Abstract

To sustain energy balance, cells have evolved intricate molecular metabolic networks.

Mitochondria are cellular compartments controlling many metabolic pathways important to ensure functioning of these networks and maintain energy homeostasis. Functional mitochondria are vital for enabling our metabolism to adapt to varying environmental conditions, such as diet, physical activity, or stress. As we age, mitochondrial function and the capacity of our metabolism to adjust to these changing conditions decline, leading to disruptions in energy balance and contributing to age-related metabolic disorders. However, exercise training can significantly enhance mitochondrial function, reshape metabolism, and help prevent or mitigate many chronic diseases associated with aging, ultimately promoting a longer, healthier life. Despite these insights, our understanding of the precise molecular mechanisms involved remains incomplete. Recently, we identified the diet-derived unusual amino acid ergothioneine (EGT) to accumulate in muscle mitochondria with exercise training and boost mitochondrial function and exercise performance via direct activation of the mercaptopyruvate sulfurtransferase (MPST). The current project investigates the role of the EGT-MPST axis in metabolic diseases associated with mitochondrial dysfunction such as muscle disorders and obesity. 

Project-related publications

Hans-Georg Sprenger*^#, Melanie J. Mittenbühler^#, Yizhi Sun, Jonathan G. Van Vranken, Sebastian Schindler, Abhilash Jayaraj, Sumeet Khetarpal, Amanda L. Smythers, 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 Mills, Steven P. Gygi, Joao A. Paulo, Haribabu Arthanari, Edward T. Chouchani, David M. Sabatini, Bruce M. Spiegelman* (2025). Ergothioneine controls mitochondrial function and exercise performance via direct activation of MPST. Cell Metabolism, 2025. ^# = equal contribution, * = co-corresponding author. DOI: 10.1016/j.cmet.2025.01.024        

Sumeet A. Khetarpal, Haobo Li, Tevis Vitale, James Rhee, Louisa Grauvogel, Claire Castro, Melanie J. Mittenbühler, Nicholas E. Houstis, Ariana Vargas-Castillo, Amanda L. Smythers, Jing Liu, Casie Curtin, Hans-Georg Sprenger, Katherine A. Blackmore, Alexandra Kuznetsov, Rebecca Freeman, Dina Bogoslavski, Patrick T. Ellinor, Aarti Asnani, Phillip A. Dumesic, Pere Puigserver, Jason D. Roh, Bruce M. Spiegelman, Anthony Rosenzweig (2024). Cardiomyocyte PGC-1α enables physiological adaptations to endurance exercise through suppression of GDF15 and cardiac atrophy. bioRxiv, 2024. DOI: 10.1101/2024.01.30.578093

Weihai Liu, Yun Wang, Luiz H. M. Bozi, Patrick Fischer, Mark P. Jedrychowski, Haopeng Xiao, Tao Wu, Narek Darabedian, Xiadi He, Evanna Mills, Nils Burger, Sanghee Shin, Anita Reddy, Hans-Georg Sprenger, Nhien Tran, Sally Winther, Stephen M. Hinshaw, Jingnan Shen, Hyuk-Soo Seo, Kijun Song, Andrew Z. Xu, Luke Sebastian, Jean Zhao, Sirano Dhe-Paganon, Jianwei Che, Steven Gygi, Haribabu Arthanari, Edward T. Chouchani (2023). Lactate regulates cell cycle and proliferation by remodeling the anaphase promoting complex. Nature, 2023. DOI: 10.1038/s41586-023-05939-3

Melanie J. Mittenbühler, Mark P. Jedrychowski, Jonathan G. Van Vranken, Hans-Georg Sprenger, Sarah Wilensky, Phillip A. Dumesic, Yizhi Sun, Andrea Tartaglia, Dina Bogoslavski, Mu A, Haopeng Xiao, Katherine A. Blackmore, Anita Reddy, Steven P. Gygi, Edward T. Chouchani, Bruce M. Spiegelman (2023). Isolation of extracellular fluids reveals novel secreted bioactive proteins from muscle and fat tissues. Cell Metabolism, 2023. DOI: 10.1016/j.cmet.2022.12.014

Jessica B. Spinelli, Paul C. Rosen, Hans-Georg Sprenger, Anna M. Puszysnka, Jessica L. Mann, Julian M. Roessler, Andrew L. Cangelosi, Antonia Henne, Kendall J. Condon, Tong Zhang, Tenzin Kunchok, Caroline A. Lewis, Navdeep S. Chandel, David M. Sabatini (2021). Fumarate is a terminal electron acceptor in the mammalian electron transport chain. Science, 2021. DOI: 10.1126/science.abi7495