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Ergothioneine boosts mitochondrial respiration and exercise performance via direct activation of MPST

Hans-Georg Sprenger et al. bioRxiv. .

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  • Ergothioneine controls mitochondrial function and exercise performance via direct activation of MPST.
    Sprenger HG, Mittenbühler MJ, Sun Y, Van Vranken JG, Schindler S, Jayaraj A, Khetarpal SA, Smythers AL, Vargas-Castillo A, Puszynska AM, Spinelli JB, Armani A, Kunchok T, Ryback B, Seo HS, Song K, Sebastian L, O'Young C, Braithwaite C, Dhe-Paganon S, Burger N, Mills EL, Gygi SP, Paulo JA, Arthanari H, Chouchani ET, Sabatini DM, Spiegelman BM. Sprenger HG, et al. Cell Metab. 2025 Apr 1;37(4):857-869.e9. doi: 10.1016/j.cmet.2025.01.024. Epub 2025 Feb 17. Cell Metab. 2025. PMID: 39965563

Abstract

Ergothioneine (EGT) is a diet-derived, atypical amino acid that accumulates to high levels in human tissues. Reduced EGT levels have been linked to age-related disorders, including neurodegenerative and cardiovascular diseases, while EGT supplementation is protective in a broad range of disease and aging models in mice. Despite these promising data, the direct and physiologically relevant molecular target of EGT has remained elusive. Here we use a systematic approach to identify how mitochondria remodel their metabolome in response to exercise training. From this data, we find that EGT accumulates in muscle mitochondria upon exercise training. Proteome-wide thermal stability studies identify 3-mercaptopyruvate sulfurtransferase (MPST) as a direct molecular target of EGT; EGT binds to and activates MPST, thereby boosting mitochondrial respiration and exercise training performance in mice. Together, these data identify the first physiologically relevant EGT target and establish the EGT-MPST axis as a molecular mechanism for regulating mitochondrial function and exercise performance.

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