By: Abbey Rebok

Mushrooms are a vital part of any healthy ecosystem, but are they also a vital component to human health? Mushrooms possess various environmental roles such as decomposing plant matter to recycle nutrients, generating symbiotic relationships with other organisms, breaking down environmental pollutants, and in some species, controlling pest populations. While most people are familiar with mushrooms, the vast majority may be unaware of the magic hidden within these scavenging fungi. I am not referring to psilocybin or psilocin, the active compounds in psychedelic mushroom varieties like Psilocybe cubensis, but rather ergothioneine (ERGO), a powerful antioxidant with seemingly endless health benefits.

What is ERGO?

ERGO is a sulfur-containing derivative of histidine, an essential amino acid that humans must consume to form proteins. Like histidine, ERGO cannot be formed by the human body, and can only be obtained through our diet. ERGO is biosynthesized in fungi, certain yeasts, and some microorganisms, but it is also found in plants that uptake it from the soil or from symbiotic interactions with ERGO-producing organisms¹. ERGO is primarily found in the fruiting bodies, or part of the mushroom that produces spores, and levels can vary greatly depending upon the species. A South Korean study of 28 mushroom species (Table 1) identified ERGO levels ranging from 0.06 to 5.54 mg/g DW (milligrams ERGO per grams of dried mushroom)².

Common name	Scientific name	ERGO (mg/g DW)
Wood blewit	Collybia nuda	5.54 ± 0.26
Pinkmottle woodwax	Hygrophorus russula	4.98 ± 0.31
Chanterelle	Cantharellus cibarius	4.09 ± 0.20
Plums and custard	Tricholomopsis rutilans	2.50 ± 0.30
Scaly sawgill	Neolentinus lepideus	2.41 ± 0.09
Butter-foot bolete	Boletus auripes	2.40 ± 0.05
Cauliflower fungus	Sparassis crispa	2.37 ± 0.42
Slippery jack	Suillus luteus	2.27 ± 0.24
Oyster	Pleurotus ostreatus	2.20 ± 0.13
Honey fungus	Armillaria mellea	1.94 ± 0.01

^{Table 1. Top 10 ERGO-containing mushrooms found in local South Korean forests and markets[2]. The amount of ERGO is reported as milligrams per grams dry weight ± standard deviation of the experiments.}

While this study highlights the diversity in ERGO levels among some mushroom species, its small sample size may not accurately reflect ERGO levels across mushroom species. In fact, there are over 2,200 edible mushroom varieties worldwide, and the golden oyster mushroom, Pleurotus citrinopileatus, boasts an astonishing 10.65 mg/g DW ERGO^3,4. While mushroom genetics has a role in ERGO production, environmental conditions may also affect total ERGO levels. The same mushroom species grown in different geographical regions have been reported to contain varying levels of ERGO², suggesting that ERGO levels can be manipulated by growing conditions. Although ERGO is structurally similar to histidine, ERGO cannot be used for protein synthesis⁵. Instead, research suggests ERGO acts as an antioxidant to neutralize harmful free radicals.

What are antioxidants?

Antioxidants are natural or synthetic compounds that neutralize free radicals to prevent cellular damage. Free radicals are unstable atoms that can form during normal cellular processes and are very reactive due to having an unpaired electron (negatively charged subatomic particle). Unpaired electrons occupy an orbital (circular movement and location around an atom) by themselves and do not have a complementary electron. This electron deficiency results in free radicals “stealing” electrons from nearby molecules, causing damage to protein, lipids, and DNA by destabilizing their molecular structures. Antioxidants stabilize free radicals by supplying electrons to the atom, making these free radicals less likely to steal from nearby molecules. One example of a major antioxidant is glutathione (GSH), which is naturally produced by humans in all organs but is largely produced and concentrated in the liver⁶. To prevent cellular damage, enzymes called glutathione peroxidases oxidize, or remove electrons from, glutathione in the presence of free radical-causing chemicals such as hydrogen peroxide (Figure 1)⁷. In this process, hydrogen peroxide is converted to water and oxygen, while two glutathione molecules combine to form glutathione disulfide (GSSG). Enzymes termed glutathione reductases are then able to recycle GSSG back to GSH to continue the cycle.

ERGO can follow an antioxidant mechanism similar to glutathione. One possible oxidized form of ERGO is an ERGO-disulfide that, interestingly enough, can be recycled back to ERGO by glutathione reductase in the presence of GSH⁹. While this does represent one possible pathway, it’s important to note that oxidation of ERGO is much more complex and can result in a variety of structures that have various mechanisms of recycling. So, how is all this talk about antioxidants relevant to human health?

ERGO and disease

Free radicals are naturally produced from normal biological processes. Under homeostatic conditions, free radicals are kept mostly in check by antioxidants. Oxidative stress occurs when the concentration of free radicals exceeds the neutralization abilities of antioxidants. Oxidative stress is linked to cancers, cardiovascular disease, neurological diseases, and other illnesses. It is, therefore, critical to neutralize free radicals to prevent excessive oxidative stress that could lead to disease development. One way to minimize oxidative stress is to consume more antioxidants like ERGO in our diet. But if foods like blueberries and spinach are also rich in antioxidants, why should we consume mushrooms specifically to increase our ERGO intake? Wouldn’t any antioxidant prevent oxidative stress?

The short answer is yes, any antioxidant can reduce free radical levels and prevent oxidative stress, but research suggests a surprising link between ERGO and disease. Interestingly, humans possess a cell membrane transport protein highly selective for ERGO¹⁰. Defects in this protein are associated with susceptibility to Crohn’s disease and rheumatoid arthritis, both of which have oxidative stress as a key component. Additionally, ERGO can cross the blood brain barrier and is linked to neurological diseases like Parkinson’s Disease (PD). Decreased ERGO levels have been reported in PD patients¹¹. While the link between ERGO and PD is unclear, growing evidence suggests that increasing ERGO consumption may be neuroprotectant and provide therapeutic benefit. In cellular PD models, ERGO treatment prevented neuronal cell death^12,13. However, further studies are needed to examine the therapeutic potential in PD patients.

ERGO is commonly referred to as the “longevity vitamin,” despite not meeting the classical requirements to be defined as a vitamin. ERGO deficiency does not elicit disease in a short time frame – thus why it is not defined as a vitamin – but rather is likely a key player in long-term health. Supplementation of ERGO in the diet of male mice increased the average survival age by 21 percent¹⁴, but it is unclear whether increased ERGO consumption has a significant effect on human life expectancy. Interestingly, ERGO levels have been reported to decline with age, highlighting the need to further examine the importance of ERGO in aging¹⁵.

While the importance of ERGO in human health is still undecided due to limited research in humans, growing evidence suggests ERGO plays a key role in disease prevention. Importantly, no toxicity has been observed with ERGO at levels exceeding dietary supplementation, although a potential interaction with gabapentin, an anticonvulsant, has been suggested. If you want to combat oxidative stress and reap the potential benefits of ERGO, be sure to make room for some shrooms.

TL;DR

• Ergothioneine (ERGO), an antioxidant, is synthesized in mushrooms.
• Antioxidants stabilize free radicals to prevent oxidative stress.
• Increased dietary ERGO may combat oxidative stress and aid in disease prevention.

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Reference

1.  Borodina, I. et al. The biology of ergothioneine, an antioxidant nutraceutical. Nutr Res Rev 33, 190-217, doi:10.1017/s0954422419000301 (2020).

2. Lee, W. Y., Park, E. J., Ahn, J. K. & Ka, K. H. Ergothioneine contents in fruiting bodies and their enhancement in mycelial cultures by the addition of methionine. Mycobiology 37, 43-47, doi:10.4489/myco.2009.37.1.043 (2009).

3. Anusiya, G. et al. A review of the therapeutic and biological effects of edible and wild mushrooms. Bioengineered 12, 11239-11268, doi:10.1080/21655979.2021.2001183 (2021).

4. Lin, S. Y., Chien, S. C., Wang, S. Y. & Mau, J. L. Submerged Cultivation of Mycelium with High Ergothioneine Content from the Culinary-Medicinal Golden Oyster Mushroom, Pleurotus citrinopileatus (Higher Basidiomycetes). Int J Med Mushrooms 17, 749-761, doi:10.1615/intjmedmushrooms.v17.i8.50 (2015).

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10. Gründemann, D. et al. Discovery of the ergothioneine transporter. Proc Natl Acad Sci U S A 102, 5256-5261, doi:10.1073/pnas.0408624102 (2005).

11. Hatano, T., Saiki, S., Okuzumi, A., Mohney, R. P. & Hattori, N. Identification of novel biomarkers for Parkinson’s disease by metabolomic technologies. J Neurol Neurosurg Psychiatry 87, 295-301, doi:10.1136/jnnp-2014-309676 (2016).

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13. Yuzawa, S. et al. Ergothioneine Prevents Neuronal Cell Death Caused by the Neurotoxin 6-Hydroxydopamine. Cells 13, doi:10.3390/cells13030230 (2024).

14. Katsube, M. et al. Ergothioneine promotes longevity and healthy aging in male mice. Geroscience 46, 3889-3909, doi:10.1007/s11357-024-01111-5 (2024).

15. Cheah, I. K., Feng, L., Tang, R. M. Y., Lim, K. H. C. & Halliwell, B. Ergothioneine levels in an elderly population decrease with age and incidence of cognitive decline; a risk factor for neurodegeneration? Biochem Biophys Res Commun 478, 162-167, doi:10.1016/j.bbrc.2016.07.074 (2016).