Some time ago hydrogen sulphide (H2S) was suggested to play a role in ME/CFS 1,2. Since then the general research literature has continued to forge ever more intricate and compelling links between H2S, health and disease. Gone are the days of H2S being exclusively viewed as an environmental toxicant; H2S is now widely recognised as a major biological mediator (even in mitochondria! 3). Recently H2S was even found to mediate the beneficial effects of dietary restriction on stress resistance and lifespan 4.
So what things might influence the H2S system in health and disease? Apparently lots of things, as shown in my table below, some of which relate to specific tissues, cells or subcellular compartments.
As can be seen, many things can influence H2S. I wonder if this may create some dichotomies in ME/CFS, and other chronic conditions. For instance immune activation decreases H2S in the brain, but increases H2S in the periphery. Also autonomic dysfunction (parasympathetic dominance) might serve to augment vascular H2S. However nutritional deficiencies and elevated homocysteine could blunt H2S production everywhere. Also at a subcellular level, perhaps oxidative stress might inhibit 3-MST and lower H2S in mitochondria, hindering its pro-bioenergetic effects 3?
1. Lemle, M. D. Hypothesis: chronic fatigue syndrome is caused by dysregulation of hydrogen sulfide metabolism. Med. Hypotheses 72, 108–9 (2009).
2. De Meirleir, K., Roelant, C. & Fremont, M. Unravelling the Origin of Myalgic Encephalomyelitis: Gastrointesinal Dysfunction, Production of Neurotoxins and Environmental Exposure. in (2009). at
3. Szabo, C. et al. Regulation of Mitochondrial Bioenergetic Function by Hydrogen Sulfide. Part I. Biochemical and Physiological Mechanisms. Br. J. Pharmacol. (2013). doi:10.1111/bph.12369
4. Mitchell, J. R., Hine, C. M., Ph, D. & Mair, W. B. Endogenous Hydrogen Sulfide Production Is Essential for Dietary Restriction Benefits. Cell 160, 132–144 (2015).
5. Kimura, H. Hydrogen sulfide and polysulfides as signaling molecules. Proc. Jpn. Acad. Ser. B. Phys. Biol. Sci. 91, 131–59 (2015).
6. Mishanina, T. V, Libiad, M. & Banerjee, R. Biogenesis of reactive sulfur species for signaling by hydrogen sulfide oxidation pathways. Nat. Chem. Biol. 11, 457–464 (2015).
7. Benavides, G. A. et al. Hydrogen sulfide mediates the vasoactivity of garlic. Proc. Natl. Acad. Sci. U. S. A. 104, 17977–82 (2007).
8. Flannigan, K. L. et al. Impaired hydrogen sulfide synthesis and IL-10 signaling underlie hyperhomocysteinemia-associated exacerbation of colitis. Proc. Natl. Acad. Sci. U. S. A. 111, 13559–64 (2014).
9. Li, J.-J. et al. Homocysteine Triggers Inflammatory Responses in Macrophages through Inhibiting CSE-H2S Signaling via DNA Hypermethylation of CSE Promoter. Int. J. Mol. Sci. 16, 12560–12577 (2015).
10. Sen, U., Mishra, P. K., Tyagi, N. & Tyagi, S. C. Homocysteine to hydrogen sulfide or hypertension. Cell Biochem. Biophys. 57, 49–58 (2010).
11. Mitsuhashi, H. et al. Oxidative stress-dependent conversion of hydrogen sulfide to sulfite by activated neutrophils. Shock 24, 529–34 (2005).
12. Kolluru, G. K., Shen, X. & Kevil, C. G. A tale of two gases: NO and H2S, foes or friends for life? Redox Biol. 1, 313–318 (2013).
13. Módis, K., Asimakopoulou, A., Coletta, C., Papapetropoulos, A. & Szabo, C. Oxidative stress suppresses the cellular bioenergetic effect of the 3-mercaptopyruvate sulfurtransferase/hydrogen sulfide pathway. Biochem. Biophys. Res. Commun. 433, 401–7 (2013).
14. Niu, W.-N., Yadav, P. K., Adamec, J. & Banerjee, R. S-glutathionylation enhances human cystathionine β-synthase activity under oxidative stress conditions. Antioxid. Redox Signal. 22, 350–61 (2015).
15. Paul, B. D. & Snyder, S. H. H2S signalling through protein sulfhydration and beyond. Nature Reviews Molecular Cell Biology 13, 499–507 (2012).
16. Carbonero, F., Benefiel, A. C., Alizadeh-Ghamsari, A. H. & Gaskins, H. R. Microbial pathways in colonic sulfur metabolism and links with health and disease. Front. Physiol. 3, 448 (2012).
17. Shen, X. et al. Microbial regulation of host hydrogen sulfide bioavailability and metabolism. Free Radic. Biol. Med. 60, 195–200 (2013).
18. Sen, N. et al. Hydrogen sulfide-linked sulfhydration of NF-κB mediates its antiapoptotic actions. Mol. Cell 45, 13–24 (2012).
19. Zheng, Y. et al. Lipopolysaccharide regulates biosynthesis of cystathionine γ-lyase and hydrogen sulfide through Toll-like receptor-4/p38 and Toll-like receptor-4/NF-κB pathways in macrophages. In Vitro Cell. Dev. Biol. Anim. 49, 679–88 (2013).
20. Miller, T. W. et al. Hydrogen sulfide is an endogenous potentiator of T cell activation. J. Biol. Chem. 287, 4211–21 (2012).
21. Wallace, J. L., Ferraz, J. G. P. & Muscara, M. N. Hydrogen sulfide: an endogenous mediator of resolution of inflammation and injury. Antioxid. Redox Signal. 17, 58–67 (2012).
22. Dufton, N., Natividad, J., Verdu, E. F. & Wallace, J. L. Hydrogen sulfide and resolution of acute inflammation: A comparative study utilizing a novel fluorescent probe. Sci. Rep. 2, 499 (2012).
23. Lee, M., Schwab, C., Yu, S., McGeer, E. & McGeer, P. L. Astrocytes produce the antiinflammatory and neuroprotective agent hydrogen sulfide. Neurobiol. Aging 30, 1523–34 (2009).
24. Gong, Q.-H. et al. Hydrogen sulfide attenuates lipopolysaccharide-induced cognitive impairment: a pro-inflammatory pathway in rats. Pharmacol. Biochem. Behav. 96, 52–8 (2010).
25. Gong, Q.-H. et al. S-propargyl-cysteine, a novel hydrogen sulfide-modulated agent, attenuates lipopolysaccharide-induced spatial learning and memory impairment: involvement of TNF signaling and NF-κB pathway in rats. Brain. Behav. Immun. 25, 110–9 (2011).
26. Manna, P. & Jain, S. K. Vitamin D up-regulates glucose transporter 4 (GLUT4) translocation and glucose utilization mediated by cystathionine-γ-lyase (CSE) activation and H2S formation in 3T3L1 adipocytes. J. Biol. Chem. 287, 42324–32 (2012).
27. Wiliński, B., Wiliński, J., Somogyi, E., Piotrowska, J. & Opoka, W. Vitamin D3 (cholecalciferol) boosts hydrogen sulfide tissue concentrations in heart and other mouse organs. Folia Biol. (Praha). 60, 243–7 (2012).