MOTS-c
Also known as: Mitochondrial ORF of 12S rRNA Type-c · Mitochondrial-derived peptide
Contents
MW
2174.68 Da
Amino Acids
16 AA
Half-Life
4-6 hours
Route
SubQ
Formula
C101H152N28O22S2
Amino Acid Sequence
MRWQEMGYIFYPRKLR
Mechanism of Action
MOTS-c (Mitochondrial Open Reading Frame of the Twelve S rRNA type-c) is a 16-amino acid peptide encoded in the mitochondrial genome. It is the first mitochondria-derived peptide shown to regulate nuclear gene expression — demonstrating mitochondria-to-nucleus retrograde signaling.
PRIMARY MECHANISM — AMPK ACTIVATION: Activates AMP-activated protein kinase (AMPK), the master cellular energy sensor. AMPK activation → increased glucose uptake (via GLUT4 translocation), enhanced fatty acid oxidation, mitochondrial biogenesis (via PGC-1α), and suppression of lipogenesis and gluconeogenesis.
EXERCISE MIMETIC: Produces metabolic effects similar to physical exercise — improved insulin sensitivity, increased energy expenditure, enhanced glucose metabolism. MOTS-c is released from skeletal muscle during exercise (exercise-induced mitokine).
AGING: MOTS-c levels decline with age, correlating with metabolic disease onset (insulin resistance, obesity, type 2 diabetes). Restoring youthful MOTS-c levels improves metabolic parameters in aged animal models.
NUCLEAR TRANSLOCATION: Under metabolic stress, MOTS-c translocates to the nucleus where it regulates gene expression of adaptive stress response genes — a remarkable example of mitochondrial peptides directly controlling nuclear function.
Dosing Protocol
Low Dose
███ – ███ mcg/day
Standard Dose
███ mcg/day
High Dose
███ – ███ mcg/day
Dosing protocols are for paid members
Get exact dosing ranges, injection frequency, timing rationale, and reconstitution math.
Get Clinical Access — $79/moFrequency
3–5x/week SubQ.
Half-Life
4-6 hours
Reconstitution Guide
Full reconstitution protocol with BAC water volumes, concentration math, and units-to-draw per dose is available on the Clinical plan.
Unlock reconstitution guide →Clinical Warnings
Very early research — no human RCTs.
AMPK activation may interact with metformin (additive).
Mitochondrial-derived peptide — novel biology with unknown long-term effects.
Not FDA approved.
Contraindications
Absolute
Pregnancy
Relative Cautions
Diabetes (monitor glucose closely)
Hypoglycemia risk
Side Effect Profile
Mild
- ●Injection site reaction
- ●Mild flushing
Moderate
- ●Headache
- ●Mild hypoglycemia
- ●Fatigue
Severe (Rare)
- ●Severe hypoglycemia (with insulin)
Synergistic Peptides
Common Stacks
SS-31
NAD+
5-Amino-1MQ
Research Status
EARLY. PMID 25738459 (Lee C 2015 Cell Metabolism): Original characterization — AMPK activation, exercise mimetic. PMID 33972967 (Kim 2021): Insulin sensitivity in aging. Mostly preclinical/mechanistic.
Frequently Asked Questions
How does MOTS-c work?
MOTS-c (Mitochondrial Open Reading Frame of the Twelve S rRNA type-c) is a 16-amino acid peptide encoded in the mitochondrial genome. It is the first mitochondria-derived peptide shown to regulate nuclear gene expression — demonstrating mitochondria-to-nucleus retrograde signaling. PRIMARY MECHANISM — AMPK ACTIVATION: Activates AMP-activated protein kinase (AMPK), the master cellular energy sensor. AMPK activation → increased glucose uptake (via GLUT4 translocation), enhanced fatty acid oxidati
What is the standard dose of MOTS-c?
MOTS-c dosing protocols are available with a ClinPep Clinical subscription. Dosing varies by indication and patient factors — consult a licensed healthcare provider. General frequency: 3–5x/week SubQ.
What is the half-life of MOTS-c?
The half-life of MOTS-c is 4-6 hours. This determines optimal dosing frequency and timing.
Who should not use MOTS-c?
MOTS-c is absolutely contraindicated in: Pregnancy. Use with caution in: Diabetes (monitor glucose closely); Hypoglycemia risk.
What are the side effects of MOTS-c?
Common mild side effects include: Injection site reaction, Mild flushing. Moderate effects: Headache, Mild hypoglycemia, Fatigue.
What peptides stack well with MOTS-c?
MOTS-c is commonly stacked with: SS-31, NAD+, 5-Amino-1MQ.
How do you reconstitute MOTS-c?
MOTS-c is reconstituted with bacteriostatic water. Exact volumes, concentrations, and units-to-draw calculations are available in the ClinPep Clinical plan. Always follow your compounding pharmacy's instructions.
How long should you cycle MOTS-c?
MOTS-c cycle protocols vary by indication. Detailed cycle length, on/off schedules, and monitoring guidelines are available with ClinPep Clinical access. Consult your healthcare provider for personalized cycling guidance.
References & Citations
10 PubMed studies · 3 clinical trials
Exercise-Induced Muscle-Fat Crosstalk: Molecular Mediators and Their Pharmacological Modulation for the Maintenance of Metabolic Flexibility in Aging.
Tero-Vescan Amelia, Degens Hans, Matsakas Antonios, Ștefănescu Ruxandra et al.. Pharmaceuticals (Basel, Switzerland). 2025
Regular physical activity induces a dynamic crosstalk between skeletal muscle and adipose tissue, modulating the key molecular pathways that underlie metabolic flexibility, mitochondrial function, and
The impact of mitokine MOTS-c administration on the soleus muscle of rats subjected to a 7-day hindlimb suspension.
Sidorenko Daria A, Lvova Irina D, Tyganov Sergey A, Shenkman Boris S et al.. Journal of muscle research and cell motility. 2025
The aim of the study was to investigate the effect of MOTS-c on the key functional alterations in the rat soleus muscle during 7-day unloading - the transformation of slow fibers into fast ones, atrop
Mitochondrial-Derived Peptides as Therapeutics and Biomarkers for Combating Vascular Aging and Associated Cardiovascular Diseases.
Sivakumar Rooban, Aravaanan Arul Senghor Kadalangudi, Mohanakrishnan Vinodhini Vellore, Kumar Janardhanan. Current cardiology reviews. 2026
Vascular aging profoundly affects the onset of cardiovascular diseases in the elderly, mostly as a result of mitochondrial dysfunction. This review examines the protective roles of mitochondrial- deri
MOTS-c-modified functional self-assembly peptide hydrogels enhance the activity of nucleus pulposus-derived mesenchymal stem cells of intervertebral disc degeneration.
Lin Yuan, Yang Ruo-Yu, Li Jie, Shao Shan-Zhong et al.. Materials today. Bio. 2025
Intervertebral disc degeneration (IDD) is characterized by oxidative-stress driven progressive apoptosis and senescence of nucleus pulposus mesenchymal stem cells (NP-MSCs). MOTS-c, a 16-amino acid pe
MOTS-c Promotes Glycolysis via AMPK-HIF-1α-PFKFB3 Pathway to Ameliorate Cardiopulmonary Bypass-induced Lung Injury.
Shen Zihao, Lu Peng, Jin Wanjun, Wen Ziang et al.. American journal of respiratory cell and molecular biology. 2025
Cardiopulmonary bypass (CPB) is essential during cardiac surgery but frequently leads to lung ischemia-reperfusion injury (LIRI), a significant contributor to postoperative complications. We investiga
Exploring the therapeutic potential of MOTS-c in age-related macular degeneration: from cellular responses to patient-derived cybrids.
Mohtashami Zahra, Schneider Kevin, Azimi Reza, Atilano Shari et al.. Human cell. 2025
Age-related macular degeneration (AMD), the leading cause of irreversible vision loss in the US, is on the rise among the elderly. Uncontrolled mitochondria-derived peptide production from mtDNA disru
Endurance training enhances skeletal muscle mitochondrial respiration by promoting MOTS-c secretion.
Feng Yiwei, Rao Zhijian, Tian Xu, Hu Yi et al.. Free radical biology & medicine. 2025
The mitochondrial open reading frame of 12S rRNA-c (MOTS-c) is a biologically active mitochondria-derived peptide. However, the relationship between MOTS-c, skeletal muscle mitochondrial function, and
MOTS-c relieves hepatocellular carcinoma resistance to TRAIL-induced apoptosis under hypoxic conditions by activating MEF2A.
Shen Haiying, Nie Junjie, Wang Xiaojun, Li Guangqing et al.. Experimental cell research. 2025
Mitochondrial ORF of the 12S rRNA type-c (MOTS-c) as an AMPK agonist can regulate the expression of adaptive nuclear genes to promote cell homeostasis. However, the investigation of MOTS-c in hepatoce
Registered Clinical Trials
Long Term Outcomes After Vestibular Implantation
Analysis of Effects of High-intensity Physical Exercise in Subjects With Dialyzed Chronic Kidney Disease and in Conservative Treatment
Platelet Reactivity, B-amyloid, MOTS-c and Mortality of Type II Diabetics With CAD
Symptom Indications
Full Clinical Access
Complete MOTS-c Protocol
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This information is for educational and research reference purposes only. ClinPep does not provide medical advice, diagnosis, or treatment recommendations. All protocols should be reviewed by a licensed healthcare provider.