MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA-c) is a 16-amino acid peptide with the sequence MRWQEMGYIFYPRKLR. It is encoded within the 12S ribosomal RNA gene of the mitochondrial genome — a highly unusual genomic location for a protein-coding sequence. MOTS-c is registered under CAS number 1627580-64-6 and has a molecular weight of approximately 2174 Da. Its discovery was reported by Lee et al. in Cell Metabolism in 2015, establishing MOTS-c as a founding member of the mitochondria-derived peptide (MDP) class.

The discovery that the mitochondrial genome encodes bioactive peptides beyond the 13 proteins of the oxidative phosphorylation machinery represented a paradigm shift in mitochondrial biology. Prior to the identification of humanin (the first MDP, discovered in 2001) and MOTS-c, the mitochondrial genome was considered to encode only structural components of the respiratory chain. The identification of MDPs suggests that mitochondria communicate with the rest of the cell and with other tissues through peptide signaling, adding a new dimension to the understanding of mitochondrial function.

MOTS-c has been studied primarily for its effects on metabolic regulation. Research published in Cell Metabolism demonstrated that MOTS-c treatment in mice improved insulin sensitivity, reduced fat accumulation, and protected against diet-induced obesity. Mechanistic studies identified AMPK activation as a key downstream effect of MOTS-c, with MOTS-c appearing to activate AMPK through effects on the folate cycle and one-carbon metabolism. AMPK is a master regulator of cellular energy homeostasis, and its activation by MOTS-c provides a molecular link between mitochondrial signaling and systemic metabolic regulation.

Age-related research has examined changes in MOTS-c levels across the lifespan. Studies have documented declining circulating MOTS-c levels with age in both mice and humans, paralleling the age-associated decline in mitochondrial function. Research has examined whether giving MOTS-c to aged animals restores aspects of metabolic function, with published studies reporting improvements in exercise capacity, insulin sensitivity, and inflammatory markers.

For in vitro research, MOTS-c is typically used at nanomolar concentrations in metabolic assays. Common applications include studies of AMPK activation (by Western blot or AMPK activity assay), glucose uptake assays in muscle or adipose cell lines, mitochondrial biogenesis assays, and gene expression studies examining metabolic pathway regulation.

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