MOTS-c
Animal-onlyMOTSc · MOTS c · Mitochondrial ORF of the 12S rRNA type-c
Limited evidence: the strongest curated study is Animal-only; no human-trial data found as of 2026-06-04.
Chemical & identity
- Sequence
- MRWQEMGYIFYPRKLR
- Length
- 16 residues
- Molecular formula
- C101H152N28O22S2
- Molecular weight
- 2174.6 g/mol · PubChem
- PubChem CID
- 146675088 · PubChem
- SMILES
- CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)N3CCC[C@H]3C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O)NC(=O)[C@H](CC4=CC=C(C=C4)O)NC(=O)CNC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC5=CNC6=CC=CC=C65)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CCSC)N
- InChIKey
- WYTHCOXVWRKRAH-LOKRTKBUSA-N
- UniProt
- A0A0C5B5G6 · UniProt
- Category
- Mitochondrial
Chemical/structural fields are auto-pulled and source-linked.
Mechanism (curated)
Mitochondrial-derived peptide encoded in the 12S rRNA; activates AMPK and translocates to the nucleus to regulate stress-response/metabolic gene expression, promoting metabolic homeostasis. Therapeutic data are preclinical.
Pharmacology & handling
- Half-life
- Short — 16-residue peptide rapidly cleared; circulating endogenous levels decline with age.
Research
Reynolds JC et al. · Nature communications · 2021 · Animal study
This study reports that MOTS-c, a mitochondrial-encoded peptide, enhances physical performance in young, middle-aged, and old mice. MOTS-c regulated nuclear genes related to metabolism and proteostasis, skeletal muscle metabolism, and myoblast adaptation to metabolic stress. Late-life intermittent MOTS-c treatment administered 3 times per week increased physical capacity and healthspan in mice. In humans, exercise induced endogenous MOTS-c expression in skeletal muscle and circulation. The authors conclude that aging is regulated by genes encoded in both mitochondrial and nuclear genomes.
Mitochondrial-encoded peptide MOTS-c prevents pancreatic islet cell senescence to delay diabetes.
Animal-onlyKong BS et al. · Experimental & molecular medicine · 2025 · Other
This study investigates MOTS-c, a mitochondrial-encoded peptide, in pancreatic islet cell senescence and diabetes. Researchers found that MOTS-c levels decrease with aging and senescence in pancreatic islet cells. In mouse models (aged C57BL/6 and nonobese diabetic mice), MOTS-c treatment reduced pancreatic islet senescence, modulated gene expression and metabolites involved in β-cell senescence, and improved glucose intolerance. In humans, circulating MOTS-c levels were lower in type 2 diabetes patients compared with healthy controls. The authors propose MOTS-c as a potential senotherapeutic agent to prevent pancreatic islet cell senescence and diabetes progression.
Gudiksen A et al. · Free radical biology & medicine · 2026 · Animal study
This study investigated how MOTS-c, a mitochondrial-derived peptide, affects skeletal muscle mitochondrial function using two transgenic mouse strains. In mice, MOTS-c administration improved mitochondrial bioenergetic performance through PGC-1α and AMPK-dependent pathways, reduced mitochondrial reactive oxygen species emission, and improved mitochondrial redox handling and OXPHOS efficiency without changing respiratory protein content. RNA-sequencing suggested these effects were mediated through multiple mitochondrial parameters. In humans, increased circulating MOTS-c during one-legged knee extensor exercise did not show arterio-venous differences, suggesting skeletal muscle may not be the source of exercise-induced circulating MOTS-c.
MOTS-c attenuates cardiac dysfunction following high altitude exposure by promoting mitophagy.
Animal-onlyFeng Z et al. · Free radical biology & medicine · 2026 · Animal study
Mice exposed to simulated high altitude (6000 m for 10 days) developed persistent cardiac dysfunction during a subsequent 10-day de-acclimatization period, accompanied by mitochondrial dysfunction and MOTS-c deficiency. Exogenous MOTS-c supplementation during de-acclimatization alleviated cardiac dysfunction by activating the Pink1/Parkin mitophagy pathway; silencing Pink1 abolished these protective effects. Reduced circulating MOTS-c levels were also observed in patients with high altitude heart disease and acute coronary syndrome. The findings suggest MOTS-c maintains mitochondrial quality through mitophagy promotion and may have therapeutic potential for high altitude-induced cardiac dysfunction.
Kim KH et al. · Cell metabolism · 2018 · Animal study
This study demonstrates that MOTS-c, a peptide encoded by the mitochondrial genome, translocates to the nucleus and regulates nuclear gene expression in response to metabolic stress through an AMPK-dependent mechanism. The researchers found that MOTS-c regulates a broad range of genes during glucose restriction, including those with antioxidant response elements, and interacts with stress-responsive transcription factors such as NRF2. The findings suggest that mitochondrial and nuclear genomes have co-evolved to encode factors that cross-regulate each other. The study type and species/model system are not specified in the abstract.
Lee C et al. · Cell metabolism · 2015 · Animal study
This study identifies MOTS-c, a 16-amino-acid mitochondrial-derived peptide encoded by a short open reading frame in the mitochondrial 12S rRNA. In mice, MOTS-c treatment prevented age-dependent and high-fat-diet-induced insulin resistance and diet-induced obesity. The peptide's primary target organ is skeletal muscle, where it works by inhibiting the folate cycle and de novo purine biosynthesis, leading to AMPK activation. The findings suggest that mitochondria regulate metabolic homeostasis through peptides encoded in their genome.
Fuku N et al. · Aging cell · 2015 · Narrative review
Mitochondrial-derived peptides (MDPs) including MOTS-c are encoded by short open reading frames in mitochondrial DNA. The abstract proposes that the m.1382A>C polymorphism in the MOTS-c-encoding mtDNA, which occurs in Northeast Asian populations, may be a biological mechanism contributing to high longevity in Japanese people. The authors note that further research is needed to establish this connection.
Zhang Y et al. · Antioxidants (Basel, Switzerland) · 2024 · Animal study
This study examined the mitochondrial-derived peptide MOTS-c in an animal model of radiation pneumonitis (RP), a complication of thoracic radiotherapy. C57BL/6 mice exposed to 20 Gy lung irradiation received daily intraperitoneal MOTS-c injections for 2 weeks. MOTS-c reduced lung tissue damage, inflammation, oxidative stress, and apoptosis in irradiated mice and also protected lung epithelial cells in culture from oxidative stress and mitochondrial damage. Mechanistically, MOTS-c worked through activation of the Nrf2 pathway, and Nrf2 deficiency eliminated the protective effect in mice. The authors conclude MOTS-c may be a protective agent against radiation pneumonitis via Nrf2-dependent mitochondrial protection.
MOTS-c peptide regulates adipose homeostasis to prevent ovariectomy-induced metabolic dysfunction.
Animal-onlyLu H et al. · Journal of molecular medicine (Berlin, Germany) · 2019 · Animal study
This study examined MOTS-c, a 16-amino acid mitochondrial-derived peptide, in mice with ovariectomy-induced metabolic dysfunction. MOTS-c treatment prevented ovariectomy-induced obesity and insulin resistance by increasing brown fat activation, reducing white adipose tissue fat accumulation and inflammation, and lowering serum and liver fatty acid levels. The peptide activated the AMPK pathway to improve energy dissipation and insulin sensitivity, and blocking AMPK attenuated MOTS-c's effects on adipocyte lipid metabolism. The authors conclude MOTS-c is a candidate for treating menopausal-induced metabolic dysfunction.
Leciejewska N et al. · Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology · 2025 · In-vitro study
This in-vitro study investigated MOTS-c effects on muscle cell differentiation and metabolism using C2C12 and L6 cell lines representing different metabolic fiber types. MOTS-c at 10 and 100 nM increased C2C12 cell survival, stimulated ERK phosphorylation within 5 minutes, and promoted differentiation by increasing muscle regulatory factor expression; these effects were not observed in L6 cells. Both cell lines showed reduced proliferation with MOTS-c treatment. When combined with free fatty acids, MOTS-c decreased lipid accumulation in C2C12 cells but increased it in L6 cells. The findings indicate fiber-type-dependent responses to MOTS-c in survival, differentiation, and lipid metabolism.
Summaries are our own; we link to originals (PubMed / DOI) and never rehost full text.
Regulatory status
- FDA approved
- No
- WADA prohibited
- No
- Compounding status
- Not an approved drug; investigational / research use only.
- Notes
- Not FDA-approved; investigational. Human literature to date is largely endogenous-biomarker association, not interventional administration. As of 2026-06-04, not listed on the WADA prohibited list.
Legal/regulatory status varies by jurisdiction and changes over time — accurate as of last review (2026-06-04).
Data sources: Curated IDs (PubChem/UniProt/ChEMBL) + Europe PMC + ClinicalTrials.gov (2026-06-04).
Last reviewed 2026-06-04