MOTS-c

MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA Type-c) is a 16-amino-acid peptide with the sequence MRWQEMGYIFYPRKLR, encoded in the mitochondrial genome — one of the few known mitochondrial-derived peptides (MDPs). It was first described in 2015 by Changhan Lee and Pinchas Cohen at the Leonard Davis School of Gerontology (University of Southern California) and has since revolutionized the understanding of mitochondrial retrograde signaling. MOTS-c is not merely a passive metabolic product: it functions as an active signaling molecule that transmits metabolic information from the mitochondrion to the nucleus. The primary mechanism of action is based on activation of the AMPK signaling cascade (AMP-activated protein kinase), the central energy sensor of the cell. Through AMPK activation, MOTS-c regulates folate metabolism and the methionine cycle, which in turn influences de novo purine biosynthesis and modulates the cellular nucleotide pool. Notable is the translocation of the peptide from the mitochondrion to the nucleus under metabolic stress — a mechanism described in 2018 by Kim et al. (Cell Metabolism), in which MOTS-c binds to regulatory DNA regions (ARE, Antioxidant Response Elements) and acts as a genomic regulator. Studies show a marked age-dependent decline in endogenous MOTS-c levels: D'Souza et al. (Aging Cell, 2020) documented a decline of approximately 30% between ages 20 and 70 in skeletal muscle tissue. In animal studies, exogenous MOTS-c improves glucose tolerance, increases skeletal muscle performance and protects against age-related insulin resistance. Reynolds et al. (Aging, 2021) showed that MOTS-c injections in older mice increased running performance by 25% and significantly increased muscle fiber size. The peptide is supplied as lyophilized powder and, due to its unique position at the intersection of mitochondrial biology, epigenetics and metabolism, is one of the most fascinating molecules in longevity research.