MOTS-c

MOTS-c at a Glance

MOTS-c is a 16-amino-acid peptide encoded not by nuclear DNA but by the mitochondrial genome — one of a small group of mitochondrial-derived peptides discovered only in the last two decades. It acts as a signal from the mitochondria to the rest of the cell, activating AMPK and shifting metabolism toward glucose utilisation, which is why it is studied for insulin sensitivity and exercise capacity. It is investigational, injected as a research chemical, and on the WADA prohibited list.

History & Development

MOTS-c is encoded by the mitochondrial genome rather than the nucleus - a peptide written in the DNA of the cell’s power plants, discovered only after the human genome was supposedly complete.

First described	Not established in the sources consulted for this section
Discovered / synthesised by	Not established in the sources consulted for this section
Institution	Not established in the sources consulted for this section
Origin	Endogenous 16-amino-acid mitochondrial-derived peptide, encoded in the mitochondrial 12S rRNA open reading frame
Key patent	Not established in the sources consulted for this section
Assignee	Not established in the sources consulted for this section
Development status	Research chemical - never approved anywhere; on the WADA Prohibited List

Discovery

Mitochondria carry their own small genome, and it was long assumed to encode only the components of the respiratory chain. Mitochondrial-derived peptides overturned that: short open reading frames inside mitochondrial rRNA genes produce peptides that act as signalling molecules on the rest of the cell, and on the body.

MOTS-c is one, sixteen residues, encoded in the 12S rRNA region. Its biology is metabolic - insulin sensitivity and metabolic regulation - which made it immediately interesting as a candidate for diabetes and ageing. Humanin is the founding member of the same class.

Development & ownership

There is no corporate development programme. What exists is academic and preclinical.

One safety consideration follows directly from it being endogenous, and it is more subtle than the usual purity concern: because the body makes MOTS-c itself, an immune response to injected material could produce antibodies that neutralise the body’s own MOTS-c, not merely the injected dose. Subcutaneous administration carries higher immunogenicity risk than intravenous, and subcutaneous is the route the grey market uses.

Substance identity is also unresolved. Commercial acetate forms circulate with no UNII or CAS identifier - meaning there is no authoritative reference standard defining what is being sold.

There is zero toxicology in any species, and it is on the WADA Prohibited List under Hormone and Metabolic Modulators.

How it reached the market

MOTS-c moved from academic mitochondrial biology into the longevity peptide market on the strength of its metabolic mechanism, sold as an injectable for fat loss and metabolic health with no human trial, no toxicology and no settled chemical identity.

What It's Used For

MOTS-c (mitochondrial open reading frame of the 12S rRNA-c) is a 16-amino-acid mitochondrial-derived peptide — one of a small family of hormone-like microproteins (with humanin and the SHLPs) encoded not in the nucleus but within the mitochondrial genome, in this case inside the 12S rRNA gene. It behaves as a metabolic stress signal: under exercise or nutrient stress it moves to the nucleus and activates AMPK, the cell’s master energy sensor, shifting cells toward glucose uptake and stress resistance — which is why it is popularly framed as an “exercise mimetic.” The evidence posture is preclinical-first and should be read that way: essentially all therapeutic findings come from mice, rats, or cell culture. The strongest and most-replicated signal is metabolic (insulin sensitivity and diet-induced obesity in rodents); the emerging signal is that, for the first time, a peptide-administration human trial exists — a Phase 2a study in prediabetes began recruiting in 2026, with no results yet. Crucially, every completed human study to date measured the body’s own MOTS-c as a biomarker (it rises with exercise, falls in diabetes) — none tested giving MOTS-c as a drug. Route matters: like most peptides it is given by subcutaneous injection because oral bioavailability is negligible, so oral or topical products cannot be assumed to do anything.

Evidence by IndicationStrength of support · Beta

Support is an experimental score I’m building — a composite weighted by study type (human > animal > in vitro > review) and study volume. It’s a beta: a fast way to rank strength of evidence at a glance, not a validated metric. For a peptide like MOTS-c the ceiling is set by the fact that almost all administration data are in animals, so even the best-supported rows sit mid-scale while the human gap is stated in each toggle. Each application links down to its write-up.

01Insulin sensitivity & glucose metabolismPromising52%Foundational mouse + in-vitro, replicated rat models, clear AMPK mechanism; human biomarker/genotype signal; Phase 2 trial recruiting (no results) ^{1,6,10,12Reference 1Lee C et al. · 2015In vitroThe mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance — mouse / in vitroView study →Reference 6Ikonomidis I et al. · 2020ObservationalIkonomidis I, et al. (2020). β-Amyloid and mitochondrial-derived peptide-c are additive predictors of adverse outcome in type 2 diabetics with revascularized coronary artery disease — human cohort (biomarker). Journal of Thrombosis and Thrombolysis. https://pubmed.ncbi.nlm.nih.gov/32052315/View study →Reference 10Mills AR et al. · 2026AnimalMitochondrial peptide MOTS-c suppresses systemic and cardiac inflammasome activation in a diabetic rat model — ratView study →Reference 12Gao Y et al. · 2023ReviewMOTS-c functionally prevents metabolic disorders — reviewView study →}

02Obesity & metabolic syndromeShaky44%Diet-induced obesity reversed in mice; mechanistic reviews; no human efficacy data ^{1,12Reference 1Lee C et al. · 2015In vitroThe mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance — mouse / in vitroView study →Reference 12Gao Y et al. · 2023ReviewMOTS-c functionally prevents metabolic disorders — reviewView study →}

03Exercise mimetic & physical performanceShaky42%Mouse running-capacity; multiple human RCTs show exercise raises endogenous MOTS-c — not administration ^{1,2,3,5Reference 1Lee C et al. · 2015In vitroThe mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance — mouse / in vitroView study →Reference 2von Walden F et al. · 2021RCTAcute endurance exercise stimulates circulating levels of mitochondrial-derived peptides in humans — human randomised crossover (biomarker)View study →Reference 3Dieli-Conwright CM et al. · 2021RCTEffect of aerobic and resistance exercise on the mitochondrial peptide MOTS-c in Hispanic and Non-Hispanic White breast cancer survivors — human RCT (biomarker)View study →Reference 5Elhusseiny R et al. · 2025RCTRepeated heat stress modulates the levels of the mitokines MOTS-c and FGF21 in active men during calf muscle immobilization — human RCT (biomarker)View study →}

04Cardiovascular & cardiac protectionShaky40%Rat ischemia-reperfusion, diabetic cardiomyopathy, atrial fibrillation, neonatal-hyperoxia models; human biomarker inverse-association in CAD ^{6,10,11,18,19Reference 6Ikonomidis I et al. · 2020ObservationalIkonomidis I, et al. (2020). β-Amyloid and mitochondrial-derived peptide-c are additive predictors of adverse outcome in type 2 diabetics with revascularized coronary artery disease — human cohort (biomarker). Journal of Thrombosis and Thrombolysis. https://pubmed.ncbi.nlm.nih.gov/32052315/View study →Reference 10Mills AR et al. · 2026AnimalMitochondrial peptide MOTS-c suppresses systemic and cardiac inflammasome activation in a diabetic rat model — ratView study →Reference 11Santhanam SS et al. · 2026AnimalMOTS-c preserves mitochondrial subpopulation bioenergetics and genome integrity to attenuate cardiac ischemia reperfusion injury — rat (ex-vivo Langendorff)View study →Reference 18Liao Y et al. · 2026In vitroHumanin and MOTS-c attenuate atrial fibrillation by suppressing fibrosis and mitochondrial dysfunction — rodent / in vitroView study →Reference 19Li SH et al. · 2026AnimalMOTS-c attenuates hyperoxia-induced neonatal cardiac injury by inhibiting oxeiptosis via maintaining the KEAP1-PGAM5 interaction — mouseView study →}

05Bone metabolism & bone painShaky36%Mouse cancer bone-pain model; osteoblast/osteoclast in-vitro + review ^{7,8Reference 7Yi X et al. · 2023ReviewRole of MOTS-c in the regulation of bone metabolism — reviewView study →Reference 8Yang L et al. · 2024AnimalMOTS-c is an effective target for treating cancer-induced bone pain through AMPK-mediated mitochondrial biogenesis — mouseView study →}

06Sarcopenia & muscle wastingShaky34%Mouse nanocomposite & C26-cachexia models; human K14Q genotype–sarcopenia association ^{13,14,17Reference 13Liu Z et al. · 2026AnimalMuscle-targeted nanocomposite therapy alleviates age-related sarcopenia via antioxidant and metabolic reprogramming — mouse (BP-PEG-MOTS-c)View study →Reference 14Jamnick NA et al. · 2026In vitroMOTS-c partially protects against skeletal muscle deterioration in C26 cachexia — mouse / in vitroView study →Reference 17Kim S et al. · 2024ObservationalThe relationship between MOTS-c K14Q polymorphism and sarcopenia, blood lipids, and mental health in older Korean adults — human cross-sectional (genotype)View study →}

07Liver protectionShaky32%Mouse acetaminophen/NASH injury models; reviews; no human data ^{15Reference 15Amado CA et al. · 2026ReviewMOTS-c: how a secreted mitochondrial microprotein may become a potential treatment for inflammatory lung diseases — reviewView study →}

08Inflammatory lung diseaseShaky30%Mouse radiation-pneumonitis model; review notes reduced circulating MOTS-c in ARDS ^{9,15Reference 9Zhang Y et al. · 2024AnimalThe mitochondrial-derived peptide MOTS-c alleviates radiation pneumonitis via an Nrf2-dependent mechanism — mouseView study →Reference 15Amado CA et al. · 2026ReviewMOTS-c: how a secreted mitochondrial microprotein may become a potential treatment for inflammatory lung diseases — reviewView study →}

09Aging & longevityShaky26%Human K14Q/longevity genotype associations + mechanism; no controlled-administration data — largely inferred ^{17Reference 17Kim S et al. · 2024ObservationalThe relationship between MOTS-c K14Q polymorphism and sarcopenia, blood lipids, and mental health in older Korean adults — human cross-sectional (genotype)View study →}

Mechanisms

Pharmacokinetics

MOTS-c is a 16-residue peptide, so like most peptides its oral bioavailability is negligible — it would be digested before absorption. In animal studies it is delivered by injection (intraperitoneal in most rodent work; subcutaneous in the human Phase 2 protocol), and the recruiting human trial uses a fixed once-daily subcutaneous dose [NCT07505745]. Circulating MOTS-c is measurable as an endogenous hormone by ELISA and rises acutely with exercise and heat stress and chronically with training ^{2,5Reference 2von Walden F et al. · 2021RCTAcute endurance exercise stimulates circulating levels of mitochondrial-derived peptides in humans — human randomised crossover (biomarker)View study →Reference 5Elhusseiny R et al. · 2025RCTRepeated heat stress modulates the levels of the mitokines MOTS-c and FGF21 in active men during calf muscle immobilization — human RCT (biomarker)View study →}, indicating active regulation and clearance, but formal human pharmacokinetic parameters — half-life, distribution, clearance route — are not established in the public literature; the peptide is expected to be short-lived in plasma as small peptides generally are. This expectation now has a concrete data point behind it: reviewing the field in 2026, FDA reported that it could identify no in-vivo pharmacokinetic or toxicokinetic study of MOTS-c in any species, and that the only PK-relevant work it found was an in-vitro experiment incubating MOTS-c with human whole blood, in which the peptide was rapidly hydrolyzed from the N-terminus into the shorter fragments MOTS-c(2–16), (3–16), (4–16) and (5–16) — degradation the authors described as fast and not requiring long incubation. FDA drew the obvious inference and left it open: “It remains to be determined whether exogenous administration of MOTS-c to humans can generate pharmacologically active concentrations of the peptide over time.” That is a live question about whether injected MOTS-c can work at all, not merely about how it is dosed. Research-grade material is supplied as a lyophilized powder requiring reconstitution (typically in bacteriostatic water) and refrigerated storage after reconstitution. Because activity is tied to parenteral delivery, oral, nasal, or topical “MOTS-c” products cannot be assumed to reproduce the injected-peptide findings.

Clinical & regulatory status

MOTS-c is not an approved drug anywhere — it has no FDA, EMA, TGA, or PMDA approval and is not an approved dietary supplement; it is sold as an unapproved research chemical (“not for human consumption”). It is not a scheduled/controlled substance. For most of its history the only human data were observational: studies measuring endogenous MOTS-c as a biomarker of exercise, diabetes, cardiovascular risk, drug treatment and aging ^{2,3,4,5,6,17Reference 2von Walden F et al. · 2021RCTAcute endurance exercise stimulates circulating levels of mitochondrial-derived peptides in humans — human randomised crossover (biomarker)View study →Reference 3Dieli-Conwright CM et al. · 2021RCTEffect of aerobic and resistance exercise on the mitochondrial peptide MOTS-c in Hispanic and Non-Hispanic White breast cancer survivors — human RCT (biomarker)View study →Reference 4Cuyàs E et al. · 2022RCTCirculating levels of MOTS-c in patients with breast cancer treated with metformin — human RCT (biomarker)View study →Reference 5Elhusseiny R et al. · 2025RCTRepeated heat stress modulates the levels of the mitokines MOTS-c and FGF21 in active men during calf muscle immobilization — human RCT (biomarker)View study →Reference 6Ikonomidis I et al. · 2020ObservationalIkonomidis I, et al. (2020). β-Amyloid and mitochondrial-derived peptide-c are additive predictors of adverse outcome in type 2 diabetics with revascularized coronary artery disease — human cohort (biomarker). Journal of Thrombosis and Thrombolysis. https://pubmed.ncbi.nlm.nih.gov/32052315/View study →Reference 17Kim S et al. · 2024ObservationalThe relationship between MOTS-c K14Q polymorphism and sarcopenia, blood lipids, and mental health in older Korean adults — human cross-sectional (genotype)View study →}. That changed in 2026 with the first interventional study to administer the peptide: a Phase 2a, randomized, double-blind, placebo-controlled trial of daily subcutaneous MOTS-c in adults with prediabetes and overweight/obesity (industry-sponsored, n≈120, primary endpoint OGTT-derived insulin sensitivity at 12 weeks), currently recruiting with results estimated in 2027 [NCT07505745]. No efficacy or safety results from peptide administration have yet been published.

A second regulatory thread opened in 2026. FDA evaluated MOTS-c free base and MOTS-c acetate for the section 503A Bulks List — the substances compounding pharmacies may legally compound from — and its briefing document, published ahead of the Pharmacy Compounding Advisory Committee meeting of 23–24 July 2026, concludes that a balancing of the criteria weighs against listing either form, proposing that neither be added. The committee has not yet voted, and FDA will not issue a final determination until that process concludes, so this is the agency’s stated pre-meeting position rather than a final rule. The reasoning is an inventory of absences — no clinical studies or human exposure data by any route, no toxicology of any kind in any species, no in-vivo pharmacokinetics, no USP/EP/JP monograph, no Ema-authorized product, and no recorded outsourcing-facility compounding between 2017 and 2025 — and is set out in Sourcing, Route & Legal Status below. MOTS-c is also a prohibited substance under the WADA Prohibited List (Hormone and Metabolic Modulators).

Last checked: 18 July 2026.

Sourcing, Route & Legal Status

Regulatory status. MOTS-c is not an approved drug or dietary supplement in any jurisdiction — it has no FDA, EMA, TGA, or PMDA approval, and no monograph as a supplement ingredient. It is sold by peptide vendors as a research chemical labeled “not for human consumption,” a designation that lets it be distributed without the manufacturing, purity, or safety oversight that applies to medicines. It is not a scheduled or controlled substance. The only regulated human use is inside a clinical trial: a Phase 2a study now administering MOTS-c under an investigational protocol [NCT07505745]. Being an endogenous human peptide does not make the injected research-grade product a supplement — it is an unapproved investigational agent sold ahead of approval.

FDA’s 2026 evaluation — pending before an advisory committee. In May 2026 FDA published a briefing document evaluating MOTS-c-related bulk drug substances (MOTS-c free base and MOTS-c acetate) for the section 503A Bulks List — the list of substances compounding pharmacies are permitted to work from — ahead of the Pharmacy Compounding Advisory Committee meeting of 23–24 July 2026 (FDA briefing document). FDA’s evaluation, published ahead of that meeting, concludes that “a balancing of the criteria weighs against” adding either substance, and proposes not adding them; the committee has not yet voted, and FDA states it will not issue a final determination until the advisory process is complete and all reviews are finalized. The finding should be read as the agency’s pre-meeting position, not a settled rule. What makes the document unusually valuable is that it is a systematic search by a regulator, and it reports what it failed to find:

• No human data of any kind, by any route. In FDA’s words: “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.” It found no clinical pharmacokinetic data either.
• No toxicology whatsoever. FDA identified no acute toxicity, no repeat-dose toxicity, no genotoxicity, no developmental or reproductive toxicity, and no carcinogenicity study of MOTS-c free base or acetate — in any species, by any route — and no in-vivo PK/TK study. The absence is total, not partial.
• Zero adverse-event reports. Searches of the FDA Adverse Event Reporting System (FAERS) through 28 February 2024, and again from 26 February 2024 through 9 March 2025, retrieved no reports. FDA notes this is uninformative rather than reassuring — 503A compounders generally do not report adverse events to FDA.
• Zero recorded compounding. Outsourcing facilities reported preparing no single- or multi-ingredient compounded products containing MOTS-c or MOTS-c acetate from January 2017 to December 2025, and FDA found no published study in which a compounded MOTS-c product was used in a human. Despite this, the withdrawn nomination answered “YES” to whether the substance had previously been used to compound drug products, and supplied no historical-use data.
• No monograph, no foreign authorization. There is no USP or NF drug substance monograph; searches of the European Pharmacopoeia (11.5, 2024) and Japanese Pharmacopoeia (18th ed.) returned nothing; and the European Medicines Agency lists no authorized product containing MOTS-c.
• It is a banned substance in sport. MOTS-c appears as a prohibited substance in the Global Drug Reference Online database, drawn from the 2024 World Anti-Doping Agency Prohibited List under Hormone and Metabolic Modulators. Anyone subject to anti-doping testing should treat it accordingly.

FDA draws the same biomarker-versus-administration line. The nomination — submitted by Wells Pharmacy Network, for insulin resistance, obesity, osteoporosis, vascular calcification, muscle/fat metabolism and longevity, as 5 mg and 10 mg lyophilized vials for subcutaneous injection — was later withdrawn, though FDA continued the evaluation on its own initiative. FDA records that the nomination “cited 12 literature references in support of the nomination; these did not include clinical studies,” and that its own search found no study administering MOTS-c to humans. The substitution is visible in the nomination itself: asked directly whether there were safety and efficacy data on compounded drugs using the nominated substance, the nominator listed rodent and in-vitro papers, a human genotype-association paper asking whether MOTS-c is “a player in exceptional longevity,” and a paper on hepatic mitochondrial dysfunction and diet-induced insulin resistance that is not about MOTS-c at all. None of these is evidence that injecting the peptide does anything in a person. FDA declined to evaluate the six proposed uses at all, on the grounds that the nomination lacked sufficient information and that it identified no clinical studies of those uses. Its reviewers add two limits that constrain even the animal case: the rodent studies never assessed dose–response in vivo, and because the molecular target of MOTS-c remains unknown, “it is difficult to predict which organs might be targeted and affected.”

FDA’s chemistry and immunogenicity findings. Both forms were judged not well-characterized. MOTS-c is a common name, not a USAN, and FDA warns that inconsistent naming across suppliers means a patient “may be dosed with a different BDS than the physician ordered”; the free base (CAS 1627580-64-6, UNII A5CV6JFB78) and the acetate salt are chemically distinct substances, but the acetate has no UNII of its own and is sold commercially under the free base’s CAS number. The nomination’s own paperwork was internally inconsistent — the certificate of analysis named one substance in its title and a different one by CAS number. Vendor certificates typically report purity and little else: FDA found no testing results for impurities, aggregates, microbial bioburden or bacterial endotoxin in either the nominator-supplied CoA or the CoAs it located in the wild, and endotoxin testing is a critical control for an injectable. On that basis FDA states it cannot rule out immunogenicity from peptide-related impurities and aggregates, and notes that the subcutaneous route carries higher immunogenicity risk than intravenous. One consequence is specific to an endogenous peptide like this one: an immune response to injected MOTS-c could produce neutralizing antibodies that neutralize the activity of the body’s own MOTS-c — a risk that has no counterpart for a foreign small molecule. (FDA’s literature searches for this document ran to early 2025, and the document does not mention the Phase 2a trial [NCT07505745], which registered later; the two are consistent — as of the evaluation, no completed or reported human administration data existed.)

How it’s supplied & administered. Research MOTS-c is shipped as a lyophilized (freeze-dried) powder that must be reconstituted before use — typically with bacteriostatic or sterile water — and kept refrigerated once reconstituted. The route is subcutaneous injection (the human trial uses fixed once-daily SC dosing; rodent studies mostly used intraperitoneal injection). This is not optional chemistry: as a 16-amino-acid peptide, MOTS-c has negligible oral bioavailability — it is broken down in the gut — so oral capsules, sublingual drops, nasal sprays, or topical creams marketed as “MOTS-c” cannot be assumed to deliver active peptide, and no data support those formats.

Sourcing reality (a safety issue). Because MOTS-c sits outside the regulated drug and supplement systems, every quality risk falls on the buyer. Unregulated vendors vary widely in purity; independent testing of the gray-market peptide sector routinely finds under-dosing, mislabeling, wrong or degraded peptides, and bacterial endotoxin contamination — a particular hazard for an injectable product, where contaminants bypass the gut and enter the bloodstream directly. There is no manufacturing oversight, no guarantee of sterility, and no batch accountability. Third-party certificates of analysis (identity by mass spec, purity by HPLC, endotoxin testing) are the only partial check available, and even those can be faked. This monograph does not recommend or link vendors; the sourcing environment is itself a reason for caution independent of the peptide’s pharmacology.

Safety

There is no human safety data from administering MOTS-c at all — the first interventional trial is still recruiting — and no toxicology study in any species. Everything known comes from short rodent pharmacology experiments and from the mechanism, which is not the same thing as a safety record.

Safety at a Glance

❔ Toxicity unknown

• No human safety data, and no toxicology in any species. No acute, repeat-dose, genotoxicity, reproductive or carcinogenicity study of MOTS-c exists.
• Avoid in pregnancy and breastfeeding. Not assessed — see the box below.
• An unregulated injectable. Under-dosing, mislabeling, degraded peptide and bacterial endotoxin are routine findings in the gray-market sector, and contaminants enter the bloodstream directly.
• Possible additive glucose-lowering. Inferred from AMPK activation, not demonstrated — a hypoglycemia concern for anyone on insulin or sulfonylureas.

Full Safety & Interactions Detail

What’s actually known. There is no human safety data from administering MOTS-c — the only interventional trial is still recruiting, so its safety readout (treatment-emergent adverse events, a co-primary endpoint) does not yet exist [NCT07505745]. Everything below is therefore drawn from animal studies and from the peptide’s mechanism/class, and is labeled as such.

• Animal tolerability. In rodent studies MOTS-c has generally been well tolerated at the doses used (typically intraperitoneal), with the reported effects being metabolic and anti-inflammatory rather than toxic. No characteristic organ toxicity or dose-limiting toxicity has been described — but these are short-term animal experiments, not safety studies, and absence of reported harm is not evidence of safety. FDA’s 2026 review confirms this positively: it identified no acute, repeat-dose, genotoxicity, developmental/reproductive or carcinogenicity study of MOTS-c in any species. The rodent literature is pharmacology, not toxicology; the toxicology simply does not exist.
• Mechanism-based cautions. MOTS-c activates AMPK and improves insulin sensitivity, so a plausible (untested) concern is additive glucose-lowering if combined with insulin, sulfonylureas, or other glucose-lowering agents — i.e., risk of hypoglycemia in someone already on antidiabetic medication. This is inferred from mechanism, not demonstrated in an interaction study.
• Injection-specific risks. As a reconstituted injectable of unregulated origin, the dominant real-world risks are not the peptide itself but the delivery: injection-site reactions, infection from non-sterile technique or contaminated product, and systemic reaction to endotoxin in impure material. These are sourcing/administration hazards, present regardless of the molecule’s pharmacology.
• Who should avoid it. Anyone pregnant or breastfeeding; anyone on glucose-lowering therapy without medical supervision; and, in general, anyone unwilling to accept that this is an untested investigational peptide from an unregulated supply.

Scope disclosure (not a claim):

• Human data? None from administration — human evidence is biomarker/genotype observation only; the first administration trial (Phase 2a) is ongoing with no results.
• Interactions assessed? No formal interaction studies. The glucose-lowering-drug interaction noted above is inferred from mechanism, not tested.
• Pregnancy/lactation assessed? No. Not studied; avoid.
• Long-term safety established? No. There are no long-term or repeat-dose human safety data. Do not infer safety from the absence of reports — the peptide simply has not been studied in humans over time.

Never imply safety from silence. Where MOTS-c “wasn’t studied,” that is stated rather than treating no-news as good-news.

Pregnancy & Lactation

? Not established in pregnancy? Not established in lactation

Not assessed / not established. There are no human or dedicated animal reproductive-safety studies of administered MOTS-c, and no label statement exists. Should be avoided in pregnancy and lactation on the default-caution principle for unapproved peptides.

Dosage

There is no established human dose for MOTS-c, and none is recommended here. It is not an approved supplement or drug, and every figure below is research data reported for context, not a personal recommendation — do not read it as a protocol.

No human dose has ever been validated. The single interventional human study administers a fixed once-daily subcutaneous dose × 12 weeks, but the numeric amount is not public in the trial registration [NCT07505745], so there is no defensible human figure to quote. Preclinical work used injection (mostly intraperitoneal in rodents), and those animal doses do not translate to a human amount. The gray-market “research peptide” circulates as a lyophilized powder with vendor-suggested reconstitution and injection amounts, but these are not derived from any human trial and should not be treated as a dose. Because oral bioavailability is negligible, any oral, sublingual, or topical “MOTS-c” product has no basis for a dose at all (see Sourcing, Route & Legal Status). This entry is informational only.

References

1. Lee C, Zeng J, Drew BG, et al. (2015). The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance — mouse / in vitro. Cell Metabolism. https://pubmed.ncbi.nlm.nih.gov/25738459/
2. von Walden F, et al. (2021). Acute endurance exercise stimulates circulating levels of mitochondrial-derived peptides in humans — human randomised crossover (biomarker). Journal of Applied Physiology. https://pubmed.ncbi.nlm.nih.gov/34351816/
3. Dieli-Conwright CM, et al. (2021). Effect of aerobic and resistance exercise on the mitochondrial peptide MOTS-c in Hispanic and Non-Hispanic White breast cancer survivors — human RCT (biomarker). Scientific Reports. https://pubmed.ncbi.nlm.nih.gov/34413391/
4. Cuyàs E, et al. (2022). Circulating levels of MOTS-c in patients with breast cancer treated with metformin — human RCT (biomarker). Aging (Albany NY). https://pubmed.ncbi.nlm.nih.gov/36490309/
5. Elhusseiny R, et al. (2025). Repeated heat stress modulates the levels of the mitokines MOTS-c and FGF21 in active men during calf muscle immobilization — human RCT (biomarker). Medicine & Science in Sports & Exercise. https://pubmed.ncbi.nlm.nih.gov/40674654/
6. Ikonomidis I, et al. (2020). β-Amyloid and mitochondrial-derived peptide-c are additive predictors of adverse outcome in type 2 diabetics with revascularized coronary artery disease — human cohort (biomarker). Journal of Thrombosis and Thrombolysis. https://pubmed.ncbi.nlm.nih.gov/32052315/
7. Yi X, et al. (2023). Role of MOTS-c in the regulation of bone metabolism — review. Frontiers in Physiology. https://pubmed.ncbi.nlm.nih.gov/37200834/
8. Yang L, et al. (2024). MOTS-c is an effective target for treating cancer-induced bone pain through AMPK-mediated mitochondrial biogenesis — mouse. Acta Biochimica et Biophysica Sinica. https://pubmed.ncbi.nlm.nih.gov/38716540/
9. Zhang Y, et al. (2024). The mitochondrial-derived peptide MOTS-c alleviates radiation pneumonitis via an Nrf2-dependent mechanism — mouse. Antioxidants (Basel). https://pubmed.ncbi.nlm.nih.gov/38790718/
10. Mills AR, et al. (2026). Mitochondrial peptide MOTS-c suppresses systemic and cardiac inflammasome activation in a diabetic rat model — rat. Experimental Physiology. https://pubmed.ncbi.nlm.nih.gov/42321010/
11. Santhanam SS, et al. (2026). MOTS-c preserves mitochondrial subpopulation bioenergetics and genome integrity to attenuate cardiac ischemia reperfusion injury — rat (ex-vivo Langendorff). Molecular Biology Reports. https://pubmed.ncbi.nlm.nih.gov/42228044/
12. Gao Y, et al. (2023). MOTS-c functionally prevents metabolic disorders — review. Metabolites. https://pubmed.ncbi.nlm.nih.gov/36677050/
13. Liu Z, et al. (2026). Muscle-targeted nanocomposite therapy alleviates age-related sarcopenia via antioxidant and metabolic reprogramming — mouse (BP-PEG-MOTS-c). ACS Nano. https://pubmed.ncbi.nlm.nih.gov/41468174/
14. Jamnick NA, et al. (2026). MOTS-c partially protects against skeletal muscle deterioration in C26 cachexia — mouse / in vitro. Frontiers in Medicine. https://pubmed.ncbi.nlm.nih.gov/42266945/
15. Amado CA, et al. (2026). MOTS-c: how a secreted mitochondrial microprotein may become a potential treatment for inflammatory lung diseases — review. Journal of Translational Medicine. https://pubmed.ncbi.nlm.nih.gov/42243958/
16. Xing L, et al. (2026). Mitochondrial-derived peptide MOTS-c activates metabolic signaling but blunts reparative function in human mesenchymal stromal cells — human cells, in vitro. Inflammation and Regeneration. https://pubmed.ncbi.nlm.nih.gov/42324588/
17. Kim S, et al. (2024). The relationship between MOTS-c K14Q polymorphism and sarcopenia, blood lipids, and mental health in older Korean adults — human cross-sectional (genotype). Biomedicines. https://pubmed.ncbi.nlm.nih.gov/39457696/
18. Liao Y, et al. (2026). Humanin and MOTS-c attenuate atrial fibrillation by suppressing fibrosis and mitochondrial dysfunction — rodent / in vitro. Biomedicines. https://pubmed.ncbi.nlm.nih.gov/42193373/
19. Li SH, et al. (2026). MOTS-c attenuates hyperoxia-induced neonatal cardiac injury by inhibiting oxeiptosis via maintaining the KEAP1-PGAM5 interaction — mouse. Life Sciences. https://pubmed.ncbi.nlm.nih.gov/42128272/

View all 19 references▾

Registered trials (ClinicalTrials.gov)

• NCT07505745 — A Phase 2a randomised, double-blind, placebo-controlled study of subcutaneous MOTS-c for insulin sensitivity in prediabetes (daily SC × 12 weeks; n≈120; primary endpoint OGTT-derived insulin sensitivity; recruiting, primary completion est. 2027). The first trial to administer MOTS-c; no results posted. https://clinicaltrials.gov/study/NCT07505745