MOTS-c

MOTS-c is encoded inside mitochondrial DNA and released into circulation, where it acts as a signal to the rest of the body. When the cell is under metabolic stress it moves into the nucleus and changes which genes are switched on — a mitochondrial peptide directly instructing the nuclear genome. In mice it improves insulin sensitivity, prevents diet-induced obesity and improves physical performance in old animals. In humans, levels have been measured and correlate with exercise and metabolic health, but nobody has been given it in a trial.

A 16-amino-acid peptide encoded in the mitochondrial 12S rRNA gene MT-RNR1. Under metabolic stress it translocates to the nucleus and regulates adaptive nuclear gene expression through ATF1 and antioxidant response elements. Activates AMPK, increases GLUT4 translocation and shifts folate-methionine cycle flux, reducing purine biosynthesis. In mice, administration prevents diet-induced obesity and insulin resistance and improves physical capacity in aged animals. Human plasma levels rise acutely with exercise and are lower in insulin-resistant states. A common East Asian mitochondrial variant, m.1382A>C, alters the MOTS-c sequence and has been associated with longevity in Japanese cohorts.