MOTS‑c
Mitochondrial-derived peptide (16 amino acids, 12S rRNA mtDNA-encoded), discovered by Lee 2015 Cell Metab PMID 25738457. AMPK activator with preclinical evidence for glucose homeostasis + insulin sensitization; human Phase 1/2 trials preliminary, fat-loss effect subtle.
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WHAT IS MOTS-C?
Detailed overview
MOTS-c (Mitochondrial Open Reading frame of the Twelve S rRNA-c) is a 16-amino-acid peptide discovered by the Lee/Pinchas Cohen lab (USC) in 2015 (Cell Metab PMID 25738457). Its unique property is that it is not encoded in the nuclear genome but in a short open reading frame (sORF) of the mitochondrial 12S rRNA gene – making it the first extensively characterized member of the mitochondrial-derived peptide (MDP) class. Its endogenous function: transducing mitochondrial dysfunction signals to the nucleus ("retrograde signaling") via AMPK activation, which elevates glucose uptake + upregulates fatty-acid oxidation in skeletal muscle. Kim 2018 Aging Cell PMID 30276962 demonstrated in mouse trials that exogenous MOTS-c administration prevents high-fat-diet-induced obesity + insulin resistance and corrects its age-dependent decline. Reynolds 2021 Sci Rep PMID 33526809 documented exercise-induced endogenous MOTS-c elevation in human plasma. Clinical human Phase 1/2 trials are in preliminary status (CohBar Inc + Stealth BioTherapeutics pipeline 2024-2025), full publication expected in 2026. Off-label cutting-cycle use has emerged on the blackmarket peptide scene since 2022, typically 5-10 mg SC 2-3x/week. Human fat-loss effects are subtle; AMPK-activator mechanism is Metformin-adjacent. MolekulaX has NO peptide-library counterpart – this is the first MOTS-c entry on the site.
Mechanism
Mitochondrial-derived peptide (16 aa), AMPK activator, upregulates glucose uptake + fatty-acid oxidation
Dosing (off-label)
5-10 mg SC 2-3x/week, 4-8 week cycle
Half-life
~1-2 hours (SC IM, mouse extrapolation)
Onset time
Acute AMPK activation 1-2 h; metabolic effect 2-4 weeks
Legal status
Research-only – NOT an FDA / EMA Rx in any jurisdiction. WADA NOT explicitly banned (but S0 'non-approved substance' catch-all risk).
Data console
Lab data
Safety
Side effects, stop signs, contraindications
Side effects · 6
- Risk of hypoglycemia: as an AMPK activator it improves insulin sensitivity and drives insulin-independent glucose uptake, so blood sugar can drop, especially in a calorie deficit or combined with other antidiabetics (metformin, insulin, GLP-1).
- Local injection-site reactions: redness, tenderness, itching or swelling at the subcutaneous injection site.
- Gastrointestinal complaints: its AMPK-activating mechanism parallels metformin, so nausea, bloating or mild digestive discomfort may occur (anecdotal, human dosing data sparse).
- Lactate elevation and theoretical metabolic acidosis risk: as a modulator of mitochondrial metabolism it may raise lactate; a marked rise (>2x baseline) warrants dose reduction or stopping the cycle.
- Unknown long-term safety profile: human data are at a preliminary Phase 1/2 stage and the full safety profile is unpublished as of early 2026; effects of supraphysiological, long-term dosing are unknown.
- Black-market quality risk: illicit UGL vials carry the risk of counterfeiting, underdosing, degraded peptide and endotoxin contamination; without an HPLC-tested source and COA the actual content and purity are uncertain.
Contraindications · 6
- Pregnancy and breastfeeding: the peptide has only preclinical data with no teratogenicity information, so it should be avoided during pregnancy and lactation.
- Diabetes treated with insulin or a sulfonylurea: the insulin-sensitizing effect is additive with a risk of severe hypoglycemia; contraindicated without close glucose monitoring and medical supervision.
- Active malignancy: the preclinical proliferation data of this mitochondrial-biogenesis modulator are inconclusive, so it should be avoided in active cancer (theoretical risk).
- Children and adolescents: there is no Phase 2 indication or safety data for pediatric use, so it is contraindicated.
- Conditions predisposing to lactic acidosis (renal or hepatic impairment, chronic alcohol use): the AMPK-activator mechanism and lactate-raising potential may add hepatic/metabolic stress, warranting heightened caution or avoidance.
- Known hypersensitivity to the peptide or to components of the reconstitution solution: local or, rarely, systemic allergic reactions may occur.
Related Performance Compounds
Same therapeutic category
Studies
Related research and clinical findings
The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance.
Lee C, Zeng J, Drew BG, Sallam T, Martin-Montalvo A, Wan J, Kim SJ, Mehta H, Hevener AL, de Cabo R, Cohen P
MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis.
Reynolds JC, Lai RW, Woodhead JST, Joly JH, Mitchell CJ, Cameron-Smith D, Lu R, Cohen P, Graham NA, Benayoun BA, Merry TL, Lee C
The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress.
Kim KH, Son JM, Benayoun BA, Lee C
Naturally occurring mitochondrial-derived peptides are age-dependent regulators of apoptosis, insulin sensitivity, and inflammatory markers
Cobb LJ, Lee C, Xiao J et al.
Humanin and Its Pathophysiological Roles in Aging: A Systematic Review.
Coradduzza D, Congiargiu A, Chen Z, Zinellu A, Carru C, Medici S
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The information here is for educational and scientific purposes only. Performance-enhancing compounds (AAS, prohormones, stimulants, doping agents) are illegal without prescription in Hungary and most of the EU, and carry serious health and legal risks. WADA bans them in competitive sport. This is NOT a usage guide, and we do not encourage any illegal use. If you do use them, medical supervision and regular bloodwork are ESSENTIAL. Severe endocrine, cardiovascular, hepatic and psychiatric side effects are possible.