Peptide Profile
MOTS-c
Mitochondrial-Derived Peptide
CLINICAL DEVELOPMENT STAGE:
Phase 2
MOTS-c is a 16-amino-acid mitochondrial-derived peptide studied for its role in cellular energy metabolism, AMPK signaling, insulin sensitivity, stress adaptation, and metabolic homeostasis.
Compound Overview
Molecular Formula
C₁₀₁H₁₅₂N₂₈O₂₂S₂
Molecular Weight
2174.6 g/mol
CAS Number
1627580-64-6
Classification
Mitochondrial-Derived Peptide
Regulatory Status
Investigational; not FDA approved.
Targets / Receptors
AMPK signaling; folate-AICAR metabolic pathway; mitochondrial-to-nuclear signaling; skeletal muscle metabolism; glucose utilization; insulin sensitivity; cellular stress-response pathways
Research Focus
Mitochondrial signaling; cellular energy metabolism; AMPK activation; insulin sensitivity; glucose homeostasis; metabolic stress response; skeletal muscle signaling; healthy aging
Mechanism of Action
MOTS-c is a 16-amino-acid mitochondrial-derived peptide encoded within mitochondrial 12S rRNA. Unlike many signaling peptides encoded by nuclear DNA, MOTS-c originates from mitochondrial genetic information and participates in communication between mitochondria and the rest of the cell.
Research suggests that MOTS-c influences cellular energy metabolism primarily through the folate-AICAR-AMPK pathway. Activation of AMP-activated protein kinase (AMPK), a central cellular energy sensor, has been associated in preclinical studies with changes in glucose utilization, insulin sensitivity, fatty-acid metabolism, and adaptation to metabolic stress.
Under cellular stress, MOTS-c has also been reported to translocate to the nucleus, where it may influence expression of genes involved in antioxidant responses and stress adaptation. These findings support the concept of MOTS-c as a mitochondrial-to-nuclear signaling molecule rather than a peptide acting through one clearly established cell-surface receptor.
Research Evidence
Most of the published MOTS-c evidence has historically come from cell and animal studies examining metabolic regulation, insulin sensitivity, exercise physiology, inflammation, and age-related changes. These studies have repeatedly implicated AMPK signaling and skeletal muscle as important components of MOTS-c biology.
A major development occurred in 2026 with the launch of MOTS-MET, a randomized Phase 2a clinical trial evaluating MOTS-c in adults with prediabetes and overweight or obesity. The study plans to enroll approximately 120 participants and is assessing insulin sensitivity, HbA1c, fasting glucose, glucose tolerance, metabolic markers, and safety.
The trial is currently recruiting, and no efficacy results have yet been posted. As a result, claims involving metabolic improvement, insulin sensitivity, exercise capacity, longevity, or other proposed human effects remain investigational until controlled human results become available.
Safety & Limitations
MOTS-c remains investigational, and its long-term safety profile in humans has not been established. Much of the current mechanistic and efficacy literature comes from cell and animal models, which cannot be assumed to predict equivalent outcomes in humans.
The ongoing Phase 2a MOTS-MET trial includes structured monitoring of adverse events, laboratory findings, vital signs, ECG measurements, and potential immunogenicity. Because results have not yet been reported, the safety and efficacy of MOTS-c for metabolic disorders remain undetermined.
Claims involving longevity, weight reduction, enhanced exercise performance, or treatment of metabolic disease should therefore be regarded as investigational rather than established clinical effects.
Key References
- Wan W, et al. Mitochondria-derived peptide MOTS-c: effects and mechanisms related to stress, metabolism and aging. Journal of Translational Medicine. 2023.
- Lee C, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metabolism. 2015.
- Kim KH, et al. The mitochondrial-encoded peptide MOTS-c translocates to the nucleus to regulate nuclear gene expression in response to metabolic stress. Cell Metabolism. 2018.
- ClinicalTrials.gov. MOTS-c for Improving Insulin Sensitivity in Adults With Prediabetes and Overweight/Obesity, NCT07505745. Phase 2a clinical trial.
Last scientifically reviewed: September 4, 2026
