MOTS-c (Mitochondrial Open reading frame of the twelve S rRNA-c) is a mitochondria-derived peptide encoded within the 12S rRNA gene of the mitochondrial genome. It acts as a retrograde signal from mitochondria to the nucleus, influencing gene expression programs related to metabolism and stress resistance. Research has shown MOTS-c can enhance insulin sensitivity, activate AMPK signaling, promote fatty acid oxidation, and improve physical capacity in aged and metabolically compromised models. It is studied as a potential exercise mimetic and longevity-associated peptide due to its role in mitochondrial communication and cellular energy regulation.