisolandcatecholamines (e.g., adrenaline) increase mitochondrial ROS through electron leakage in the electron transport chain (ETC), damaging mitochondrial membranes and ex- acerbating MCAS inflammation (9).

  • CellDangerResponse(CDR):TraumatriggersasustainedCDR,amitochondrial- driven protective state that reduces ATP synthesis and redirects energy to de- fense, depleting exclusion zone (EZ) water and destabilizing collagen in EDS (8).

  • Mitochondrial DNA Damage: Chronic ROS exposure damages mitochondrial DNA, impairing ETC efficiency and contributing to POTS fatigue (9).

    Immune Dysregulation and Mast Cell Activation

    Chronic stress and trauma sensitize mast cells, amplifying MCAS hypersensitiv- ity and inflammation:

  • Mast Cell Sensitization: Stress-induced catecholamines and cortisol enhance mast cell degranulation, releasing histamine, cytokines (e.g., IL-6), and elas- tase, driving allergic responses and collagen degradation in EDS (12; 2).

  • InflammatoryPathways:ROSandCDRupregulateinflammatorycytokines(e.g., TNF-α), increasing systemic inflammation and exacerbating MCAS symptoms (8; 2).

  • BarrierPermeability:Stress-inducedinflammationcompromisesgutandblood- brain barrier integrity, allowing toxin infiltration, triggering mast cell activa- tion, and worsening MCAS (12; 6).

Oxidative Stress and Cellular Damage

Chronic stress and trauma generate ROS, causing cellular damage and amplify- ing symptoms:

• Cellular Component Damage: ROS catalyze Fenton reactions (e.g., Fe2+ + H2O2 → ·OH), damaging mitochondrial DNA, myelin, and collagen, exacerbating EDS tissue instability (9; 10).

• Neuroinflammation:Stress-inducedROSandcytokinesactivatemicroglia,caus- ing neuroinflammation and contributing to POTS neurological symptoms (e.g., brain fog) (4).

• Microtubule Disruption: ROS impair microtubule stability, disrupting extracel- lular matrix (ECM) organization and worsening EDS tissue fragility (3).

Autonomic Dysregulation

Chronic stress and trauma disrupt autonomic balance, exacerbating POTS symp- toms:

– Sympathetic Overdrive: Stress triggers sustained sympathetic activation via the CDR, increasing catecholamine release and impairing baroreceptor func- tion, contributing to POTS orthostatic intolerance (8; 13).

– VagalSuppression:Traumasuppressesvagaltone,reducinganti-inflammatory signaling via the cholinergic pathway, amplifying MCAS inflammation (5; 11).

– HypothalamicInflammation:Chronicstressinflamestheparaventricularnu- cleus (PVN), elevating vasopressin and cortisol, worsening POTS blood pool- ing and vascular instability (1).

References

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[8] Naviaux, R. K. (2017). Metabolic features of the cell danger response. Mi- tochondrion, 46, 139–153. DOI: 10.1016/j.mito.2018.05.006

[9] Picard, M., Wallace, D. C., & Burelle, Y. (2016). The rise of mitochondria in medicine. Mitochondrion, 30, 105–116. DOI: 10.1016/j.mito.2016.07.003

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[12] Theoharides, T. C., Alysandratos, K.-D., Angelidou, A., Delivanis, D.-A., Sismanopoulos, N., Zhang, B., Asadi, S., Vasiadi, M., Weng, Z., Miniati, A., & Kalogeromitros, D. (2015). Mast cells and inflammation. New England Journal of Medicine, 373(2), 163–172. DOI: 10.1056/NEJMra1409760

[13] van der Kolk, B. A. (2014). The Body Keeps the Score: Brain, Mind, and Body in the Healing of Trauma. New York: Viking.