MOTS-c

MOTS-c (Mitochondrial ORF of the 12S rRNA type-c) is a 16-amino-acid peptide that represents a novel class of signaling molecules: mitochondrial-derived peptides (MDPs). Unlike the vast majority of peptides encoded in the nuclear genome, MOTS-c is translated from a small open reading frame (sORF) within the 12S ribosomal RNA gene of mitochondrial DNA. Its discovery by Kim and colleagues in 2015 (published in Cell Metabolism) established that the mitochondrial genome encodes bioactive peptides with systemic metabolic effects, challenging the conventional understanding of mitochondrial coding capacity.

The metabolic functions of MOTS-c have been studied primarily in the context of insulin sensitivity and glucose homeostasis. In mouse models, systemic MOTS-c administration improved insulin sensitivity, reduced body weight in high-fat diet conditions, and enhanced skeletal muscle glucose uptake. These effects involve AMPK (AMP-activated protein kinase) activation and downstream effects on the folate cycle and methionine metabolism, as well as GLUT4 translocation in muscle cells.

A particularly interesting research application is the role of MOTS-c in exercise physiology. Studies have shown that circulating MOTS-c levels increase in response to exercise in both rodent models and human subjects, with exercise-induced MOTS-c appearing to mediate some of the metabolic adaptations to physical activity. This makes MOTS-c a research tool for studying the crosstalk between mitochondrial function and systemic metabolism during physiological stress.

MOTS-c is also being studied in models of aging, where circulating levels have been reported to decline with age in some populations. Research by Bhanu and colleagues, as well as work from the lab of Pinchas Cohen at USC, has examined MOTS-c as a potential regulator of lifespan and age-related metabolic dysfunction. MOTS-c is available for research use only.