MOTS-c

MOTS-c is a 16-amino-acid peptide encoded by the mitochondrial 12S rRNA gene (MT-RNR1), making it one of the first identified mitochondrial-derived peptides (MDPs). Discovered by Dr. Pinchas Cohen's laboratory at the University of Southern California in 2015, MOTS-c is translated in the cytoplasm and can translocate to the nucleus under metabolic stress, where it regulates nuclear gene expression.

The primary mechanism of action involves activation of the AMPK (AMP-activated protein kinase) pathway, the cell's master energy sensor. MOTS-c inhibits the folate-methionine cycle, leading to accumulation of AICAR, an endogenous AMPK activator. This triggers downstream metabolic effects including enhanced glucose uptake in skeletal muscle, improved insulin sensitivity, increased fatty acid oxidation, and activation of mitochondrial biogenesis. Under metabolic stress, MOTS-c translocates to the nucleus where it interacts with transcription factors to regulate adaptive gene expression.

Research has demonstrated that MOTS-c improves insulin sensitivity and prevents diet-induced obesity in mouse models. Studies show it enhances exercise capacity and physical performance, particularly under metabolic stress. The peptide's levels decline with age, correlating with age-related metabolic dysfunction. Clinical interest has grown rapidly, with MOTS-c being added to the World Anti-Doping Agency (WADA) prohibited list due to its performance-enhancing potential. Its evolutionary conservation across species underscores its fundamental biological importance.