MOTS-c is a 16-amino-acid peptide encoded by mitochondrial DNA that acts like an exercise signal, activating AMPK and improving glucose handling in rodents. Human evidence is thin: the only completed trial tested an analog (CB4211) in a Phase 1 study, where liver enzymes improved but the liver-fat imaging endpoint did not beat placebo. A Phase 2 trial of native MOTS-c in prediabetes started recruiting in 2026. Everything else is rodent data and observational correlations.
Summary drafted from this entry’s sources; editorial review pending.
01Key questions
Has MOTS-c been tested in humans?
Not directly, until now. The only completed trial (Phase 1a/1b) tested CB4211, a synthetic analog, in obese NAFLD subjects: ALT and AST improved but the MRI liver-fat endpoint did not separate from placebo, and the results were never peer-reviewed. A Phase 2 trial of native MOTS-c in prediabetes (NCT07505745, n=120) began recruiting in February 2026.1
Does MOTS-c work for insulin sensitivity and weight?
In mice, yes: it prevents high-fat-diet weight gain, restores insulin sensitivity, protects islet cells from senescence, and improves muscle mitochondrial function through PGC-1a/AMPK. In humans, low MOTS-c levels correlate with prediabetes, obesity and age, but no completed trial shows benefit.58
How does MOTS-c work?
It is encoded in mitochondrial DNA but translated in the cytosol; under metabolic stress it moves to the nucleus and turns on antioxidant genes via NRF2. It activates AMPK, which improves glucose uptake, and inhibits inflammatory MAPK and TGF-beta signaling.25
Is MOTS-c legal and is it safe?
It is not FDA-approved, and FDA staff proposed keeping it off the 503A compounding list, citing missing characterization data and no human clinical studies. WADA lists it as a prohibited hormone and metabolic modulator. In the analog's Phase 1 trial there were no serious adverse events; injection-site reactions were common.14
What would change this rating?
NCT07505745, the first randomized trial of native MOTS-c for insulin sensitivity (n=120, primary completion expected February 2027). A positive result would strengthen the case; a placebo-level result would repeat the analog's failed imaging endpoint.1
Aliases: Mitochondrial ORF of the 12S rRNA Type-C, Mitochondrial-derived peptide MOTS-c Sequence: MRWQEMRIFYLRKLF (16 amino acids) — encoded by mitochondrial 12S rRNA gene Molecular Weight: ~2.1 kDa Origin: Mitochondrial-derived peptide (MDP) — encoded by mitochondrial DNA, translated in cytoplasm
02Overview
MOTS-c is a mitochondrial-derived peptide of 16 amino acids encoded by the mitochondrial 12S rRNA gene — one of a small family of mtDNA-encoded signaling microproteins (Humanin, SHLP1–6, SHMOOSE). Discovered in 2015 in the Pinchas Cohen / Changhan Lee labs at USC, it established the concept of a mitochondrial genome-encoded signal that regulates nuclear gene expression and systemic metabolism.
Functionally it behaves as an "exercise mimetic": skeletal muscle MOTS-c rises ~12-fold after exercise, and treatment recapitulates exercise-like metabolic adaptations (AMPK activation, improved glucose handling) in rodents.
Evidence Level (2026): Moderate — strong preclinical data, human observational correlations, one completed Phase 1a/1b trial of an analog (CB4211), and — as of February 2026 — a first Phase 2 trial of native MOTS-c itself in prediabetes, recruiting (NCT07505745). The July 23-24 2026 PCAC meeting produced an FDA briefing that proposes against placing MOTS-c (free base) or MOTS-c acetate on the 503A Bulks List for obesity/osteoporosis — see FDA Peptide Reclassification 2026 — Regulatory Intelligence for the compounding-pharmacy context.
03Mechanism of Action
Unique Biology
- Translation: in the cytosol (not mitochondria) — the polyadenylated 12S rRNA transcript is exported because sORF uses mitochondrial-specific codons
- Trafficking: resting state — mitochondrial; under metabolic stress — translocates to the nucleus in an AMPK-dependent manner
- Nuclear action: binds ARE-regulated transcription factors → upregulates antioxidant/stress-response genes (NRF2 axis)
- Conservation: first 11 residues conserved across 14 mammalian species
Key Pathways
- AMPK activation → enhanced glucose uptake, insulin sensitivity, folate-cycle inhibition → AICAR-like metabolic stress response
- Akt → positive feedback in skeletal muscle
- NRF2 → mitochondrial protective gene expression
- MAPK inhibition (ERK/JNK/p38) → anti-inflammatory
- TGF-β pathway inhibition — reported in ovariectomy-model bone loss (PMID 26861024)
Exercise Response (Human Data — Reynolds 2021, Nat Commun, PMC8228264)
| Tissue | Change | Timecourse |
|---|---|---|
| Skeletal muscle (endogenous) | 11.9-fold increase post-exercise | Elevated ≥4 h |
| Plasma | 1.6-fold during, 1.5-fold after exercise | Back to baseline by ~4 h |
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04Clinical Evidence
Human Interventional Data — NEW (2021–2026)
CB4211 (synthetic MOTS-c analog, CohBar) — the only completed interventional human data - NCT03998514 (Phase 1a/1b, completed): ~88 subjects in ascending-dose Ph1a in healthy volunteers; Ph1b in obese NAFLD subjects — 25 mg SC daily × 28 days (n=11) vs placebo (n=9) - Safety: primary endpoint met; no SAEs; injection-site reactions common (trial paused 2018 to amend protocol after persistent painless injection-site nodules) - Biomarkers: ALT −21% (placebo +4%), AST −28% (placebo −11%), glucose −6% vs placebo — all p<0.05 (topline, Aug 2021 press release; Loomba quote) - Caveat: primary imaging endpoint (MRI-PDFF liver fat) −5.03% vs −4.88% placebo — NOT separated from placebo. Biomarkers moved; the disease-relevant measure did not. Program discontinued before Phase 2 when CohBar hit financial trouble (assets later acquired by Molexus, 2024) — treat the topline "positive" framing with skepticism. - Press-release data only; never published in a peer-reviewed journal.
Native MOTS-c Phase 2 (first ever) — NCT07505745 - "MOTS-c for Improving Insulin Sensitivity in Adults With Prediabetes and Overweight/Obesity" - Phase 2, randomized, n=120 estimated, started 2026-02-02, recruiting, primary completion Feb 2027 - Primary endpoints: change in OGTT-derived insulin sensitivity (Matsuda Index); TEAE incidence - Secondary: HbA1c, fasting glucose, 2-h OGTT glucose - This is the first randomized trial of the native peptide in a metabolic indication — a genuine inflection point for the evidence base. Results expected ~2027.
Human Observational Data
- Prediabetes/diabetes correlation: plasma MOTS-c inversely associated with fasting insulin, HbA1c, BMI (meta-analysis: Diabetology & Metabolic Syndrome 16:197, 2024; PROSPERO CRD42021248167)
- Obese children (5–14 y): ~20% lower MOTS-c vs lean controls
- Aging: young adults ~11% higher than middle-aged, ~21% higher than elderly
- Exceptional longevity: MOTS-c m.1382A>C polymorphism enriched in Japanese centenarians (Fuku 2015–2016, Aging Cell); generalizability to other populations unclear
Key Preclinical Studies (2025 additions)
- Diabetes prevention (Kong et al., Exp Mol Med 57:1861–1877, 2025, open access): MOTS-c reduced pancreatic islet/β-cell senescence in three mouse models; suppressed Cdkn1a, Cdkn2a, Cxcl10, Il-1b; human islet data included
- Diabetic heart (Pham et al., Front Physiol 16:1602271, 2025): restored mitochondrial respiration/ATP and reduced ROS in type-2-diabetic rat myocardium — perfused-heart model
- Sepsis brain injury (Bai et al., 2025): protection against LPS-induced sepsis-associated brain injury
- Insulin sensitivity rescue: 7 days of MOTS-c restored old-mouse insulin sensitivity to young-mouse levels
- HFD protection: prevents weight gain/hyperinsulinemia on high-fat diet without effect on chow-fed mice
Key Preclinical Studies (2026 additions)
- Skeletal-muscle bioenergetics (Gudiksen A et al., Free Radic Biol Med 246:682–696, Jan 2026, PMID 41520850): MOTS-c improves intrinsic muscle mitochondrial bioenergetic health and efficiency in a PGC-1α/AMPK-dependent manner (mouse model, University of Copenhagen, Novo Nordisk Foundation–funded). Mechanism-level confirmation that the exercise-mimetic effect is intrinsic to muscle mitochondria, not merely a systemic AMPK read-out.
- Bone health (Qin Z et al., Cell Mol Life Sci 2025, doi 10.1007/s00018-025-05802-w): review of mitochondrial quality-control in bone; cites MOTS-c for PGC-1α induction in primary osteoblasts and osteoblast-senescence suppression that promotes bone healing in osteoporotic mice — consistent with the AMPK–RANKL axis originally reported by Hu & Chen 2018 (PMID 30387425) and the OVX model.
- Russian-language review (Bobylev AG, Nekrasov PV, Human Physiology 52(2):280, 2026): "Mitochondrial Peptide MOTS-c: Regulation of Metabolism and Prospects for Clinical and Sports Medicine Applications" — independent clinical/sports-medicine synthesis (no new primary data).
Delivery / Probiotic Engineering
- No established clinical delivery route beyond SC injection; USC group proposed synthetic-biology MOTS-c expression in probiotics (Lactobacillus, E. coli Nissle 1917)
05Primary Uses & Applications
| Application | Evidence Level | Notes |
|---|---|---|
| Insulin sensitivity / prediabetes | Phase 2 recruiting | NCT07505745; first native-peptide RCT |
| NAFLD/NASH | Ph1b analog data (mixed) | CB4211 enzymes↓ but MRI-PDFF = placebo |
| Metabolic syndrome / obesity | Strong preclinical | HFD protection in mice |
| Diabetes prevention | Preclinical (strong, 2025) | Islet senescence prevention (Exp Mol Med) |
| Anti-aging / longevity | Epidemiological | Age-decline + centenarian polymorphism |
| Cardiovascular | Preclinical | Diabetic-heart respiration rescue (2025) |
| Exercise performance | Human correlative only | Endogenous rise with exercise; no exogenous RCT |
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06Doses in studies
⚠️ Disclaimer: No approved human dosing exists. The only randomized human dosing on record is CB4211 25 mg SC daily × 28 days (analog, Phase 1b). Gray-market protocols are extrapolations.
| Purpose | Notes |
|---|---|
| Phase 1b (CB4211 analog) | Only RCT-grade human dosing |
| NCT07505745 (native) | Await registration details |
| Gray-market "metabolic support" | Unvalidated extrapolation |
| Gray-market "anti-aging" | Unvalidated extrapolation |
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- No published human pharmacokinetics for native MOTS-c
07Safety Profile
| Aspect | Assessment |
|---|---|
| Human safety | CB4211 Ph1a/1b: no SAEs; injection-site nodules/reactions most common AE |
| Animal safety | Well-tolerated across rodent studies |
| Hepatotoxicity | None observed; avoids the lactic-acidosis/hepatic issues of metformin/AICAR comparators |
| Long-term human safety | Not established |
| Drug interactions | Not characterized |
| Regulatory | Not FDA-approved; see FDA Peptide Reclassification 2026 — Regulatory Intelligence for the 503A/Category 2 landscape |
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08Source & Origin
- Discovered: 2015, Cohen/Lee laboratories, USC (Lee C et al., Cell Metab 21:443–454)
- Encoding: mitochondrial 12S rRNA gene (mtDNA), sORF, cytosolic translation
- Family: MDPs — Humanin, SHLP1–6, SHMOOSE, MOTS-c
- Commercial lineage: CohBar (Cohen co-founded) → CB4211 → program dropped → assets to Molexus (2024)
09Regulatory Status — PCAC July 2026 Update
The July 23-24 2026 meeting of the FDA Pharmacy Compounding Advisory Committee (PCAC) included MOTS-c (free base) and MOTS-c acetate as a single nominated bulk drug substance (BDS) pair. The nomination was originally submitted by Wells Pharmacy Network (docket FDA-2015-N-3534-0293) and later withdrawn (FDA-2015-N-3534-0484), so FDA evaluated the substances at its own initiative. Federal Register notice 91 FR 20465 (April 16 2026, FR Doc. 2026-07361, Docket FDA-2025-N-6895); briefing documents released June 29 2026 (fda.gov/media/193347).
FDA staff position: Proposes against placing MOTS-c (free base) or MOTS-c acetate on the 503A Bulks List.
FDA evaluation framework (503A criteria) — where MOTS-c landed: | Criterion | FDA finding | |---|---| | Physicochemical characterization | Not well characterized. Nomenclature inconsistency (free base vs acetate), no impurities/aggregates/endotoxin data in published literature, no Certificate of Analysis in the nomination, missing water-solubility data | | Historical compounding use | Unknown / not characterized | | Effectiveness evidence | No clinical studies in humans for any proposed use | | Safety evidence | No nonclinical data to inform safety for the potential clinical uses; no human clinical studies; FDA notes it lacks the information needed to assess immunogenicity risk for a 16-aa peptide |
Uses FDA evaluated: Obesity and osteoporosis (the two proposed indications for which the nomination contained enough information to review). Other proposed uses — vascular calcification, muscle/fat metabolism, longevity, insulin resistance — were not evaluated because the nomination did not include sufficient supporting information and FDA did not identify clinical studies for them.
Specifics that distinguish this file: - MOTS-c appears as a prohibited substance in Global Drug Reference Online (under the 2024 WADA Prohibited List, "hormone and metabolic modulators" category) — a compounding decision would not change anti-doping status. Same situation as TB-500 (Thymosin Beta-4). - FDA's own internet search identified a holistic clinic advertising compounded MOTS-c and a wellness clinic promoting an IV MOTS-c cocktail without disclosing co-ingredients — signals an active gray-market footprint that the briefing document was specifically built to address. - Nominated uses (longevity, exercise-mimetic) are popular talking points but not what FDA evaluated — the agency reviews a BDS in the context of the use proposed.
Status as of Sept 2026: FDA's July 23-24 2026 recommendation is a staff position; the agency will issue a final determination after considering committee input and finalizing reviews. A "no" recommendation at PCAC does not mean MOTS-c was found dangerous — the briefing documents almost exclusively cite missing information, not positive harm findings. Reporting that framing either way ("FDA says dangerous" / "FDA found no safety problems") is inaccurate.
10Where to get it
MOTS-c is sold mainly through gray-market vendors whose products are not independently tested. We don't link to sellers of compounds like this, affiliate or otherwise. How we make money
11Connections
12Sources
- ClinicalTrials.gov NCT07505745 : MOTS-c for Improving Insulin Sensitivity in Adults With Prediabetes and Overweight/Obesity (Phase 2, recruiting, started 2026-02-02).NCT07505745
- PubMed 26861024PubMed 26861024
- Reynolds JC, Lai RW, Woodhead JST et al. (2021). "MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis." Nat Commun 12:470. PMC8228264PMC8228264
- CohBar Inc. (2021). Phase 1a/1b topline results, CB4211 in NASH/obesity ( NCT03998514 ). GlobeNewswire, Aug 10 2021. Press release — peer-reviewed publication absent.NCT03998514
- Gudiksen A, Hansen CC, van der Stede T et al. (2026). "MOTS-c improves intrinsic muscle mitochondrial bioenergetic health and efficiency in a PGC-1α/AMPK-dependent manner." Free Radic Biol Med 246:682–696. PMID 41520850 . Direct mechanism confirmation in skeletal muscle.PubMed 41520850
- Qin Z et al. (2025). Mitochondrial quality-control in bone. Cell Mol Life Sci . doi 10.1007/s00018-025-05802-w . Reviews MOTS-c osteoblast-senescence suppression.DOI 10.1007/s00018-025-05802-w
- Hu B, Chen W (2018). "MOTS-c improves osteoporosis by promoting osteogenic differentiation of bone marrow mesenchymal stem cells via TGF-β/Smad pathway." Eur Rev Med Pharmacol Sci 22(21):7156–7163. PMID 30387425 .PubMed 30387425
- Lee C, Zeng J, Drew BG et al. (2015). "The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance." Cell Metab 21:443–454. PMID 25801541PubMed 25801541
- Zheng Y, Wei Z, Wang T (2023). "MOTS-c: a promising mitochondrial-derived peptide for therapeutic exploitation." Front Endocrinol . PMC9905433PMC9905433
- Wei M et al. (2020). "Mitochondrial-derived peptide MOTS-c attenuates vascular calcification and secondary myocardial remodeling via AMPK signaling." Cardiorenal Med 10(1):42–50. PMID 31694019 .PubMed 31694019
13Entry history
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