Ergothioneine boosts mitochondrial respiration and exercise performance via direct activation of MPST
Hans-Georg Sprenger; Melanie J. Mittenbühler; Yizhi Sun; Jonathan G. Van Vranken; Sebastian Schindler; Abhilash Jayaraj; Sumeet A. Khetarpal; Ariana Vargas-Castillo; Anna M. Puszynska; Jessica B. Spinelli; Andrea Armani; Tenzin Kunchok; Birgitta Ryback; Hyuk-Soo Seo; Kijun Song; Luke Sebastian; Coby O’Young; Chelsea Braithwaite; Sirano Dhe-Paganon; Nils Burger; Evanna L. Mills; Steven P. Gygi; Haribabu Arthanari; Edward T. Chouchani; David M. Sabatini; Bruce M. Spiegelman
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.
Link | PDF (Preprint: BioRxiv) [Open Access]
Hans-Georg Sprenger; Melanie J. Mittenbühler; Yizhi Sun; Jonathan G. Van Vranken; Sebastian Schindler; Abhilash Jayaraj; Sumeet A. Khetarpal; Ariana Vargas-Castillo; Anna M. Puszynska; Jessica B. Spinelli; Andrea Armani; Tenzin Kunchok; Birgitta Ryback; Hyuk-Soo Seo; Kijun Song; Luke Sebastian; Coby O’Young; Chelsea Braithwaite; Sirano Dhe-Paganon; Nils Burger; Evanna L. Mills; Steven P. Gygi; Haribabu Arthanari; Edward T. Chouchani; David M. Sabatini; Bruce M. Spiegelman
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.
Link | PDF (Preprint: BioRxiv) [Open Access]