MOTS-C

What Is MOTS-C?

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. Discovered in 2015 by Lee et al. at USC, it is a founding member of mitochondrial-derived peptides (MDPs). Its plasma levels decline with age and obesity, inversely correlating with insulin resistance and metabolic syndrome.

Key Mechanisms

• AMPK activation via AICAR — inhibits MTHFD1 in the folate cycle, accumulating AICAR (endogenous AMP-mimetic) that phosphorylates AMPK at Thr172
• Nuclear retrograde signalling — translocates to nucleus under stress to modify ARE/Nrf2 gene expression
• GLUT4 translocation — drives skeletal muscle glucose uptake independently of insulin receptor
• β-Oxidation enhancement — AMPK→ACC inhibition→CPT-1 relief→increased mitochondrial fat import
• mTORC1 suppression — via TSC2/Raptor phosphorylation — longevity-associated metabolic state

Research Applications

• Metabolic syndrome and obesity biology
• Exercise adaptation and skeletal muscle metabolism
• Insulin resistance mechanisms
• Aging and healthspan research
• Mitochondrial biology and retrograde signalling

Key References

1. Lee C et al. “MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance.” Cell Metab, 2015;21(3):443–454.
2. Reynolds JC et al. “MOTS-c is an exercise-induced mitochondrial-encoded regulator.” Nat Commun, 2021;12:470.