Human mitochondrial DNA (mtDNA) encodes 37 known genes, including 2rRNAs, 22 tRNAs and 13 polypeptide subunits of the electron transport chain (ETC) complexes. Recent work has revealed that the rRNA loci contain small open reading frames (ORFs) that can be transcribed and translated into short peptides called mitochondrial-derived peptides (MDPs), which have biological activity. MOTS-c is a mitochondrial-encoded peptide with 16-aa’s encoded within the 12S rRNA locus of mtDNA in human cells.

MOTS-c can translocate into the nucleus in response to metabolic stress and regulation of adaptive nuclear gene expression. This allows the peptide to promote resistance of metabolic stress by upregulating the mitochondrial genome. Upregulating these genes encourages mitochondrial biogenesis. MOTS-c inhibits the methionine-folate cycle resulting in purine synthesis, increase in PCG-1α (a key regulator of energy metabolism), and AICAR (5- Aminoimidazole-4-carboxamide ribonucleotide) accumulation which activates AMPK (5’- adenosine monophosphate-activated protein kinase). This acts as an energy sensor by monitoring the ratio of AMP and ATP. AMPK restores homeostasis by initiating catabolic processes for ATP production in case of energy deficits. In addition, literature suggest that MOTS-c decreases insulin resistance and increases GLUT4 uptake in muscle.

The peptide is mainly used for weight loss (regulating muscle and fat metabolism) and energy (cell survival in toxic conditions). MOTS-c is consistently used by sports performance athletes to enhance one’s performance. It also displays a promising effect in longevity. The Japanese long-lived people (population with the longest lifespan in the world) have demonstrated a phenotypic expression and biological link between MOTS-c and an extended lifespan.