Research-use-only context. This article summarizes published third-party scientific literature and laboratory practice. It is not medical advice, not a therapeutic or performance claim, and not a usage guide. US Prime Peptides products are supplied strictly for in vitro laboratory research and are not for human or veterinary use.
This article explains what MOTS-c is, how a sixteen-residue peptide came to be assigned to the mitochondrial genome, what the 2015 Cell Metabolism discovery paper reported, and what the cell, mouse, rat, and human-cohort studies published since then have measured. It separates the mechanistic cell work from the rodent phenotypes, describes the nuclear-translocation finding, and states plainly what has not been established in humans.
MOTS-c is a 16-residue peptide encoded inside the mitochondrial 12S rRNA gene
MOTS-c stands for mitochondrial open reading frame of the 12S rRNA type-c. It is a sixteen-amino-acid peptide with the sequence Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg, formula C101H152N28O22S2, molecular weight about 2,174.6 daltons, PubChem CID 146675088, and CAS number 1627580-64-6. Lee and colleagues reported it in a 2015 Cell Metabolism paper after searching mitochondrial DNA for short open reading frames of the kind that had earlier yielded humanin, a 24-residue peptide encoded within the 16S rRNA gene. MOTS-c is therefore the second member of a small family now called mitochondrial-derived peptides; the family is compared in Humanin vs MOTS-c vs SS-31, and humanin has its own overview.
Two chemical features matter for a laboratory. The sequence contains two methionines, at positions 1 and 6, which are the residues most prone to oxidation to methionine sulfoxide during storage in solution; that adds 16 daltons per oxidized residue and appears as an earlier-eluting shoulder on a reverse-phase chromatogram. And the peptide carries four basic residues (three arginines and one lysine) with no acidic residue beyond a single glutamate, so it is strongly cationic at neutral pH, binds acetate or trifluoroacetate counter-ions in the lyophilized powder, and adsorbs readily to standard polypropylene. The practical handling consequences are covered in aliquots, freeze-thaw cycles, and oxidation.
What the 2015 discovery paper reported
The 2015 paper made three kinds of claims, and it helps to keep them separate. The first was genetic: a short open reading frame within the 12S rRNA gene is transcribed and translated, and an antibody raised against the predicted peptide detected it in cells and in plasma. The second was mechanistic and was done in cultured cells: the peptide inhibited the folate cycle and the de novo purine synthesis tethered to it, which caused the intermediate AICAR to accumulate and the energy sensor AMPK to become activated. The third was physiological and was done in mice: animals on a high-fat diet that received the peptide gained less body mass and retained better glucose handling than vehicle controls, and older mice given the peptide showed less of the age-related decline in insulin sensitivity. The authors identified skeletal muscle as the main responsive tissue.
The folate-AICAR-AMPK mechanism is the part that later groups have most often built on, and it is why MOTS-c is frequently grouped with AMPK activators such as AICAR in doping-control discussions. Thevis and Schänzer, in a 2016 Rapid Communications in Mass Spectrometry review of emerging compounds relevant to skeletal muscle and mitochondrial biogenesis, included it among substances for which sports-testing laboratories were preparing analytical methods. The regulatory side of that is covered in the WADA prohibited list article.
The nuclear translocation finding and the gene-expression work that followed
Kim and colleagues, from the same laboratory, reported in a 2018 Cell Metabolism paper that MOTS-c moves from the cytoplasm into the nucleus of cultured cells under metabolic stress, specifically glucose restriction, and that the movement depends on AMPK. In the nucleus the peptide was found in association with chromatin near antioxidant response elements and interacted with the stress-responsive transcription factor NRF2. The authors framed this as evidence that a factor encoded in the mitochondrial genome can regulate nuclear gene expression, which inverts the usual direction of control between the two genomes.
Li and colleagues extended the translocation finding in a 2025 Redox Biology paper using rat lung ischemia-reperfusion and cultured endothelial cells. They reported that hypoxia-reoxygenation triggered reactive-oxygen-species-dependent phosphorylation of the motor protein MYH9 by casein kinase II, that MOTS-c bound MYH9-gamma-actin complexes for nuclear transport, and, using chromatin immunoprecipitation sequencing, that the peptide associated with promoters of antioxidant genes including HMOX1 and NQO1. In the same study, a rise in serum MOTS-c within 24 hours after cardiopulmonary bypass in a human cohort tracked later lung complications, which is an observational biomarker finding rather than an intervention.
Mohtashami and colleagues, in a 2022 International Journal of Molecular Sciences review, summarize the consensus picture: the peptide is co-localized with mitochondria across tissues, is detectable in plasma, declines in plasma with age, and relocates to the nucleus under stress to regulate a broad set of nuclear genes. The review also lists many disease-model claims, most of which rest on a single rodent study each.
Mouse and rat studies since 2015
The rodent literature is broad but thin per model. Reynolds and colleagues, in a 2021 Nature Communications paper, reported that MOTS-c given to young (2-month), middle-aged (12-month), and old (22-month) mice raised treadmill running capacity, that the peptide altered nuclear gene expression related to metabolism and proteostasis in skeletal muscle, and that cultured myoblasts exposed to it adapted differently to metabolic stress. They also started intermittent exposure at 23.5 months of age and measured higher physical capacity and a longer period of good health in the exposed animals. Lu and colleagues, in a 2019 International Journal of Molecular Sciences paper, reported that serum MOTS-c fell after cold exposure in mice and that peptide-exposed animals showed higher brown-adipose thermogenic gene expression through an ERK-dependent pathway.
Inflammation and tissue-injury models make up the rest. Xinqiang and colleagues, in a 2020 International Immunopharmacology paper, exposed mice to MOTS-c before intratracheal lipopolysaccharide and measured less pulmonary edema, less neutrophil infiltration, lower TNF-alpha, IL-1beta, and IL-6, higher IL-10 and superoxide dismutase, more phosphorylated AMPK and SIRT1, and less activation of ERK, JNK, p38, p65, and STAT3 in lung tissue. Zhong and colleagues, in a 2022 Journal of Cellular and Molecular Medicine paper, used transverse aortic constriction in mice to impose pressure overload and reported less cardiac dysfunction and remodeling, lower inflammatory markers, and AMPK activation in peptide-exposed hearts; in cultured H9C2 cardiac cells, overexpressing MOTS-c activated AMPK and reduced hydrogen-peroxide-induced apoptosis.
One rodent-cell result cuts the other way. Mendelsohn and Larrick, in a 2018 Rejuvenation Research commentary, drew attention to a report that both humanin and MOTS-c increased secretion of IL-6, IL-1beta, IL-8, IL-10, and TNF-alpha by senescent cells, amplifying the senescence-associated secretory phenotype rather than suppressing it. The cytoprotective and pro-secretory findings come from different cell states, but together they show that the peptide's effects depend on context.
| Finding | Model | Source |
|---|---|---|
| Folate-cycle inhibition, AICAR rise, AMPK activation | Cultured cells | Lee 2015 |
| Less mass gain on high-fat diet; retained insulin sensitivity with age | Mice | Lee 2015 |
| Nuclear translocation under glucose restriction; NRF2 interaction | Cultured cells | Kim 2018 |
| Higher running capacity at three ages; late-life initiation | Mice | Reynolds 2021 |
| Lower lung inflammation after lipopolysaccharide | Mice | Xinqiang 2020 |
| Less cardiac remodeling after pressure overload | Mice, H9C2 cells | Zhong 2022 |
| MYH9-dependent nuclear transport; antioxidant-gene promoters | Rat, endothelial cells | Li 2025 |
| Amplified secretory phenotype in senescent cells | Cultured senescent cells | Mendelsohn 2018 |
Human data: polymorphism, plasma levels, and exercise
Every human study of MOTS-c to date is observational. The most distinctive line of work concerns a single-nucleotide variant. Fuku and colleagues, in a 2015 Aging Cell letter, pointed out that the mitochondrial polymorphism m.1382A>C, found in Northeast Asian populations, lies within the MOTS-c reading frame and proposed it as a candidate contributor to Japanese longevity. Kumagai and colleagues followed up in a 2022 Biochimica et Biophysica Acta General Subjects paper: the variant changes residue 14 from lysine to glutamine (K14Q), a form with less biological activity in their assays. In 211 healthy Japanese adults, C-allele carriers had a higher proportion of fast-twitch MHC-IIx fibers; in 86 physically active young men, C-allele carriers produced higher leg flexion and extension torque; and across 721 athletes and 873 controls, the C allele was more frequent in sprint and power athletes (6.5 percent) than in controls (5.1 percent) or endurance athletes (2.9 percent). Young mice given a MOTS-c-neutralizing antibody showed a shift in the same direction.
Plasma and muscle measurements come from two groups. D'Souza and colleagues, in a 2020 Aging paper, measured MOTS-c in plasma and vastus lateralis biopsies from young, middle-aged, and older healthy men. Circulating MOTS-c fell with age, but muscle MOTS-c was about 1.5-fold higher in the two older groups than in the young, and muscle levels correlated with markers of slow-type fibers. They also presented evidence that the MOTS-c transcript may be regulated independently of the full 12S rRNA in which it sits. Reynolds's 2021 paper reported that a single bout of exercise raised MOTS-c in human skeletal muscle and in circulation. Von Walden and colleagues, in a 2021 Journal of Applied Physiology study of 30 volunteers randomized to endurance cycling, resistance exercise, or rest, found that endurance exercise significantly raised circulating humanin while MOTS-c showed only a trend upward, and that resting MOTS-c levels did not correlate with fitness measures.
What is not established, and what a certificate should show
No controlled trial of exogenous MOTS-c in humans has been published, so none of the rodent phenotypes have a human counterpart. The peptide is not an approved drug in any jurisdiction. A synthetic analog has entered early-phase testing according to registry listings, with no peer-reviewed efficacy data published. The human-cohort findings establish that the peptide is measurable, that circulating levels change with age and exercise, and that a natural variant associates with muscle fiber type; they do not establish causation. Even within rodents, most disease-model claims rest on a single paper, and the senescent-cell secretory finding has not been reconciled with the cytoprotective results.
Because the molecule is a 2,175-dalton peptide with two oxidation-prone methionines and a high positive charge, a certificate should show identity by LC-MS with the expected multiply charged ions, the doubly protonated ion near m/z 1,088 and the triply protonated ion near m/z 726, and an HPLC purity line in which any methionine-sulfoxide shoulder is quantified separately. Net peptide content matters more than usual here, since four basic residues each carry a counter-ion. US Prime Peptides lists MOTS-c 10 mg and MOTS-c 40 mg with lot-matched certificates posted before purchase; how to read each line is explained in how to read a certificate of analysis.
Frequently Asked Questions
What is MOTS-c?
MOTS-c is a sixteen-amino-acid peptide encoded by a short open reading frame inside the 12S ribosomal RNA gene of mitochondrial DNA. It was reported in 2015 as the second mitochondrial-derived peptide after humanin. In cultured cells it inhibits the folate cycle, raises AICAR, and activates AMPK, and under metabolic stress it moves into the nucleus.
Is MOTS-c a hormone?
It is detectable in plasma and in several tissues, and a 2021 study found it rises in muscle and blood after exercise, so some authors describe it as a mitochondria-derived signaling peptide with hormone-like properties. Whether circulating MOTS-c acts on distant tissues in humans has not been shown.
Has MOTS-c been tested in humans?
Only observationally. Studies have measured plasma and muscle levels across age groups, tracked changes after exercise, and examined a mitochondrial variant (m.1382A>C, K14Q) that associates with muscle fiber type in Japanese cohorts. No controlled human trial of the peptide itself has been published, and MOTS-c is not an approved drug.
Why does MOTS-c need careful storage?
The sequence has two methionines, which oxidize to methionine sulfoxide in solution and in the presence of air, and it carries four basic residues that promote adsorption to plastic. Lyophilized powder stored cold and dry is stable; reconstituted solution should be aliquoted and kept frozen, with oxidation checked by HPLC.
Citations
- Lee C, Zeng J, Drew BG, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015;21:443-454. PMID 25738459
- Fuku N, Pareja-Galeano H, Zempo H, et al. The mitochondrial-derived peptide MOTS-c: a player in exceptional longevity? Aging Cell. 2015;14:921-923. PMID 26289118
- Thevis M, Schänzer W. Emerging drugs affecting skeletal muscle function and mitochondrial biogenesis: potential implications for sports drug testing programs. Rapid Commun Mass Spectrom. 2016;30:635-651. PMID 26842585
- Kim KH, Son JM, Benayoun BA, Lee C. The mitochondrial-encoded peptide MOTS-c translocates to the nucleus to regulate nuclear gene expression in response to metabolic stress. Cell Metab. 2018;28:516-524. PMID 29983246
- Mendelsohn AR, Larrick JW. Mitochondrial-derived peptides exacerbate senescence. Rejuvenation Res. 2018;21:369-373. PMID 30058454
- Lu H, Tang S, Xue C, et al. Mitochondrial-derived peptide MOTS-c increases adipose thermogenic activation to promote cold adaptation. Int J Mol Sci. 2019;20:2456. PMID 31109005
- Xinqiang Y, Quan C, Yuanyuan J, Zhanfang Z. Protective effect of MOTS-c on acute lung injury induced by lipopolysaccharide in mice. Int Immunopharmacol. 2020;80:106174. PMID 31931370
- D'Souza RF, Woodhead JST, Hedges CP, et al. Increased expression of the mitochondrial derived peptide, MOTS-c, in skeletal muscle of healthy aging men is associated with myofiber composition. Aging (Albany NY). 2020;12:5244-5258. PMID 32182209
- Reynolds JC, Lai RW, Woodhead JST, et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun. 2021;12:470. PMID 33473109
- von Walden F, Fernandez-Gonzalo R, Norrbom J, et al. Acute endurance exercise stimulates circulating levels of mitochondrial-derived peptides in humans. J Appl Physiol. 2021;131:1035-1042. PMID 34351816
- Kumagai H, Natsume T, Kim SJ, et al. The MOTS-c K14Q polymorphism in the mtDNA is associated with muscle fiber composition and muscular performance. Biochim Biophys Acta Gen Subj. 2022;1866:130048. PMID 34728329
- Zhong P, Peng J, Hu Y, Zhang J, Shen C. Mitochondrial derived peptide MOTS-c prevents the development of heart failure under pressure overload conditions in mice. J Cell Mol Med. 2022;26:5369-5378. PMID 36156853
- Mohtashami Z, Singh MK, Salimiaghdam N, Ozgul M, Kenney MC. MOTS-c, the most recent mitochondrial derived peptide in human aging and age-related diseases. Int J Mol Sci. 2022;23:11991. PMID 36233287
- Li X, Zhan F, Qiu G, et al. MOTS-c attenuates lung ischemia-reperfusion injury via MYH9-dependent nuclear translocation and transcriptional activation of antioxidant genes. Redox Biol. 2025;84:103681. PMID 40403491
This article is for laboratory research reference only. US Prime Peptides products are supplied strictly for in vitro research. Not for human consumption.
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