MOTS-c (mitochondrial open reading frame of the 12S rRNA type-c) is a 16-amino-acid mitochondrial-derived peptide. It is encoded not by nuclear DNA but by a short open reading frame within the mitochondrial genome itself, making it part of a small family of peptides discovered only in the last decade. It was first reported in 2015.

Under metabolic stress, MOTS-c translocates from the mitochondria to the cell nucleus, where it influences the expression of nuclear genes. Its primary described pathway involves the folate-methionine cycle and subsequent activation of AMPK, with additional reported involvement of AKT and mTOR signaling. Research has also linked it to regulation of genes including GLUT4, STAT3, and IL-10.

Published research has examined MOTS-c primarily in the context of glucose metabolism and insulin sensitivity in skeletal muscle, with rodent studies reporting effects on metabolic homeostasis and body composition. Circulating MOTS-c levels have been observed to decline with age in both human and animal data, which has driven interest in aging and longevity research. Additional preclinical work has explored cardiovascular, bone, and immune-related endpoints. Human clinical application remains undeveloped.