MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA-c) is a recently discovered 16-amino acid peptide encoded within the mitochondrial genome (12S rRNA region) that functions as a mitochondrial-derived peptide (MDP) hormone. This unique peptide translocates from mitochondria to the nucleus under metabolic stress, where it regulates nuclear gene expression and mimics exercise-induced adaptations. MOTS-c primarily targets skeletal muscle and liver metabolism, improving insulin sensitivity, glucose utilization, and metabolic homeostasis through AMPK activation, making it a groundbreaking tool for studying exercise mimetics, metabolic disease, and mitochondrial-nuclear communication.