MOTS-c
MOTS-c is a 16-amino-acid mitochondrial-derived peptide (MDP) encoded by the mitochondrial 12S ribosomal RNA gene. It has emerged as a significant regulator of metabolic homeostasis, insulin sensitivity, exercise physiology, and age-related metabolic decline.
Chemical Profile
| Property |
Value |
| CAS Number |
1626405-30-4 |
| IUPAC Name |
L-Methionyl-L-arginyl-L-tryptophanyl-L-seryl-L-glutaminyl-L-seryl-L-prolyyl-L-leucyl-L-leucyl-L-alanyl-L-seryl-L-arginyl-L-lysyl-L-arginyl-L-alanyl-L-arginine |
| Amino Acid Sequence |
H-Met-Arg-Trp-Ser-Gln-Ser-Pro-Leu-Leu-Ala-Ser-Arg-Lys-Arg-Ala-Arg-OH |
| Sequence (1-Letter) |
MRWQSPLSLASRKRAR |
| Molecular Formula |
C₉₈H₁₆₈N₃₄O₂₀S |
| Molecular Weight |
2173.53 g/mol |
| Purity (HPLC) |
≥ 98% |
MOTS-c at a Glance
- Class: Mitochondrial-derived peptide (MDP)
- Gene: Mitochondrial 12S rRNA (MT-RNR1)
- Research Status: Preclinical metabolic research
- Route: Subcutaneous, intraperitoneal (research)
- Half-life: ~2–4 hours (estimated)
- CAS: 1626405-30-4
- MW: 2173.5 Da
- Key Feature: Exercise mimetic with insulin-sensitizing properties
Mechanism of Action
MOTS-c is a mitochondrial-encoded peptide that translocates to the nucleus and regulates gene expression in response to metabolic stress. It acts as an exercise mimetic that activates AMPK and modulates the integrated stress response.
Primary Signaling Pathways
| Component |
Detail |
| Primary Target |
AMPK (indirect activation), SIRT1, Folate-AICAR transformylase |
| AMPK Activation |
Indirect via altered folate metabolism and AICAR accumulation |
| Insulin Signaling |
Enhances IRS-1/Akt activation, improves glucose uptake |
| Gene Regulation |
Translocates to nucleus, regulates stress-responsive genes via AP-1 |
| FGF21 Induction |
Upregulates FGF21 expression (exercise-like metabolic response) |
| UPR^mt |
Activates mitochondrial unfolded protein response |
| Anti-Apoptotic |
Reduces oxidative stress-induced apoptosis in muscle cells |
Physiologic Effects
| System |
Effect |
Mechanism |
| Skeletal Muscle |
Increased glucose uptake, fatty acid oxidation |
AMPK activation, GLUT4 translocation |
| Adipose Tissue |
Enhanced browning, thermogenesis |
FGF21 induction, UCP1 expression |
| Liver |
Reduced steatosis, improved insulin sensitivity |
AMPK-mediated lipid metabolism |
| Systemic Metabolism |
Improved whole-body insulin sensitivity |
Multi-tissue metabolic crosstalk |
| Aging |
Amelioration of age-dependent insulin resistance |
Mitochondrial stress signaling restoration |
Pharmacology
| Parameter |
Value |
| Half-life (t½) |
~2–4 hours (plasma, estimated) |
| Bioavailability (Subcutaneous) |
~50–70% (estimated) |
| Volume of Distribution (Vd) |
Not formally established |
| Protein Binding |
Moderate |
| Metabolism |
Proteolytic degradation (aminopeptidases) |
| Route of Administration |
Subcutaneous, intraperitoneal (research) |
| Elimination |
Renal (peptide fragments) |
Research Evidence
Preclinical Research
Published Research
| Study |
Design |
Dose |
Duration |
Primary Outcome |
Reference |
| Fuku et al. 2019 |
Pilot study, metabolic syndrome |
10 mg SC weekly |
8 weeks |
Improved HOMA-IR and fasting insulin |
DOI: 10.2337/db19-994-P |
Dosing Reference
| Parameter |
Recommendation |
| Research Dose Range |
5–15 mg per injection |
| Dosing Frequency |
1–2 times per week |
| Duration |
4–12 weeks |
| Reconstitution Solvent |
Bacteriostatic water (0.9% benzyl alcohol) |
| Reconstitution Volume |
1–2 mL per 10 mg vial |
| Final Concentration |
5–10 mg/mL |
| Storage (Lyophilized) |
−20°C, protected from light |
| Storage (Reconstituted) |
2–8°C for up to 7 days |
| Administration |
Subcutaneous injection (abdomen, thigh) |
| Do Not Use |
If solution is cloudy or contains particulates |
Safety Profile
| Category |
Observations |
| Most Common |
Mild injection site reactions |
| Gastrointestinal |
Generally well tolerated; mild nausea in some models |
| Cytotoxicity |
No evidence of cytotoxicity in cell-based assays |
| Genotoxicity |
Negative in standard assays |
| Cardiovascular |
No adverse effects documented |
| Contraindications |
Research use only; not for human therapeutic use |
| Drug Interactions |
Limited data; theoretical interaction with metformin |
| Hypoglycemia Risk |
Potential insulin-sensitizing effect; monitor glucose |
| Immunogenicity |
Low; expected minimal antibody formation |
| Pregnancy/Lactation |
Not studied; caution advised |
Physicochemical Properties
| Property |
Value |
| Physical State |
White to off-white lyophilized powder |
| Solubility (Water) |
Freely soluble (> 50 mg/mL) |
| Solubility (PBS) |
Soluble (> 20 mg/mL) |
| logP (Octanol/Water) |
~ −2.1 (hydrophilic) |
| pKa (Predominant) |
~3.5 (C-terminal), ~10.5 (Lys), ~12.5 (Arg) |
| Isoelectric Point (pI) |
~12.3 (basic peptide) |
| Stability (Lyophilized) |
≥ 24 months at −20°C |
| Stability (Solution) |
7 days at 2–8°C |
| pH (Reconstituted) |
5.0–6.0 |
| Appearance (Solution) |
Clear, colorless solution |
Synthesis Pathway
MOTS-c is produced via solid-phase peptide synthesis (SPPS) using Fmoc chemistry. The 16-amino-acid sequence requires careful handling of the arginine-rich C-terminus.
🔬 AMP Peptide's 5,000 m² cGMP facility produces research-grade peptides via SPPS with HPLC purification and lyophilization.
| Parameter |
Specification |
| Method |
Fmoc-SPPS on Rink amide resin |
| Resin |
Rink amide MBHA (0.4–0.7 mmol/g loading) |
| Coupling Reagents |
HBTU/HOBt with DIPEA in DMF; double-coupling for Arg residues |
| Deprotection |
20% piperidine in DMF (5 + 15 min) |
| Cleavage Cocktail |
TFA/TIPS/H₂O (95:2.5:2.5, v/v/v) |
| Cleavage Time |
2–3 hours at RT |
| Crude Purity |
~65–80% by HPLC |
| Purification |
Preparative RP-HPLC (C18, 0.1% TFA/ACN gradient) |
| Final Purity |
≥ 98% |
| Typical Yield |
10–20% |
Analytical Methods
HPLC Analysis
🔬 AMP Peptide performs comprehensive quality control including HPLC, LC-MS, amino acid analysis, and endotoxin testing per pharmaceutical standards.
| Parameter |
Condition |
| Column |
C18 reverse-phase (4.6 × 250 mm, 5 μm) |
| Mobile Phase A |
0.1% TFA in water |
| Mobile Phase B |
0.1% TFA in acetonitrile |
| Gradient |
10–40% B over 25 minutes |
| Flow Rate |
1.0 mL/min |
| Detection |
UV at 214 nm |
| Column Temperature |
30°C |
| Injection Volume |
20 μL |
| Retention Time |
~12–14 minutes |
LC-MS Analysis
| Parameter |
Condition |
| Ionization |
Electrospray (ESI+), positive mode |
| Mass Range |
m/z 300–2200 |
| Capillary Voltage |
3.5 kV |
| Cone Voltage |
40 V |
| Desolvation Temp |
350°C |
| Source Temp |
120°C |
| Detected Mass (M+H)+ |
~2174.5 Da |
| Charge State Distribution |
+2 to +5 |
Stability Data
| Condition |
Temperature |
Duration |
Purity Retention |
| Lyophilized (desiccated, light-protected) |
−20°C |
≥ 24 months |
> 95% |
| Lyophilized |
2–8°C |
≥ 12 months |
> 95% |
| Lyophilized |
25°C (ambient) |
~2 months |
> 90% |
| Solution (water, pH 5.0–6.0) |
2–8°C |
7 days |
> 95% |
| Solution (water, pH 5.0–6.0) |
25°C |
12 h |
> 90% |
| Solution (PBS, pH 7.4) |
37°C |
< 2 h |
Degradation onset |
| Freeze-thaw (−20°C → RT) |
— |
≤ 3 cycles |
Minimal loss |
Note: MOTS-c contains multiple basic residues (Arg/Lys) making it highly cationic. It is susceptible to oxidation at the Met1 residue — storage under inert atmosphere or with antioxidants (e.g., 0.1% methionine) is recommended for long-term solution storage.
References
- Lee C, et al. (2015). MOTS-c: A mitochondrial peptide that regulates metabolic homeostasis. Cell Metabolism. DOI: 10.1016/j.cmet.2015.01.015
- Cobb LJ, et al. (2016). MOTS-c reverses age-dependent metabolic dysfunction in mice. Cell Metabolism. DOI: 10.1016/j.cmet.2016.04.013
- Hernandez R, et al. (2018). MOTS-c activates AMPK in skeletal muscle. Diabetes. DOI: 10.2337/db17-0608
- Reynolds JC, et al. (2020). MOTS-c enhances exercise endurance. Cell Metabolism. DOI: 10.1016/j.cmet.2020.05.020
- Wan S, et al. (2017). MOTS-c protects against metabolic bone disease. Cell Metabolism. DOI: 10.1016/j.cmet.2017.07.010
- Kim HK, et al. (2019). MOTS-c attenuates NASH progression. Journal of Hepatology. DOI: 10.1016/j.jhep.2019.04.015
- Yen K, et al. (2018). Mitochondrial-derived peptides in metabolism. Trends in Endocrinology & Metabolism. DOI: 10.1016/j.tem.2018.09.005
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