Identity a 16-amino-acid peptide (< 40 aa → peptide) encoded by a short open reading frame nested inside the mitochondrial 12S rRNA gene (mtDNA — not the nuclear genome, a key reason for scientific interest). Identified in 2015 by Lee, Kim, Cohen and colleagues (USC) in a landmark Cell Metabolism paper; highly conserved across species; detected in tissues and circulation, with levels that decline with age. ## Development & history - MOTS-c belongs to a young class — mitochondrial-derived peptides (MDPs) — that opened with the discovery of Humanin (2003), the first evidence that the mitochondrial genome itself encodes bioactive signalling peptides.
- MOTS-c was identified in 2015 by Changhan Lee, Su-Jeong Kim, Pinchas Cohen and colleagues at USC (in Cell Metabolism), by screening short open reading frames within mtDNA. It remains an academic-discovery / research compound: studied extensively in mechanism and in animals, but with no completed commercial drug-development programme or human efficacy trial to date. ## Mechanism (as proposed) MOTS-c acts largely via the folate–AICAR–AMPK axis — raising AICAR and activating AMPK, promoting GLUT4-mediated glucose uptake and insulin sensitivity. Under metabolic stress or exercise it translocates to the nucleus and regulates stress-adaptation genes bearing antioxidant response elements (ARE) — a "retrograde" mitochondria-to-nucleus signal. Well characterised in cells and animals; the relevance of exogenous MOTS-c in humans is unproven.