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

Sprenger, H.-G.; Mittenbuehler, M. J.; Sun, Y.; Van Vranken, J. G.; Schindler, S.; Jayaraj, A.; Khetarpal, S. A.; Vargas-Castillo, A.; Puszynska, A. M.; Spinelli, J. B.; Armani, A.; Kunchok, T.; Ryback, B.; Seo, H.-S.; Song, K.; Sebastian, L.; O Young, C.; Braithwaite, C.; Dhe-Paganon, S.; Burger, N.; Mills, E. L.; Gygi, S. P.; Arthanari, H.; Chouchani, E. T.; Sabatini, D. M.; Spiegelman, B. M.

doi:10.1101/2024.04.10.588849

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bioRxiv · 10.1101/2024.04.10.588849

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

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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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Sprenger, H.-G., Mittenbuehler, M. J., Sun, Y., Van Vranken, J. G., Schindler, S., Jayaraj, A., Khetarpal, S. A., Vargas-Castillo, A., Puszynska, A. M., Spinelli, J. B., Armani, A., Kunchok, T., Ryback, B., Seo, H.-S., Song, K., Sebastian, L., O Young, C., Braithwaite, C., Dhe-Paganon, S., Burger, N., Mills, E. L., Gygi, S. P., Arthanari, H., Chouchani, E. T., Sabatini, D. M., Spiegelman, B. M.. 2024-04-10. Ergothioneine boosts mitochondrial respiration and exercise performance via direct activation of MPST. https://doi.org/10.1101/2024.04.10.588849

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