"MOTS-c is a 16-amino-acid mitochondrial-derived peptide encoded by the mitochondrial 12S rRNA gene, serving as an important messenger in mitochondrial-nuclear retrograde signaling communication. Unlike most peptides encoded by nuclear genes, MOTS-c originates directly from the mitochondrial genome—a discovery that has redefined the conventional view of mitochondria as mere ""energy factories"" and established their role as key regulators of cellular homeostasis.
The core mechanism of MOTS-c involves: under metabolic stress, MOTS-c translocates from mitochondria to the nucleus, directly regulating nuclear gene expression. Specifically, it inhibits the folate cycle and de novo purine synthesis, leading to AICAR accumulation, which activates the AMPK signaling pathway and downstream GLUT4 expression, thereby promoting glucose uptake and improving insulin sensitivity. Additionally, MOTS-c regulates the Nrf2/Keap1 antioxidant pathway, inhibits the NF-κB inflammatory pathway, and promotes mitochondrial biogenesis and energy metabolism. Functionally, MOTS-c has demonstrated multiple bioactivities including regulation of glucose and lipid metabolism, anti-oxidative stress, anti-inflammatory, neuroprotective, and anti-aging effects.
Currently, a Phase 2a clinical trial (NCT07505745) is underway to evaluate the efficacy and safety of MOTS-c in improving insulin sensitivity in adults with prediabetes and overweight/obesity."
