Mitochondrial Open Reading Frame of the 12S rRNA-c (MOTS-c)

Table of Contents

1. What the Peptide Is
2. Where It Came From
3. How It Is Thought to Work
4. Laboratory and Animal Research
5. Human Studies: Only the Body's Own Peptide
6. What the U.S. Food and Drug Administration Found
7. The July 2026 Advisory Committee Vote
8. The October 2026 Interim Compounding Policy
9. Safety Findings and Unknowns
10. What Is Not Known
11. Key Research Papers
12. Connections
13. Featured Videos

What the Peptide Is

The name describes where the code for the peptide was found. An “open reading frame” is a stretch of genetic code that a cell can read to build a chain of amino acids. This one lies inside the mitochondrial gene for the 12S ribosomal ribonucleic acid (rRNA), a molecule that helps mitochondria build their own proteins; the gene's official name is MT-RNR1. The U.S. Food and Drug Administration's briefing document for its July 2026 advisory committee calls it “a naturally occurring mitochondrial hexadecapeptide,” meaning a peptide of 16 amino acids, and notes that it “is expressed in different tissues, including skeletal muscle, heart, and brain” and “is present in the systemic circulation in humans and rodents.”

The sequence

The briefing gives the chain as H-Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg-OH, or MRWQEMGYIFYPRKLR in one-letter code. It starts with methionine and contains three arginines, two tyrosines and one tryptophan. Products sold under the name are made in a laboratory by chemical synthesis; they are copies of the natural sequence, not extracts from human tissue.

The name

The briefing notes that the short name “is a common name and not a United States Adopted Name (USAN),” nor an international or chemical naming-system name. The agency's own compounding-safety page spells it “MOTs-C.” The agency treats loose naming as a safety matter in itself: names that “do not follow established chemical nomenclature standards” mean patients “may be dosed with a different BDS than the physician ordered” (a BDS is a bulk drug substance).

Free base and acetate

Synthetic peptides are made either as the peptide alone (the “free base”) or paired with an acid as a salt. The acetate form is the peptide paired with acetic acid, the acid in vinegar. The two forms weigh differently and are tested differently, so the U.S. Food and Drug Administration treats each one as a separate bulk drug substance, the raw active ingredient from which a pharmacy prepares a medicine. The briefing gives these identifiers:

• Free base: molecular formula C₁₀₁H₁₅₂N₂₈O₂₂S₂, molecular weight 2174.6; Chemical Abstracts Service registry number 1627580-64-6; Unique Ingredient Identifier A5CV6JFB78.
• Acetate: C₁₀₁H₁₅₂N₂₈O₂₂S₂·CH₃COOH, molecular weight 2234.64 g/mol; no registry number or Unique Ingredient Identifier of its own. The briefing's summary table leaves the acetate's weight blank, but its text, the agency's slides and the 2026 policy all give 2234.64.

The agency added that the nomination it reviewed did not make clear which form was meant: its certificate of analysis (the supplier's test sheet) “refers to one BDS by name in the title and a different BDS by the CAS number.” There is no United States Pharmacopeia or National Formulary monograph (an official quality standard) for either form, and neither is part of any drug the agency has approved.

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Where It Came From

Mitochondria are thought to descend from bacteria that came to live inside larger cells long ago, and they still keep a small, circular genome of their own. For decades that genome was believed to code for a fixed, short list of products. In the early 2000s researchers reported a small peptide called humanin coded inside it, which raised the question of whether more such peptides existed.

The 2015 discovery

In March 2015 Changhan Lee, Pinchas Cohen and colleagues at the Leonard Davis School of Gerontology of the University of Southern California, working with groups at the University of California, Los Angeles and the U.S. National Institute on Aging, reported in Cell Metabolism “a sORF within the mitochondrial 12S rRNA encoding a 16-amino-acid peptide named MOTS-c” that, in their experiments, “regulates insulin sensitivity and metabolic homeostasis.” They reported that its main target appeared to be skeletal muscle and that treating mice with it prevented insulin resistance linked to ageing and to a high-fat diet, as well as diet-induced weight gain. The U.S. Food and Drug Administration's briefing cites this paper as the discovery of the peptide.

A variant in Japanese families

Later in 2015 a team led from Juntendo University in Japan, with researchers in Spain and at Keio University's centre for supercentenarian research, pointed to a natural variation in the peptide's code, called m.1382A>C, which they described as specific to Northeast Asian populations. In a short letter they suggested, while stating that “more research is needed,” that the variant “may be among the putative biological mechanisms explaining the high longevity of Japanese people.” That was a hypothesis, not a finding. A 2021 study by an overlapping Japanese and American team found that the same variant swaps one amino acid in the peptide (lysine at position 14 becomes glutamine) and, in a pooled analysis of three population studies with 27,527 people, that men carrying it had a higher prevalence of type 2 diabetes; women did not.

Who did the research

Much of the early work on the peptide comes from the University of Southern California group and its collaborators. Several of those papers state, in their conflict-of-interest declarations, that their senior authors were consultants for and shareholders of a biotechnology company developing drugs based on mitochondrial peptides. Groups in China, Chile, New Zealand, Sweden, Qatar, the United Kingdom and Germany have since published studies, some of them with University of Southern California co-authors; several appear below.

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How It Is Thought to Work

Everything in this section comes from cell cultures and mice. None of it has been tested by giving the peptide to people.

An energy-sensing switch

The 2015 discovery paper reported that, inside cells, the peptide “inhibit[s] the folate cycle and its tethered de novo purine biosynthesis, leading to AMPK activation.” In plain words, it slowed one of the cell's routes for building purines, raw materials of the genetic code, and this in turn switched on adenosine monophosphate-activated protein kinase, an enzyme that senses when a cell is short of energy and pushes it to burn more glucose and fat. The same energy-sensing enzyme comes up in research on metformin and on berberine. Several later animal and cell studies on fat tissue, bone and blood vessels, described below, also reported more activity of this enzyme after treatment.

A message from the mitochondria to the nucleus

In 2018 the University of Southern California group reported that, when cells were starved of glucose, the peptide moved from the mitochondria into the nucleus, where the cell's main genes are kept. There it “regulated a broad range of genes,” including genes that defend against oxidative stress, and it bound to a protein called nuclear factor erythroid 2-related factor 2, which switches those defence genes on. The move into the nucleus depended on the energy-sensing enzyme above. The authors read this as evidence that the mitochondrial genome can send signals that steer the nuclear genome.

What the U.S. Food and Drug Administration made of it

The agency's slides summarise the idea as researchers having “proposed” that the peptide acts through the energy-sensing enzyme to regulate genes involved in metabolism, and add: “The mechanism(s) by which MOTS-c stimulates AMPK signaling are poorly understood.” The briefing states that “the molecular target(s) through which MOTS-c acts remains unknown.” No receptor for the peptide has been identified in the papers the agency reviewed.

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Laboratory and Animal Research

The studies below gave synthetic peptide to mice or rats by injection, or added it to cells in a dish. The U.S. Food and Drug Administration notes that these studies “do not clearly identify the specific form of MOTS-c (free base or salt) used.”

Weight, blood sugar and fat

• The discovery study (2015). In the agency's summary, adult male mice fed a high-fat diet and treated with the peptide “gained significantly less body weight than untreated male mice fed the same diet,” and at the end of eight weeks “weighed ~20% less than vehicle-treated mice.” Treatment also prevented the insulin resistance that develops with age in mice.
• Blood chemistry in obese mice (2019). The University of Southern California group measured a broad panel of small molecules in the blood of mice made obese by diet. Three metabolic pathways that run high in models of obesity and type 2 diabetes were lower in injected mice, and the authors reported better insulin sensitivity and more fat burning. The agency's summary adds that blood glucose fell by about half.
• A model of menopause (2019). A group in Xi'an, China, removed the ovaries of mice, which lowers oestrogen and leads to fat gain, as after menopause. Treated mice did not develop the expected obesity and insulin resistance; their brown fat (the heat-producing kind) stayed more active and their white fat held less fat and less inflammation. A drug that blocks the energy-sensing enzyme weakened the effect in fat cells.
• The Japanese variant in mice (2021). In the study of the m.1382A>C variant, male mice on a high-fat diet injected with the normal peptide gained less weight and handled glucose better, while mice given the variant form did not. Female mice were unaffected by either.

Bone

• Stem cells in a dish (2018). Hu and Chen grew stem cells from rat bone marrow and reported that the peptide pushed them to become bone-forming cells, with more mineral deposits; the effect disappeared when a signalling protein called transforming growth factor beta-1 was switched off.
• Bone loss in mouse skulls (2019). A Xi'an team placed fine particles of a hard plastic used in artificial joints on the skulls of mice, which causes bone erosion and inflammation. Treated mice had less erosion and inflammation, and the authors traced this to fewer bone-dissolving cells being formed.

The agency summarised these as showing in rodents that the peptide “can promote osteogenesis” (bone formation) and “can inhibit osteolysis” (bone breakdown). No study of the peptide in people with osteoporosis was found.

Blood vessels

In a 2020 rat study, calcium deposits were induced in the arteries with vitamin D₃ plus nicotine; rats injected with the peptide at 5 mg per kg of body weight once a day for four weeks had significantly less artery calcification, more activity of the energy-sensing enzyme, and lower levels of the receptors for two hormones that act on blood vessels, angiotensin II and endothelin.

Physical performance and ageing

A 2021 study in Nature Communications reported that the peptide “can significantly enhance physical performance” in young (2 months), middle-aged (12 months) and old (22 months) mice. Treatment started late in life (23.5 months) and given three times a week improved physical capacity. The agency's briefing quotes the lifespan results: “The median and maximal lifespans were 912 and 1047 days, respectively, for vehicle-treated mice and 970 and 1120 days, respectively, for MOTS-c-treated mice.” This is part of why the peptide is discussed in longevity circles; no human ageing study exists.

How the agency read the animal work

The briefing states that “caution is warranted in interpreting the potential clinical relevance” of these results, because the studies “have been limited to in-vivo and in-vitro rodent models and have not evaluated the dose-response relationships,” and concludes that “the clinical relevance of the findings of these nonclinical studies is currently unknown.”

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Human Studies: Only the Body's Own Peptide

The U.S. Food and Drug Administration searched the medical literature and “did not identify clinical studies evaluating administration of MOTS-c-related BDSs in human subjects.” The nomination it reviewed cited 12 papers, none of them a clinical study. Every human study found for this page measured the peptide that people make themselves (the endogenous peptide) in blood or muscle. None tested whether taking the synthetic peptide does anything.

Studies of the body's own levels

• Lean and obese adults, Chile (2018). Ten lean and ten obese people had similar blood levels (0.48 and 0.52 ng/mL). Across all twenty, higher levels went with more insulin resistance on the Homeostatic Model Assessment, but when the groups were looked at separately the link held only in lean people. The authors concluded that the level “is unaltered in human obesity.”
• Waist and liver fat, New Zealand (2021). In 125 Chinese adults without diabetes or heart disease (plus 34 European women for scans), levels were higher in the 26 people with metabolic syndrome; waist size was the strongest link, and on magnetic resonance scans liver fat went with higher levels. The authors suggested that stress on the liver may raise the peptide as part of a response meant to restore metabolic balance.
• A fat infusion, Qatar and the United Kingdom (2019). Women with polycystic ovary syndrome and healthy volunteers received a five-hour infusion of a fat emulsion into a vein. Blood levels rose to about 232% of baseline in controls and 349% in the women with the syndrome; adding insulin blunted the rise. Eight weeks of moderate exercise training did not change blood levels.
• One exercise session, Sweden (2021). Thirty people were randomly assigned to 45 minutes of cycling, a leg-strength workout, or rest. A related mitochondrial peptide, humanin, rose significantly after cycling; this peptide “showed a trend to increase,” which did not reach statistical significance.
• Exercise in muscle (2021). The mouse performance study above also reported that “in humans, exercise induces endogenous MOTS-c expression in skeletal muscle and in circulation.”
• Genetics. The 2021 pooled analysis of 27,527 people found more type 2 diabetes in men carrying the m.1382A>C variant, which changes one amino acid in the body's own peptide.

The measurement problem

In 2019 the anti-doping laboratory of the German Sport University Cologne built a test based on mass spectrometry, which identifies a molecule by its exact weight. It could detect the peptide down to 100 picograms per millilitre of plasma. A commercial antibody-based test kit (an enzyme-linked immunosorbent assay) had reported levels of 45.9 to 218.5 ng/mL in 20 healthy people, but those levels “could not be confirmed” by the more specific method, and the authors reported “considerable differences” between the two. The levels reported across the studies above differ by more than a hundredfold. How much of the peptide normal human blood carries is therefore not settled, and studies that used different kits cannot simply be compared.

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What the U.S. Food and Drug Administration Found

The agency reviewed both forms in a briefing document dated 11 May 2026 for its Pharmacy Compounding Advisory Committee. The nomination had named the uses “insulin resistance, obesity, osteoporosis, vascular calcification, muscle/fat metabolism, longevity” and proposed injection under the skin. The nomination was later withdrawn, and the agency stated that it was “evaluating the substances at its discretion.” The meeting notice listed the uses under review as obesity and osteoporosis. The agency weighed four criteria set by a 2019 rule; the wider review of all seven peptides is on the compounded peptides review page.

1. Chemical characterization

The agency judged both forms “not well-characterized.” It found no certificate of analysis for the free base in the nomination; one public certificate it located “only contains purity testing result.” The acetate's certificate showed a purity of 99.2% against a limit of 98.0% or more, “However, there is no impurity quality control attribute tests to demonstrate the impurity profiles.” Tests for impurities, clumped molecules (aggregates), microbes and bacterial endotoxins were not found in the literature for either form.

2. Safety

• No toxicity studies of any kind (single or repeated doses, genes, reproduction, cancer) were submitted or found.
• No study measured how the peptide is absorbed or cleared in a living animal or person. The only data came from human blood in a test tube, where it broke down rapidly into shorter pieces. The briefing states: “It remains to be determined whether exogenous administration of MOTS-c to humans can generate pharmacologically active concentrations of the peptide over time.”
• “The nomination did not include, and FDA has not identified, any clinical studies or human exposure data for MOTS-c via any route of administration. Therefore, potential safety risks associated with the use of MOTS-c-related BDSs in humans are unknown.”
• Immunogenicity concerns are described under Safety Findings and Unknowns.

3. Effectiveness

The agency found no human data for any nominated use and wrote: “There is a lack of evidence to evaluate the effectiveness of the MOTS-c-related BDSs for the nominated uses.” It noted that “there are FDA-approved drug products for weight reduction in patients with obesity and treatment of osteoporosis.”

4. Historical use, other countries and sport

• “The earliest and extent of MOTS-c (free base) or MOTS-c acetate use in compounding is unknown.” Outsourcing facilities (large-scale compounders) reported preparing no products with it from January 2017 to December 2025.
• An internet search showed it “marketed on websites alone and in combination with other substances,” including a clinic's intravenous “cocktail”; the slides add that it appears to be offered in the United States “as single and multiple peptide injectable products.”
• The European Pharmacopoeia and the Japanese Pharmacopoeia have no monograph for it, and the European Medicines Agency “did not list any products containing MOTS-c or MOTS-c acetate that are authorized for use.” The briefing names no country where it is an authorised medicine.
• It “appears as a prohibited substance” in an anti-doping reference database drawn from the World Anti-Doping Agency's 2024 Prohibited List, under hormone and metabolic modulators.

The agency's conclusion

“On balance, the physicochemical characterization, information on historical use, lack of any safety and effectiveness information in humans for both MOTS-c (free base) and MOTS-c acetate weigh against their being added to the 503A Bulks List.” Its slides for the meeting state: “FDA is proposing that MOTS-c (free base) and MOTS-c acetate NOT be included on the 503A Bulks List.”

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The July 2026 Advisory Committee Vote

The Pharmacy Compounding Advisory Committee, a panel of outside experts, met on 23–24 July 2026 to consider seven peptides. This peptide was taken on 23 July, for obesity and osteoporosis. For each form the question was whether it “be placed on the list”; as the chair explained, a yes vote meant “recommending FDA should place this bulk drug substance on the 503A bulk list.” The counts were read aloud “for the record” by the agency's meeting officer on the agency's own broadcast of the meeting (addresses in the U.S. Food and Drug Administration webcast information document):

• Free base: 7 yes, 5 no, 2 abstentions.
• Acetate: 7 yes, 5 no, 2 abstentions.

Fourteen members were eligible to vote on this topic according to the agency's final meeting roster, which matches the total. This was a narrower count than the 8 yes, 6 no and 1 abstention recorded for Body Protection Compound-157, Lysine-Proline-Valine and the thymosin beta-4 fragment, so news reports that gave a single 8–6 tally for all of them did not apply to this peptide. As of 14 November 2026 the agency had posted no written minutes or transcript of the meeting, so the broadcast is the record. Across the two days the committee recommended six of the seven peptides; it voted against only emideltide.

Advice, not a decision

The committee's votes ran against the agency staff's written proposal, which was not to list either form. The agency's meeting page explains that advisory committees “make non-binding recommendations to the FDA, which generally follows the recommendations but is not legally bound to do so.” An agency participant told the committee on 23 July that the staff recommendations “weren't final decisions. So the final decisions would come out through rulemaking.” As of 14 November 2026 the Federal Register held no proposed or final rule adding the peptide to the list or excluding it.

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The October 2026 Interim Compounding Policy

The U.S. Department of Health and Human Services announced its policy, headed “HHS Enforcement Discretion Policy Regarding 503A Compounding Using Certain Peptide Bulk Drug Substances,” in a Federal Register notice of availability published on 30 October 2026 (91 FR 68526–68527), signed by Secretary Robert F. Kennedy, Jr. The notice calls it a “draft” policy; the policy document calls itself an “interim policy.” The full policy is described on the peptide compounding enforcement-discretion policy page.

The terms in plain words

• 503A is the section of the Federal Food, Drug, and Cosmetic Act that lets state-licensed pharmacies, federal facilities and licensed physicians prepare (compound) a medicine for an individual patient's prescription without it going through drug approval.
• The 503A bulks list is the list, made by formal rulemaking, of raw ingredients that may be compounded when no official monograph or approved drug covers them.
• Enforcement discretion means the government states that it does not intend to take action against a practice that the law does not formally permit. It is not a permission or an approval.

What it covers for this peptide

The policy covers only the acetate form, identified as H-Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg-OH·CH₃COOH, formula C₁₀₁H₁₅₂N₂₈O₂₂S₂·CH₃COOH, 2234.64 g/mol. The free base is not covered. The covered routes are “subcutaneous or intramuscular injectable dosage forms” (under the skin or into muscle), made from an ingredient that comes with a certificate of analysis meeting the policy's conditions. Oral, topical and nasal forms of the peptide are not covered.

The ten conditions, grouped

1. The peptide is on the policy's list of six and matches the identity and routes it sets out.
2. The ingredient comes from a registered manufacturer that follows current good manufacturing practice, with a valid certificate of analysis covering identity, purity, strength and contaminants such as endotoxins, heavy metals and microbes. The policy's testing table includes an immunogenicity test in the laboratory.
3. The compounder reports serious adverse events (whether or not they seem drug-related) and quality problems to the agency's MedWatch program and to the states involved.
4. The label reads “This is a compounded drug product. Not for resale.” The product holds one active ingredient, and the only device packaged with it is a syringe cleared by the agency.
5. Every other requirement of the Act still applies, including a patient-specific prescription and clean (non-insanitary) preparation.

What the policy says about this peptide

The policy's Appendix B states that the agency's Center for Drug Evaluation and Research “recommended against listing either form,” that the committee “voted in favor of both forms,” and that the peptide was in Category 2 (the agency's list of substances that may present significant safety risks) “from September 29, 2023, until April 22, 2026,” adding that neither the placement nor the removal changed its status under section 503A. It justifies inclusion on three grounds: that historical use “is now documented and quantified”; that the “characterization record has materially changed” through batch-specific certificates from registered facilities; and, on safety, that “a randomized placebo-controlled trial of a MOTS-c analogue reported no serious adverse events at an exposure well above the compounded regimen.”

The policy does not name that trial or the data behind the first ground. An analogue is a chemically modified version of a peptide, not the same substance. No record of such a trial was found in PubMed for this page, and the U.S. Food and Drug Administration's briefing had found no human study of the peptide itself, so the trial is reported here only as the department's statement.

What it does not do

• It is not an approval. The policy states that “compounded drugs are not FDA-approved, which means FDA does not review their safety, effectiveness, or quality before they are marketed.”
• It does not put the peptide on the 503A bulks list; the notice states that future rulemaking “may propose adding some or all of these peptides.”
• It is not binding: the notice states it “does not establish any rights for any person and is not binding on HHS or the public.”
• It lasts only until a final rule decides whether the peptide is on the list, and the department “may revisit” it early “if, among other things, a safety signal or product quality issue arises.”
• It names only state-licensed pharmacies, federal facilities and licensed physicians. It does not mention outsourcing facilities (section 503B), and it does not mention patient consent.

Status on 14 November 2026

No effective date is stated in the notice or the policy. Comments were accepted in public docket HHS-OASH-2026-0496 until 13 November 2026 at 11:59 p.m. Eastern Time; the Federal Register's record showed about 289 comments received and regulations.gov showed 115 posted. No final version had been found. The agency's compounding-safety page, last updated in April 2026, still listed the peptide (as “MOTs-C”) among substances “nominated but withdrawn,” and no statement about the policy was found on the agency's website. The Associated Press reported on 28 October 2026, citing six people familiar with its development, that the agency's scientific staff had little input into the policy and opposed the changes; no primary document on that point was found.

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Safety Findings and Unknowns

• No human safety data on the synthetic peptide. The U.S. Food and Drug Administration found no clinical study by any route and no toxicity studies in animals. Its briefing concludes: “There is a lack of clinical and nonclinical safety information on the use of MOTS-c. FDA is particularly concerned about the lack of human data on drug products containing this substance administered via any route of administration.”
• Adverse event reports. Searches of the U.S. Food and Drug Administration Adverse Event Reporting System through 9 March 2025 “retrieved no reports” for the peptide. The agency's slides add that “the lack of reports for MOTS-c does not imply that the substance is safe or lacks toxicities,” and the briefing notes that compounders under section 503A “generally do not report adverse events to FDA.” Those searches ran more than a year before the May 2026 memo.
• Immunogenicity. Immunogenicity is the tendency of a substance to make the immune system produce antibodies against it. The agency states that at 16 amino acids the peptide raises a concern “for immunogenicity when administered by an injection ROA [route of administration] as proposed, due to the potential for aggregation, as well as potential peptide-related impurities,” and that injection under the skin is generally more likely to provoke antibodies than injection into a vein. Because the body makes this peptide itself, the agency points to a particular possibility: antibodies that block the injected peptide could also lead to “the neutralization of the activity of the endogenous peptide counterpart”, that is, block the body's own peptide. No study has measured whether this happens.
• Short life in blood. In human blood in a test tube the peptide was broken down rapidly into shorter pieces. Whether injected peptide reaches active levels in people is unknown.
• What is actually in products. The agency found the peptide marketed online on its own and mixed with other substances. No published laboratory analysis of products sold online under this name was found for this page. The policy of the U.S. Department of Health and Human Services gives as its reason the “continued, widespread use of certain research-use-only peptides supplied by foreign manufacturers that pose a safety risk to US patients.” Five warning letters the agency sent to online peptide sellers on 24 August 2026 concerned other products and did not name this peptide.
• Sport. The peptide is on the World Anti-Doping Agency's prohibited list, and the Cologne anti-doping laboratory's test also detects four of its breakdown products.

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What Is Not Known

• Whether the synthetic peptide does anything in people. No study has given it to humans, for any purpose, by any route.
• Whether injected peptide reaches the tissues in active form, since it breaks down quickly in human blood in a test tube and no absorption or clearance study exists in animals or people.
• How much of the peptide normal human blood carries. Reported levels differ by more than a hundredfold, and an anti-doping laboratory could not confirm antibody-kit results by mass spectrometry.
• Whether higher natural levels are good or bad. In the human studies the body's own levels rose with liver fat and with a fat infusion, which may reflect a response to metabolic stress rather than a protective excess.
• What the peptide binds to. The agency states that its molecular target “remains unknown.”
• Whether injections cause antibodies, and whether such antibodies could also block the body's own peptide.
• What impurities typical products contain, and what the “analogue” trial cited by the U.S. Department of Health and Human Services tested.
• Whether the U.S. Food and Drug Administration will propose adding the peptide to, or excluding it from, the 503A bulks list, and when; and what final form the interim policy will take.

Decisions about medicines, including compounded ones, belong with a clinician who knows the person's history.

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Key Research Papers

1. Lee C, Zeng J, Drew BG, Sallam T, Martin-Montalvo A, Wan J, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015;21(3):443-54. PubMed PMID: 25738459
2. Fuku N, Pareja-Galeano H, Zempo H, Alis R, Arai Y, Lucia A, et al. The mitochondrial-derived peptide MOTS-c: a player in exceptional longevity? Aging Cell. 2015;14(6):921-3. PubMed PMID: 26289118
3. 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(3):516-524.e7. PubMed PMID: 29983246
4. Kim SJ, Miller B, Mehta HH, Xiao J, Wan J, Arpawong TE, et al. The mitochondrial-derived peptide MOTS-c is a regulator of plasma metabolites and enhances insulin sensitivity. Physiol Rep. 2019;7(13):e14171. PubMed PMID: 31293078
5. Lu H, Wei M, Zhai Y, Li Q, Ye Z, Wang L, et al. MOTS-c peptide regulates adipose homeostasis to prevent ovariectomy-induced metabolic dysfunction. J Mol Med (Berl). 2019;97(4):473-485. PubMed PMID: 30725119
6. Hu BT, Chen WZ. MOTS-c improves osteoporosis by promoting osteogenic differentiation of bone marrow mesenchymal stem cells via TGF-β/Smad pathway. Eur Rev Med Pharmacol Sci. 2018;22(21):7156-7163. PubMed PMID: 30468456
7. Yan Z, Zhu S, Wang H, Wang L, Du T, Ye Z, et al. MOTS-c inhibits Osteolysis in the Mouse Calvaria by affecting osteocyte-osteoclast crosstalk and inhibiting inflammation. Pharmacol Res. 2019;147:104381. PubMed PMID: 31369811
8. Wei M, Gan L, Liu Z, Liu L, Chang JR, Yin DC, et al. Mitochondrial-Derived Peptide MOTS-c Attenuates Vascular Calcification and Secondary Myocardial Remodeling via Adenosine Monophosphate-Activated Protein Kinase Signaling Pathway. Cardiorenal Med. 2020;10(1):42-50. PubMed PMID: 31694019
9. Reynolds JC, Lai RW, Woodhead JST, Joly JH, Mitchell CJ, Cameron-Smith D, et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun. 2021;12(1):470. PubMed PMID: 33473109
10. Zempo H, Kim SJ, Fuku N, Nishida Y, Higaki Y, Wan J, et al. A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c. Aging (Albany NY). 2021;13(2):1692-1717. PubMed PMID: 33468709
11. Cataldo LR, Fernández-Verdejo R, Santos JL, Galgani JE. Plasma MOTS-c levels are associated with insulin sensitivity in lean but not in obese individuals. J Investig Med. 2018;66(6):1019-1022. PubMed PMID: 29593067
12. Sequeira IR, Woodhead JST, Chan A, D'Souza RF, Wan J, Hollingsworth KG, et al. Plasma mitochondrial derived peptides MOTS-c and SHLP2 positively associate with android and liver fat in people without diabetes. Biochim Biophys Acta Gen Subj. 2021;1865(11):129991. PubMed PMID: 34419510
13. Ramanjaneya M, Jerobin J, Bettahi I, Bensila M, Aye M, Siveen KS, et al. Lipids and insulin regulate mitochondrial-derived peptide (MOTS-c) in PCOS and healthy subjects. Clin Endocrinol (Oxf). 2019;91(2):278-287. PubMed PMID: 31066084
14. von Walden F, Fernandez-Gonzalo R, Norrbom J, Emanuelsson EB, Figueiredo VC, Gidlund EK, et al. Acute endurance exercise stimulates circulating levels of mitochondrial-derived peptides in humans. J Appl Physiol. 2021;131(3):1035-1042. PubMed PMID: 34351816
15. Knoop A, Thomas A, Thevis M. Development of a mass spectrometry based detection method for the mitochondrion-derived peptide MOTS-c in plasma samples for doping control purposes. Rapid Commun Mass Spectrom. 2019;33(4):371-380. PubMed PMID: 30394592
16. Zheng Y, Wei Z, Wang T. MOTS-c: A promising mitochondrial-derived peptide for therapeutic exploitation. Front Endocrinol (Lausanne). 2023;14:1120533. PubMed PMID: 36761202

PubMed Topic Searches

1. PubMed: MOTS-c
2. PubMed: MOTS-c, insulin resistance and obesity
3. PubMed: MOTS-c and exercise
4. PubMed: mitochondrial-derived peptides
5. PubMed: MOTS-c, bone and osteoporosis

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Connections

• Peptides — the six peptides in the 2026 compounding policy
• Peptide Compounding News — the 14 November 2026 news report
• Peptide Compounding Enforcement Discretion — the interim policy in full
• U.S. Food and Drug Administration Review of Compounded Peptides — the seven-peptide review and committee meeting
• Drugs — every drug page on the site
• Mitochondria — animation of the cell's energy compartments, where the peptide's code lies
• Insulin Resistance — the main effect studied in mice
• Obesity — one of the two uses the committee considered
• Osteoporosis — the other use the committee considered
• Type 2 Diabetes — linked in men to a variant of the peptide's gene
• Longevity — where the mouse lifespan results are often discussed
• Exercise — studied as a trigger of the body's own peptide
• Metformin — a diabetes drug that also acts on the energy-sensing enzyme
• Body Protection Compound-157 — another peptide in the same policy

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