MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA-c)
Also Known AsMitochondrial-derived peptide · MDP MOTS-c
Discovered in 2015 by Changhan David Lee's laboratory at USC Leonard Davis School of Gerontology. MOTS-c was the first mitochondrial-derived peptide shown to regulate nuclear gene expression, establishing a new paradigm in mitochondrial-nuclear communication (retrograde signaling).
Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-ArgHow MOTS-c Works
AMPK Activation
MOTS-c activates AMPK (AMP-activated protein kinase) — the master metabolic energy sensor — by increasing the AMP/ATP ratio through inhibition of the folate-methionine cycle. This triggers downstream metabolic reprogramming including enhanced glucose uptake, fatty acid oxidation, and mitochondrial biogenesis.
Nuclear Translocation & Gene Regulation
Under metabolic stress, MOTS-c translocates from the cytoplasm to the nucleus where it interacts with ARE (Antioxidant Response Element) transcription factors to regulate adaptive gene expression. This is the first demonstrated instance of a mitochondria-encoded peptide directly regulating nuclear gene expression.
Folate Cycle Inhibition
MOTS-c inhibits the folate cycle at the level of 5-methyltetrahydrofolate, redirecting one-carbon metabolism away from de novo purine synthesis. This metabolic shift is the upstream mechanism driving AMPK activation and is unique to MOTS-c among known metabolic regulators.
Published Research
Metabolic Regulation & Insulin Sensitivity
ModeratePreclinical studies demonstrate that MOTS-c improves insulin sensitivity, enhances glucose uptake in skeletal muscle, and prevents diet-induced obesity in mouse models. In aged mice fed high-fat diets, MOTS-c prevented age-related metabolic dysfunction. Circulating MOTS-c levels correlate with metabolic health markers in human observational studies.
Exercise Physiology & Performance
ModerateMOTS-c levels increase in response to exercise in human subjects. Preclinical data shows MOTS-c improves exercise capacity, enhances skeletal muscle adaptation to training, and promotes beta-oxidation of fatty acids. Populations with naturally higher MOTS-c polymorphism frequencies (e.g., Japanese centenarian cohorts) show superior physical performance in aging.
Aging & Longevity
ModerateMOTS-c is one of several mitochondrial-derived peptides (MDPs) that decline with age. Mouse studies show that MOTS-c treatment reverses age-related physical decline and improves multiple healthspan metrics. The m.1382A>C polymorphism in the MOTS-c gene is enriched in Japanese centenarians, suggesting a longevity association.
Osteoporosis & Bone Metabolism
EmergingEmerging data demonstrates MOTS-c promotes osteoblast differentiation and bone formation through AMPK-mediated signaling while inhibiting osteoclastogenesis. Preclinical ovariectomized mouse models show protective effects against osteoporotic bone loss.
Safety Profile
As an endogenous mitochondrial-derived peptide naturally present in human circulation, MOTS-c has a favorable theoretical safety profile. Preclinical studies in mice (including chronic administration) report no adverse effects. No formal human clinical trials for safety have been completed to date.
Handling & Storage
Reconstitute with bacteriostatic water. MOTS-c is a 16-amino-acid peptide with good aqueous solubility. Store reconstituted solution at 2-8°C and use within 30 days. Lyophilized powder stable at -20°C.
Peer-Reviewed Literature
- 1
The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance
Lee C, Zeng J, Drew BG, et al.
- 2
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.
- 3
MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis
Reynolds JC, Lai RW, Woodhead JST, et al.
- 4
A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c
Zempo H, Fuku N, Nishida Y, et al.
MOTS-c FAQ
What is MOTS-c?
MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA-c) is a 16-amino-acid peptide encoded within the mitochondrial genome. Discovered in 2015 by Dr. Changhan Lee at USC, it was the first mitochondria-derived peptide shown to regulate nuclear gene expression, establishing a new paradigm in cellular communication.
How does MOTS-c relate to exercise?
MOTS-c levels increase in human skeletal muscle and plasma in response to exercise. Research published in Nature Communications (2021) demonstrated that MOTS-c treatment improves exercise capacity and reverses age-related physical decline in aged mice, suggesting it may mediate some of the metabolic benefits of exercise.
Does MOTS-c decline with age?
Yes. Circulating MOTS-c levels decrease with age in both humans and mice. This decline correlates with age-related metabolic dysfunction, reduced exercise capacity, and insulin resistance. Restoration of MOTS-c levels in aged mice reverses multiple age-related metabolic parameters.
What is the MOTS-c longevity polymorphism?
The m.1382A>C polymorphism in the MOTS-c-encoding region of mitochondrial DNA is significantly enriched in Japanese centenarian cohorts. This variant appears to confer enhanced metabolic regulation and is associated with exceptional longevity, supporting the role of MOTS-c in aging biology.
MOTS-c Products
All compounds 99%+ purity, verified by Janoshik Analytical. GMP-manufactured lyophilized powder.
MOTS-c
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- Burns fat by activating your body's metabolic furnace (AMPK)
- Mimics the benefits of exercise at the cellular level
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Disclaimer: This monograph is provided for educational and research purposes only. G26x Peptides products are sold exclusively as research chemicals. They are not intended for human consumption, therapeutic use, or as dietary supplements. All research should be conducted in compliance with applicable laws and institutional review board protocols. Information presented here is sourced from published peer-reviewed literature and does not constitute medical advice.