The Mast Cell – Mitochondria Connection

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Mast cell activation is gaining attention among patients and practitioners, yet this phenomenon is far from new.  

Mast Cell Activation Syndrome (MCAS) is a chronic condition involving excessive or dysregulated release of mast cell mediators—histamine, tryptase, prostaglandins, leukotrienes, and many others—affecting multiple systems in the body. Symptoms such as flushing, itching, brain fog, fatigue, and gastrointestinal distress can indicate underlying mast cell dysregulation.1,2,3 

Mast cells typically don’t act in isolation—excessive inflammation, oxidative stress, and mitochondrial dysfunction often overlap in chronic conditions. When mitochondrial health declines, it can adversely impact inflammatory signaling and immune regulation, perpetuating the cycle of mast cell activation.4 Addressing these interconnected pathways is essential for comprehensive patient support. 

Differentiation from Histamine Intolerance 

Unlike histamine intolerance, which is primarily related to dietary histamine intake, MCAS involves mast cells becoming overly reactive to various triggers, including allergens, physical or emotional stress, environmental toxins, alcohol intake, and even temperature shifts.5,6,7 The hundreds (and possibly thousands) of mediators released incur broad health implications and a complexity that remains poorly understood.2,8 

MCAS is frequently associated with conditions such as POTS, Lyme disease, autoimmune disorders, metabolic dysfunctions, and many more.7,9,10 

Diagnostic Challenges 

Diagnosing MCAS is largely based on clinical presentation, as objective testing can be challenging. Elevated serum tryptase and histamine levels may sometimes be detected if testing is conducted shortly after a suspected activation event, but this is not always feasible,1 making symptom awareness and targeted interventions critical. 

The Multifaceted Approach to Mast Cell Support 

Management approaches require more than mere histamine receptor antagonism or gut histamine degradation, as many pathways are involved. The condition’s complexity leaves significant gaps in support. 

Conventional therapy targets commonly include:1,2,3,5,6 

  • Degranulation: Cromolyn sodium 
  • H1 & H2 receptor blockade: Antihistamines 
  • Flushing & prostaglandin-mediated effects: Aspirin 
  • Respiratory inflammation & leukotrienes: Montelukast 

As a result, management can become cumbersome. Side effects of daily use may also be bothersome for some individuals. For example, cromolyn sodium, antihistamines, and montelukast may cause diarrhea and headaches11,12,13, while daily aspirin intake can increase the risk of stomach ulcers and bleeding 14 and may worsen symptoms for some.3 

Potential Alternative Therapies Rooted in Research 

Preliminary evidence suggests that certain dietary and nutraceutical approaches may influence healthy mast cell function. Flavonoids, for instance, are a group of polyphenolic substances with antioxidant and anti-inflammatory properties. Quercetin, luteolin, and resveratrol are three such plant-derived compounds that have been studied for their potential to inhibit histamine, mast cell degranulation, and cytokine release.15,16,17 Luteolin, derived from various fruits, vegetables, and herbs, also suppresses leukotriene production.18 

Similarly, research demonstrates that fisetin, a flavonoid found in strawberries, onions, and grapes, may play a role in stabilizing mast cells, alleviating urticaria-like symptoms, and suppressing inflammatory mediators.19,20 

Studies also support the efficacy of various herbs and herbal extracts on mast cell function. Urtica dioca, also known as stinging nettle, for example, has been shown to antagonize the H1 histamine receptor, prevent mast cell degranulation, and inhibit prostaglandin formation21, while Nigella sativa (black cumin) targets H1 and H2 histamine receptors and inhibits leukotrienes, prostaglandins, and other inflammatory mediators.22,23 Likewise, Perilla frutescens, a member of the mint family and a source of luteolin, has been shown to support mast cell stabilization.24,25 

Want to explore more on MCAS? Dr. Jill Carnahan offers her insights on this topic here. 

References 

  1. Fernandez J. Mastocytosis and Mast Cell Activation Syndrome. Merck Manual Professional Edition. Published August 2, 2024. https://www.merckmanuals.com/professional/immunology-allergic-disorders/allergic-autoimmune-and-other-hypersensitivity-disorders/mastocytosis-and-mast-cell-activation-syndrome
  2. Mihele DM, Nistor PA, Bruma G, et al. Mast Cell Activation Syndrome Update—A Dermatological Perspective. Journal of Personalized Medicine. 2023;13(7):1116. doi:https://doi.org/10.3390/jpm13071116
  1. Allergy & Asthma Network. What is Mast Cell Activation Syndrome (MCAS)? – Allergy & Asthma Network. Allergy & Asthma Network. Published November 14, 2024. https://allergyasthmanetwork.org/mast-cell-diseases/mcas/
  1. Chelombitko MA, Chernyak BV, Fedorov AV, Zinovkin RA, Razin E, Lakhsmi Bhargavi Paruchuru. The Role Played by Mitochondria in FcεRI-Dependent Mast Cell Activation. Frontiers in Immunology. 2020;11. doi:https://doi.org/10.3389/fimmu.2020.584210
  1. Parrish C, Ms, Rdn. Mast Cell Activation Syndrome – What It Is and Isn’t.; 2020. https://med.virginia.edu/ginutrition/wp-content/uploads/sites/199/2020/06/Mast-Cell-Activation-Syndrome-June-2020.pdf
  1. GĂĽlen T. A Puzzling Mast Cell Trilogy: Anaphylaxis, MCAS, and Mastocytosis. Diagnostics. 2023;13(21):3307-3307. doi:https://doi.org/10.3390/diagnostics13213307
  1. PoTS UK. Mast Cell Activation Syndrome. PoTS UK. Published July 8, 2024. https://www.potsuk.org/about-pots/associated-conditions/mcas/ 
  1. Molderings GJ, Afrin LB. A survey of the currently known mast cell mediators with potential relevance for therapy of mast cell-induced symptoms. Naunyn-Schmiedeberg’s Archives of Pharmacology. 2023;396(11):2881-2891. doi:https://doi.org/10.1007/s00210-023-02545-y
  1. Talkington J, Nickell SP. Borrelia burgdorferi spirochetes induce mast cell activation and cytokine release. Infection and Immunity. 1999;67(3):1107-1115. doi:https://doi.org/10.1128/IAI.67.3.1107-1115.1999
  1. Conway AE, Verdi M, Shaker MS, et al. Beyond Confirmed Mast Cell Activation Syndrome: Approaching Patients With Dysautonomia and Related Conditions. The Journal of Allergy and Clinical Immunology In Practice. 2024;12(7):1738-1750. doi:https://doi.org/10.1016/j.jaip.2024.03.019
  1. Mayo Clinic. Cromolyn (Oral Route) Description and Brand Names – Mayo Clinic. www.mayoclinic.org. Published February 1, 2025. https://www.mayoclinic.org/drugs-supplements/cromolyn-oral-route/description/drg-20063181
  1. Cleveland Clinic. Antihistamine Types & Side Effects. Cleveland Clinic. Published 2024. https://my.clevelandclinic.org/health/treatments/antihistamines
  1. FDA Center for Drug Evaluation and Research. FDA requires Boxed Warning about serious mental health side effects for asthma and allergy drug montelukast (Singulair); advises restricting use for allergic rhinitis. FDA. Published online March 13, 2020. https://www.fda.gov/drugs/drug-safety-and-availability/fda-requires-boxed-warning-about-serious-mental-health-side-effects-asthma-and-allergy-drug
  1. Mayo Clinic. Daily aspirin therapy: Understand the benefits and risks. Mayo Clinic. Published 2019. https://www.mayoclinic.org/diseases-conditions/heart-disease/in-depth/daily-aspirin-therapy/art-20046797
  2. Kaag S, Lorentz A. Effects of Dietary Components on Mast Cells: Possible Use as Nutraceuticals for Allergies? Cells. 2023;12(22):2602-2602. doi:https://doi.org/10.3390/cells12222602
  1. Tsilioni I, Theoharides T. Luteolin Is More Potent than Cromolyn in Their Ability to Inhibit Mediator Release from Cultured Human Mast Cells. International archives of allergy and immunology. 2024;185(8):803-809. doi:https://doi.org/10.1159/000537752
  1. Weng Z, Zhang B, Asadi S, et al. Quercetin Is More Effective than Cromolyn in Blocking Human Mast Cell Cytokine Release and Inhibits Contact Dermatitis and Photosensitivity in Humans. Taube C, ed. PLoS ONE. 2012;7(3):e33805. doi:https://doi.org/10.1371/journal.pone.0033805
  1. Jin M, Son KH, Chang HW. Luteolin-7-O-glucoside Suppresses Leukotriene C4 Production and Degranulation by Inhibiting the Phosphorylation of Mitogen Activated Protein Kinases and Phospholipase C.GAMMA.1 in Activated Mouse Bone Marrow-Derived Mast Cells. Biological and Pharmaceutical Bulletin. 2011;34(7):1032-1036. doi:https://doi.org/10.1248/bpb.34.1032
  1. Zhang Y, Huang Y, Dang B, et al. Fisetin alleviates chronic urticaria by inhibiting mast cell activation via MRGPRX2. The Journal of Pharmacy and Pharmacology. 2023;75(10):1310-1321. doi:https://doi.org/10.1093/jpp/rgad056
  1. Park HH, Lee S, Oh JM, et al. Anti-inflammatory activity of fisetin in human mast cells (HMC-1). Pharmacological Research. 2007;55(1):31-37. doi:https://doi.org/10.1016/j.phrs.2006.10.002
  1. Roschek B, Fink RC, McMichael M, Alberte RS. Nettle extract (Urtica dioica) affects key receptors and enzymes associated with allergic rhinitis. Phytotherapy Research. 2009;23(7):920-926. doi:https://doi.org/10.1002/ptr.2763
  1. Nikhat Farhana. Meticulous Endorsement of Black Seed and Jambolana: A Scientific Review. IntechOpen eBooks. Published online December 1, 2021. doi:https://doi.org/10.5772/intechopen.99225
  1. Hannan MdA, Rahman MdA, Sohag AAM, et al. Black Cumin (Nigella sativa L.): A Comprehensive Review on Phytochemistry, Health Benefits, Molecular Pharmacology, and Safety. Nutrients. 2021;13(6):1784. doi:https://doi.org/10.3390/nu13061784
  1. Adam G, Robu S, Flutur MM, et al. Applications of Perilla frutescens Extracts in Clinical Practice. Antioxidants. 2023;12(3):727. doi:https://doi.org/10.3390/antiox12030727
  1. Kamei R, Fujimura T, Matsuda M, et al. A flavanone derivative from the Asian medicinal herb ( Perilla frutescens ) potently suppresses IgE-mediated immediate hypersensitivity reactions. Biochemical and Biophysical Research Communications. 2017;483(1):674-679. doi:https://doi.org/10.1016/j.bbrc.2016.12.083