Sprenger Hans-Georg, Mittenbühler Melanie J, Sun Yizhi, Van Vranken Jonathan G, Schindler Sebastian, Jayaraj Abhilash, Khetarpal Sumeet A, Smythers Amanda L, Vargas-Castillo Ariana, Puszynska Anna M, Spinelli Jessica B, Armani Andrea, Kunchok Tenzin, Ryback Birgitta, Seo Hyuk-Soo, Song Kijun, Sebastian Luke, O'Young Coby, Braithwaite Chelsea, Dhe-Paganon Sirano, Burger Nils, Mills Evanna L, Gygi Steven P, Paulo Joao A, Arthanari Haribabu, Chouchani Edward T, Sabatini David M, Spiegelman Bruce M
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA; Whitehead Institute for Biomedical Research, Cambridge, MA, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
Cell Metab. 2025 Apr 1;37(4):857-869.e9. doi: 10.1016/j.cmet.2025.01.024. Epub 2025 Feb 17.
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. 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 these 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.
麦角硫因（EGT）是一种源自饮食的非典型氨基酸，在人体组织中会积累到很高的水平。EGT水平降低与包括神经退行性疾病和心血管疾病在内的与年龄相关的疾病有关，而补充EGT在广泛的疾病和衰老模型中具有保护作用。尽管有这些有前景的数据，但EGT直接且与生理相关的分子靶点仍然难以捉摸。在这里，我们采用一种系统的方法来确定线粒体如何响应运动训练重塑其代谢组。从这些数据中，我们发现运动训练后EGT会在肌肉线粒体中积累。全蛋白质组热稳定性研究确定3-巯基丙酮酸硫转移酶（MPST）是EGT的直接分子靶点；EGT与MPST结合并激活MPST，从而增强小鼠的线粒体呼吸和运动训练表现。总之，这些数据确定了第一个与生理相关的EGT靶点，并确立了EGT-MPST轴作为调节线粒体功能和运动表现的分子机制。
