MOTS-c
Mitochondrial-derived peptide encoded within MT-RNR1; activates AMPK signaling, increases glucose uptake, and translocates to the nucleus under metabolic stress to regulate adaptive gene programs.
MOTS-c (Mitochondrial Open Reading frame of the Twelve S rRNA-c) is a 16-residue peptide whose open reading frame is encoded entirely within the mitochondrial 12S ribosomal RNA gene (MT-RNR1). Identified by Lee and colleagues at USC in 2015, MOTS-c is now considered the most studied member of the mitochondrial-derived peptide (MDP) class.
Mechanistically, MOTS-c functions as a stress-responsive signaling peptide. Under metabolic challenge (caloric restriction, exercise, glucose deprivation), MOTS-c translocates from the mitochondrial matrix into the cytosol and then the nucleus, where it binds chromatin and engages stress-adaptive transcription factors. The downstream phenotype includes activation of AMP-activated protein kinase (AMPK), increased insulin-stimulated glucose uptake in skeletal muscle, enhanced fatty acid oxidation, and suppression of the methionine and folate cycles that contribute to age-related metabolic decline.
Plasma MOTS-c declines with age in human cohort studies, and exogenous administration in murine models reverses age-associated insulin resistance, improves exercise capacity, and extends mean lifespan. MOTS-c is currently considered a research tool for studying mitochondrial-to-nuclear signaling and is not approved for therapeutic use.