Ergothioneine controls mitochondrial function and exercise performance via direct activation of MPST

Area of Science:

• Mitochondrial biology
• Nutritional biochemistry
• Exercise physiology

Background:

• Ergothioneine (EGT) is a unique dietary amino acid found in human tissues, with lower levels linked to age-related diseases.
• EGT shows protective effects in aging and disease models, but its direct molecular target was unknown.
• Mitochondrial metabolic remodeling in response to exercise is a critical area of aging research.

Purpose of the Study:

• To identify the direct molecular target of ergothioneine (EGT).
• To investigate the role of EGT in mitochondrial adaptation to exercise.
• To elucidate the molecular mechanism linking EGT to mitochondrial function and exercise performance.

Main Methods:

• Systematic analysis of mitochondrial metabolome changes after exercise training.
• Proteome-wide thermal stability assays to identify direct EGT-protein interactions.
• Assessment of mitochondrial respiration and exercise performance in mice following EGT administration.

Main Results:

• Ergothioneine (EGT) accumulates in muscle mitochondria following exercise training.
• 3-mercaptopyruvate sulfurtransferase (MPST) was identified as a direct molecular target of EGT.
• EGT binding and activation of MPST enhanced mitochondrial respiration and improved exercise performance in mice.

Conclusions:

• The study identifies MPST as the first physiologically relevant molecular target of EGT.
• The EGT-MPST axis is established as a novel mechanism regulating mitochondrial function.
• This axis plays a significant role in exercise performance and may have implications for age-related conditions.