MOTS-c: A Mitochondrial-Derived Peptide in Metabolic Research
MOTS-c is a 16-amino-acid mitochondrial-derived peptide encoded within mitochondrial DNA. Unlike most signaling peptides encoded by nuclear DNA, MOTS-c originates from a short open reading frame within the mitochondrial 12S ribosomal RNA region.
In foundational laboratory research, investigators reported that MOTS-c influenced cellular metabolism through pathways involving folate metabolism and AMP-activated protein kinase, or AMPK. In mouse models, administered MOTS-c improved glucose regulation and reduced age-dependent and diet-induced insulin resistance and obesity. These findings were preclinical and do not establish equivalent outcomes in humans.
Human research has primarily examined naturally circulating MOTS-c rather than MOTS-c as a treatment. In a small randomized exercise experiment, researchers measured circulating mitochondrial-derived peptides before and after endurance exercise, resistance exercise, or no exercise. Endurance exercise increased some mitochondrial-derived peptide measurements, while the MOTS-c response was more limited and variable.
A phase 2a trial registered in 2026 is recruiting adults with prediabetes and overweight or obesity to evaluate investigational MOTS-c and insulin sensitivity. Its estimated primary completion is in 2027, and no efficacy or safety results are currently available.
Research significance
MOTS-c is an emerging subject in mitochondrial signaling, metabolism, exercise physiology, and aging research. At present, mechanistic and animal findings are more developed than human treatment evidence.
References
- Lee C, Zeng J, Drew BG, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metabolism. 2015;21:443–454. DOI: 10.1016/j.cmet.2015.02.009.
- von Walden F, Fernandez-Gonzalo R, Norrbom J, et al. Acute endurance exercise stimulates circulating levels of mitochondrial-derived peptides in humans. Journal of Applied Physiology. 2021;131:1035–1042. DOI: 10.1152/japplphysiol.00706.2019.
- ClinicalTrials.gov. MOTS-c for improving insulin sensitivity in adults with prediabetes and overweight or obesity. Identifier: NCT07505745.
Research and Regulatory DisclaimerThe information presented in the H3 Restore Research Library is provided solely for general scientific and educational purposes. It is not medical advice and is not intended to diagnose, treat, cure, mitigate, or prevent any disease.
References to clinical trials or FDA-approved prescription products describe the specific materials and formulations evaluated in those studies. These results do not establish that an independently manufactured research material has the same identity, purity, potency, pharmacokinetics, safety, or effectiveness.
Products labeled for research use only are not medications, dietary supplements, cosmetics, or consumer products. They are not intended for human or veterinary use.
