MOTS-c

What Is MOTS-c?

MOTS-c (Mitochondrial Open reading frame of the Twelve S rRNA-c) is a 16-amino-acid peptide encoded within the mitochondrial 12S rRNA gene rather than nuclear DNA. It is a hormone the mitochondria themselves secrete to signal to the rest of the organism, not a synthetic mimic of a host hormone. Identified by Pinchas Cohen's laboratory at USC in 2015, MOTS-c activates AMPK, the master fuel-sensing kinase, drives GLUT4 expression in skeletal muscle, and shifts cells toward glucose uptake, fatty acid oxidation, and mitochondrial biogenesis, the same adaptations produced by endurance exercise, which is why it is described as an exercise mimetic.

Under metabolic stress (fasting, exercise, caloric deficit), MOTS-c also translocates to the nucleus and directly modulates expression of stress-response genes, the proposed mechanism behind its healthspan findings in mice. The downstream effects studied in the literature fall into three areas: insulin sensitisation through the AMPK and GLUT4 axis, exercise-capacity enhancement through mitochondrial biogenesis and improved substrate handling, and preservation of lean mass during caloric restriction through an AMPK-driven shift toward oxidative metabolism and suppression of catabolic signalling. A synthetic analogue, CB4211, completed Phase 1 in humans; MOTS-c itself has no completed human efficacy trials.