MOTS-c

MOTS-c is a 16-amino-acid peptide encoded within the mitochondrial genome, specifically within the 12S rRNA gene. It was the first identified mitochondrial-derived peptide (MDP) shown to regulate nuclear gene expression by translocating from mitochondria to the cell nucleus in response to metabolic stress. This retrograde signaling mechanism represents a novel form of mito-nuclear communication that challenges the traditional view of mitochondria as passive energy producers.

MOTS-c acts primarily through activation of the AMPK pathway, the master energy sensor of the cell, promoting glucose uptake, fatty acid oxidation, and mitochondrial biogenesis. Its effects closely mimic those of exercise at the molecular level, leading researchers to describe it as an "exercise mimetic." Studies have shown that MOTS-c levels decline with age, and that certain polymorphisms in the MOTS-c gene are associated with exceptional longevity in Japanese centenarian populations.

The metabolic effects of MOTS-c include improved insulin sensitivity, enhanced fat metabolism, protection against diet-induced obesity, and preservation of skeletal muscle function during aging. Animal studies have demonstrated that exogenous MOTS-c administration can reverse age-related metabolic decline and improve physical performance in aged mice. While human clinical data is still emerging, the peptide has generated significant interest in the longevity and metabolic health communities.

MOTS-c was discovered in 2015 by Dr. Changhan David Lee and colleagues at the University of Southern California's Leonard Davis School of Gerontology. It was one of the first mitochondrial-derived peptides (MDPs) identified — peptides encoded within the mitochondrial genome rather than the nuclear genome. The discovery was published in Cell Metabolism and challenged the prevailing view that mitochondria primarily function as passive energy producers. The name stands for "Mitochondrial Open Reading Frame of the 12S rRNA Type-c." Subsequent research revealed its role as an exercise mimetic and its association with exceptional longevity in Japanese centenarians (Fuku et al., 2015). The peptide's ability to translocate from mitochondria to the nucleus to regulate gene expression represented a novel form of retrograde mitochondrial signaling.