MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA Type-c) is a 16-amino acid peptide encoded within the mitochondrial genome, not the nuclear genome. Its discovery by researchers at USC in 2015 represented a new class of mitochondria-derived peptides with systemic endocrine-like functions. MOTS-c is one of a growing family of mitochondrial-derived peptides (MDPs) that includes humanin and the SHLPs.
Insulin Sensitivity and Glucose Metabolism
MOTS-c was first characterized for its effects on insulin sensitivity and glucose uptake. In animal models, MOTS-c administration improved insulin sensitivity, reduced fat accumulation, and protected against diet-induced obesity. The mechanism involves activation of AMPK (AMP-activated protein kinase) and increased glucose uptake in skeletal muscle independent of insulin signaling, making it relevant for metabolic disease research.
Exercise Mimicry
MOTS-c levels increase in human plasma following acute exercise. This finding led researchers to characterize it as an exercise-responsive signal, with some describing MOTS-c as contributing to the systemic metabolic benefits of physical activity. In aged mice, exogenous MOTS-c administration partially recapitulated exercise benefits including improved physical performance and metabolic markers.
Aging and Longevity Research
Circulating MOTS-c levels decline with age in both animals and humans. Research has examined whether this decline contributes to age-associated metabolic deterioration and whether supplementation can restore youthful metabolic function. Animal studies have shown lifespan extension and improved physical function in older mice treated with MOTS-c, positioning it alongside epithalon and NAD+-related compounds in longevity research.
Nuclear Translocation
A key mechanistic finding is that MOTS-c translocates to the cell nucleus under stress conditions where it acts as a transcriptional regulator of metabolic gene expression. This mitochondria-to-nucleus signaling represents a novel communication pathway and distinguishes MOTS-c mechanistically from most peptide hormones that act through surface receptors.
For in vitro research use only. Not for human or veterinary use, therapeutic, or diagnostic purposes.