Forever Young Radio Show

post-header

Ergothioneine Boosts Mitochondrial Respiration and Exercise Performance Via Direct Activation of MPST

Lee Carol Herbalist BSc, BHSc (WHM)

Ergothioneine (EGT) is a naturally occurring diet-derived sulphur-containing atypical amino acid and thiol antioxidant synthesised in elevated amounts by mushrooms 1. EGT can accumulate to high levels in human tissue, however, its decline is associated with several age- related disorders suggesting EGT may be a valuable dietary nutrient for attenuating inflammatory and cardiometabolic diseases 2. Exercise training can mitigate many of these diseases and mitochondrial function is fundamental to ensuring metabolic adaption to exercise training 3.

Mitochondria are highly dynamic organelles that are constantly manufactured and recycled for maintaining cell homeostasis, however, mitochondrial dysfunctions are hallmarks of aging and are related to cardiovascular diseases, neurodegeneration, metabolic syndromes and cancer 4. Exercise can improve mitochondrial function by promoting the expression of the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1⍺), the master regulator of mitochondrial biogenesis 5. EGT can also promote mitochondrial biogenesis by activating PGC-1⍺ 6. Mitochondrial respiration is a vital cellular process that converts biochemical energy from nutrients into adenosine triphosphate (ATP), the energy molecule necessary for various cellular processes 7.

Recently Sprenger and colleagues investigated EGT’s role in mitochondrial respiration and exercise performance revealing that PGC-1⍺1 induces the expression of EGT-specific transporter (SLC22A4) from an acute bout of exercise, thereby allowing substantial increases in EGT in muscle mitochondria. They also found that EGT can bind to and directly activate mitochondrial enzyme 3-mercaptopyruvate sulfurtransferase (MPST) to enhance mitochondrial respiration in an MPST-dependent manner in various mammalian cells (Fig. 1) 8. Furthermore, the average distance ran increased from 0.73 km per hour to 0.87 km per hour (P = 0.0214 – 0.0244) for mice fed on an EGT-enriched diet (209 ng/mg), reflecting significant improvements in exercise performance by ~19% compared to the control diet-fed mice Additionally, EGT diet-fed mice ran ~28% faster at peak activity (Average 24.8 m per min) than control diet-fed mice (Average 19.4 m per min) (P =0.003) 8. MPST is an enzyme that metabolises sulphur-containing compounds, produces hydrogen sulphide (H2S) and detoxifies cyanide. H2S is a signalling molecule involved in vasodilation, neuromodulation, reduction in inflammation and cardiovascular health 9

Figure 1. Representative model showing that exercise induces the expression of EGT- specific transporter (SLC22A4) allowing for EGT to accumulate inside the mitochondria. In the mitochondria, EGT binds to and activates MPST producing pyruvate (Pyr) and hydrogen sulphide (H2S) from 3-mercaptopyruvate (3-MP) and boosts mitochondrial respiration 8.

In support of the EGT-MPST axis, supplementing mice with EGT (70mg/kg/day) for one week improved endurance and muscle recovery and reduced metabolic stress, inflammation, and oxidative stress in muscle tissue 10. Exercise increases cytosolic Ca2+, ATP turnover, and ROS emission which activate signalling kinases that converge on PGC-1⍺. Upon activation of PGC-1⍺, it translocates to the nucleus coactivating transcription factors such as NRF-1/2 to upregulate transcription of various nuclear encoded mitochondrial proteins (NuGEMPs). NuGEMPs are then translated in the cytosol and imported into the mitochondrion forming electron transport chain complexes I-V that oxidise substrates and generate protonmotive force (H+) and membrane potential leading to mitochondrial biogenesis (Fig. 2) PGC-1⍺ can also prevent protein degradation and muscular atrophy by suppressing FOXO3-mediated transcription of various E3 ubiquitin ligases 5.

Figure 2. Representative model showing how exercise influences PGC-1⍺. PGC-1⍺ influences various transcription factors that regulate mitochondrial function and mitochondrial biogenesis 5.

Cellular stress caused by 7-ketocholesterol (7KC), the major oxidation product of cholesterol, can also significantly increase SLC22A4 expression and amplify EGT uptake providing mitochondrial protection. This occurs because of EGT’s ability to modulate intracellular calcium stores in the endoplasmic reticulum or mitochondria, ATP levels, mitochondrial membrane potential and mRNA expression of the inflammatory cytokines IL-, IL-6 and IL- 8 after 7KC treatment 11.

Therefore, a combination of exercise with an EGT-enriched diet may improve mitochondrial respiration for mitigating pathologies associated with age and mitochondrial dysfunction.

References

1. Tian X, Thorne JL, Moore JB. Ergothioneine: an underrecognised dietary micronutrient required for healthy ageing? Br J Nutr. Jan 14 2023;129(1):104-114. doi:10.1017/s0007114522003592

2. Cheah IK, Halliwell B. Ergothioneine, recent developments. Redox Biol. Jun 2021;42:101868. doi:10.1016/j.redox.2021.101868

3. Furrer R, Hawley JA, Handschin C. The molecular athlete: exercise physiology from mechanisms to medals. Physiol Rev. Jul 1 2023;103(3):1693-1787. doi:10.1152/physrev.00017.2022

4. Zong Y, Li H, Liao P, et al. Mitochondrial dysfunction: mechanisms and advances in therapy. Signal Transduction and Targeted Therapy. 2024/05/15 2024;9(1):124. doi:10.1038/s41392-024-01839-8

5. Hood DA, Memme JM, Oliveira AN, Triolo M. Maintenance of Skeletal Muscle Mitochondria in Health, Exercise, and Aging. Annual Review of Physiology. 2019;81(Volume 81, 2019):19-41. doi:https://doi.org/10.1146/annurev-physiol-020518-114310

6. Wang M, YI R, Wells S, Liao K. COMPOSITION AND METHOD FOR ENHANCING MITOCHONDRIAL BIOGENESIS AND ACTIVATING PGC-1A. US Patent App. 18/586,160; 2024.

7. Hoeks J, Hesselink M, Schrauwen P. Mitochondrial Respiration. In: Mooren FC, ed. Encyclopedia of Exercise Medicine in Health and Disease. Springer Berlin Heidelberg; 2012:587-590.

8. Sprenger HG, Mittenbühler MJ, Sun Y, et al. Ergothioneine boosts mitochondrial respiration and exercise performance via direct activation of MPST. bioRxiv. Apr 10 2024;doi:10.1101/2024.04.10.588849

9. Rao SP, Dobariya P, Bellamkonda H, More SS. Role of 3-Mercaptopyruvate Sulfurtransferase (3-MST) in Physiology and Disease. Antioxidants (Basel). Mar 1 2023;12(3)doi:10.3390/antiox12030603

10. Fovet T, Guilhot C, Delobel P, Chopard A, Py G, Brioche T. Ergothioneine Improves Aerobic Performance Without Any Negative Effect on Early Muscle Recovery Signaling in Response to Acute Exercise. Front Physiol. 2022;13:834597. doi:10.3389/fphys.2022.834597

11. Leow DM-K, Cheah IK-M, Fong ZW-J, Halliwell B, Ong W-Y. Protective Effect of Ergothioneine against 7-Ketocholesterol-Induced Mitochondrial Damage in hCMEC/D3 Human Brain Endothelial Cells. International Journal of Molecular Sciences. 2023;24(6):5498.

Previous post
Next post