MOTS-c (mitochondrial open reading frame of the 12S rRNA-c) is a 16-amino acid peptide (Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg) encoded within the mitochondrial 12S rRNA gene, functioning as a mitochondrial-derived peptide (MDP) that regulates metabolic homeostasis and stress responses. Discovered in 2015, MOTS-c operates both locally within mitochondria and systemically as a hormone, influencing cellular energy metabolism by activating AMP-activated protein kinase (AMPK) and enhancing glucose uptake, fatty acid oxidation, and mitochondrial biogenesis. It interacts with nuclear transcription factors, such as NRF2, to promote antioxidant defenses and protect against oxidative stress. Studies suggest MOTS-c improves insulin sensitivity, reduces obesity-related metabolic dysfunction, and enhances exercise performance in animal models, with potential anti-aging and cardioprotective effects. Administered exogenously, typically via injection, MOTS-c shows promise for treating metabolic disorders like type 2 diabetes, though its mechanisms, optimal dosing, and long-term safety in humans require further clinical investigation.