MOTS-C

MOTS-C (Mitochondrial Open Reading Frame of the 12S rRNA-C) is a 16-amino acid mitochondria-derived peptide (MDP) encoded within the 12S rRNA gene of the mitochondrial genome. Discovered by the Cohen Laboratory at USC in 2015, it has emerged as a key regulator of metabolic homeostasis and a potential exercise mimetic. MOTS-C's primary mechanism involves activation of AMPK (5' AMP-activated protein kinase), the master cellular energy sensor, leading to downstream effects on glucose uptake, fatty acid oxidation, and mitochondrial biogenesis. Uniquely, MOTS-C translocates to the nucleus under metabolic stress where it regulates ARE (antioxidant response element) genes by interacting with the NFE2L2 transcription factor. Research has demonstrated that MOTS-C improves insulin sensitivity, enhances glucose disposal in skeletal muscle, prevents high-fat diet-induced obesity in animal models, and improves physical performance markers analogous to exercise training. Age-related decline in circulating MOTS-C levels has been documented in humans, positioning it as both a biomarker and potential therapeutic target in geroscience. Studies have also revealed population-specific MOTS-C variants (particularly m.1382A>C in Japanese centenarians) that may confer exceptional longevity.