MOTS-c

Molecular Information

Research Summary

MOTS-c was discovered by Changhan Lee and colleagues at the University of Southern California in 2015, representing a new class of mitochondrial-derived peptides (MDPs). This 16-amino acid peptide is encoded within the mitochondrial 12S rRNA gene and has been shown to regulate metabolic homeostasis in animal models. Research has demonstrated effects on AMPK activation, folate metabolism, and glucose regulation in rodent studies. MOTS-c is particularly notable as a signaling molecule that establishes a novel communication pathway between mitochondria and the cell nucleus.

Mechanism of Action

MOTS-c activates AMPK (AMP-activated protein kinase) through inhibition of the folate-methionine cycle, specifically targeting the enzyme MTHFD2. It translocates to the nucleus under metabolic stress conditions and regulates gene expression through interaction with ARE (antioxidant response element) motifs. The peptide modulates cellular metabolism by shifting energy substrate utilization and improving insulin sensitivity in animal models.

Published Animal Studies

• [1]Studies in obese mice demonstrated improved glucose homeostasis and insulin sensitivity (Lee et al., 2015)
• [2]Aging mouse models showed improved physical performance and metabolic parameters (Reynolds et al., 2021)
• [3]High-fat diet rodent studies demonstrated protection against diet-induced obesity and metabolic dysfunction
• [4]Exercise physiology studies in mice showed MOTS-c involvement in exercise-induced metabolic adaptations (Reynolds et al., 2021)

In-Vitro Research

• •Metabolomic profiling of treated cells revealed significant changes in folate cycle intermediates and de novo purine synthesis
• •Nuclear translocation assays demonstrated stress-induced nuclear accumulation of MOTS-c
• •AMPK activation assays confirmed dose-dependent activation in multiple cell types
• •Gene expression studies showed regulation of ARE-containing genes involved in antioxidant defense

Research Applications

References

1. 1.Lee C, et al. "The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance." Cell Metab. 2015;21(3):443-454.
2. 2.Reynolds JC, et al. "MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis." Nat Commun. 2021;12:470.