MOTS-c
MOTS-c — evidence, uses & status

Class: peptide
Synonyms: MOTS-c
"Mitochondrial Open Reading Frame of the 12S rRNA type-c"
a mitochondrial-derived peptide (MDP). INCI: none
Function tags: metabolic
mitochondrial
insulin sensitivity
exercise-mimetic (research context)
Overall evidence grade: C
WADA prohibited: yes
WADA note: Sport: treated as WADA-prohibited (metabolic modulator / AMPK-activating "exercise-mimetic", Section S4). Athletes should treat it as banned.
Last updated: 2026-07-11

In brief: MOTS-c is a 16-amino-acid mitochondrial-derived peptide, encoded in mtDNA and discovered in 2015, that regulates metabolism largely through the AMPK pathway. Its preclinical and mechanistic research is strong and coherent — multiple laboratories, top-tier journals — showing improved insulin sensitivity and metabolic homeostasis in animal models. But there are no published human efficacy RCTs of administering MOTS-c; in humans it remains interesting biology, not established therapy.

## Identity a **16-amino-acid** peptide (< 40 aa → peptide) encoded by a short open reading frame nested inside the **mitochondrial 12S rRNA gene** (mtDNA — not the nuclear genome, a key reason for scientific interest). Identified in **2015** by Lee, Kim, Cohen and colleagues (USC) in a landmark *Cell Metabolism* paper; highly conserved across species; detected in tissues and circulation, with levels that **decline with age**. ## Development & history - MOTS-c belongs to a young class — **mitochondrial-derived peptides (MDPs)** — that opened with the discovery of **Humanin (2003)**, the first evidence that the mitochondrial genome itself encodes bioactive signalling peptides.
- **MOTS-c was identified in 2015** by **Changhan Lee, Su-Jeong Kim, Pinchas Cohen and colleagues at USC** (in *Cell Metabolism*), by screening short open reading frames within mtDNA. It remains an **academic-discovery / research compound**: studied extensively in mechanism and in animals, but with **no completed commercial drug-development programme or human efficacy trial** to date. **Is MOTS-c FDA-approved?** No — MOTS-c is **not approved by the FDA (or any regulator) for any use**; it is a research compound only, not a medicine. ## Mechanism (as proposed) MOTS-c acts largely via the **folate–AICAR–AMPK** axis — raising AICAR and activating **AMPK**, promoting GLUT4-mediated glucose uptake and insulin sensitivity. Under metabolic stress or exercise it **translocates to the nucleus** and regulates stress-adaptation genes bearing antioxidant response elements (ARE) — a "retrograde" mitochondria-to-nucleus signal. Well characterised in cells and animals; the relevance of *exogenous* MOTS-c in humans is unproven.

Evidence grades by outcome:
outcome: Insulin sensitivity / glucose metabolism / metabolic homeostasis
grade: C
base: Strong preclinical — Lee 2015 (Cell Metab) + multiple rodent studies (diet-induced obesity, T1D/T2D models)
effect: Consistent improvement in animals
caveat: Mechanistically coherent and multi-lab, but no human efficacy RCT
outcome: Exercise-mimetic / physical capacity
grade: D
base: Rodent studies + human observation (Reynolds 2021, Nat Commun: exercise raises muscle MOTS-c ~12-fold)
effect: Suggestive
caveat: "Mimics exercise" ≠ "replaces exercise"; no human administration trial
outcome: Aging / healthspan
grade: D
base: Preclinical + observational (levels decline with age; restored in aged mice by injection)
effect: Suggestive
caveat: Human data is correlational, not interventional
outcome: Marketed "anti-aging / metabolic fix" in humans
grade: F
base: None
effect: Not demonstrated
caveat: Human efficacy unproven; hype outruns evidence
outcome: Safety & long-term
base: No human efficacy/safety RCT
effect: Unknown
caveat: WADA-banned; vendor guidance flags caution for cardiac arrhythmia, malignancy, pregnancy — i.e. unknown risk

Legal status:
region: EU
status: Not FDA-approved (gray-market)
note: Not approved for human use; not eligible for magistral/officinal compounding. Research-chemical sale does not authorise human use.
region: US
status: Not FDA-approved (under review)
note: On the PCAC agenda for 23 July 2026 (with BPC-157/TB-500); removed from Category 2 in April 2026; FDA's pre-meeting briefing documents proposed not adding it to the 503A Bulks List. Advisory only; no final rule. Not approved.
region: INT
status: Approved nowhere
note: Approved nowhere.

Cosmetic claims:

Note: Research / reference — not for sale. No dosing, reconstitution, or administration is published (intentional). Neutral scientific reference only. Strong basic-science research; note the gap between mechanism/preclinical and human clinical proof.
Status note: US review status evolving — re-check the July PCAC outcome and any Federal Register rule

Sources:
Lee C, Zeng J, Drew BG, … Cohen P. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015. (discovery paper)
Reynolds JC, et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of… Nat Commun. 2021.
Kim SJ, et al. (2017); Merry TL, et al. (2020) — AMPK/metabolic mechanism.
MOTS-c: effects and mechanisms related to stress, metabolism and aging — review, PMC9854231; MOTS-c: a promising MDP for therapeutic exploitation — PMC9905433.