MOTS-c

An unapproved peptide encoded in mitochondrial DNA

Not FDA-approved · not available for sale or prescription

FDA advisory vote, July 2026 · FDA staff opposed · no FDA action

Stylised model of the real sequence

Overview.

MOTS-c is not FDA-approved and has no completed human efficacy trial; the evidence comes mainly from animal and cell studies. It is a naturally occurring 16-amino-acid peptide encoded within the mitochondrial genome (12S rRNA region) rather than nuclear DNA, and its blood levels can rise with exercise. In animal studies it activates AMPK, improves insulin sensitivity and resists diet- and age-related weight gain.

Also known as Mitochondrial Open reading frame of the 12S rRNA-c · MOTS-C

The molecule, decoded.

Sequence: MRWQEMGYIFYPRKLR
Length: 16 residues
Molecular weight: 2,174.6 g/mol
Formula: C101H152N28O22S2
CAS number: 1627580-64-6
Half-life: Not established in humans
Routes studied: subcutaneous injection (unapproved research-chemical use), intraperitoneal (animal studies)
Modifications: None - native 16-residue sequence with a free C-terminal acid; contains two oxidation-prone Met residues (positions 1 and 6)

How it works.

MOTS-c translocates to skeletal muscle and inhibits the folate-dependent de novo purine biosynthesis pathway, raising levels of the endogenous AMP-mimetic AICAR, which activates AMP-activated protein kinase (AMPK). This stimulates glucose uptake and fatty-acid oxidation and suppresses inflammatory signaling, reproducing several molecular effects of exercise.

Evidence · Lab and animal studies only

What the research shows

phase 1 trial of an analog2021

CB4211, a MOTS-c analog developed by CohBar (not MOTS-c itself), completed a phase 1a/1b trial in healthy non-obese volunteers and people with nonalcoholic fatty liver disease (NCT03998514, completed Apr 2021).

healthy non-obese volunteers and NAFLD cohort, phase 1a/1b

Source

exercise RCT, secondary analysis2021

In a secondary analysis of a 16-week aerobic and resistance exercise RCT in breast cancer survivors (no MOTS-c was given), fasting plasma MOTS-c rose in non-Hispanic White participants but not in Hispanic participants.

49 breast cancer survivors (secondary analysis)

Source

mouse study2015

MOTS-c was identified as a 16-amino-acid peptide encoded in the mitochondrial 12S rRNA region that regulates insulin sensitivity and prevented age-dependent and high-fat-diet-induced insulin resistance and obesity in mice.

mice

Source

cell study2018

Under metabolic stress, MOTS-c translocates to the nucleus in an AMPK-dependent manner and regulates nuclear gene expression, including antioxidant-response-element genes, interacting with NRF2.

cultured cells

Source

What to know first.

Based on: lab and animal studies only; human safety is not established.

Reported side effects

no controlled human adverse-event data available for native MOTS-c

Cautions

sold only as a research chemical labeled not for human use; no quality/purity oversight
no established human dosing
FDA staff's July 2026 review found insufficient safety and effectiveness evidence to support compounding.

Checked 2026-09

Where it stands.

Not FDA-approved · not available for sale or prescription. MOTS-c is not FDA-approved and is not available for sale or prescription. In July 2026, FDA staff recommended against adding it to the list of substances pharmacies may compound; FDA’s advisory committee voted 7–5, with 2 abstentions, to recommend it anyway. The vote is advisory, and FDA has not acted on it.

FDA: Not approved. No human efficacy trial of native MOTS-c has been reported; an analog, CB4211, completed a phase 1a/1b trial (NCT03998514).
Compounding: Reviewed at FDA's Pharmacy Compounding Advisory Committee on July 23, 2026. FDA staff proposed not adding MOTS-c (free base or acetate) to the 503A Bulks List; the committee voted 7-5 with 2 abstentions to recommend inclusion. The vote is advisory: as of September 2026 FDA has not proposed or finalized a rule, and MOTS-c is not on the 503A Bulks List, so it cannot currently be compounded.
Sport (WADA): Prohibited at all times (in and out of competition): WADA 2026 Prohibited List S4.4.1 names 'mitochondrial open reading frame of the 12S rRNA-c (MOTS-c)' as an example of AMP-activated protein kinase (AMPK) activators; non-Specified Substance. Unchanged in the 2027 List.
Enforcement: FDA placed MOTS-c in Category 2 of its interim bulk-substance policy (significant safety risks: immunogenicity, peptide impurities, no human exposure data); the nominations were later withdrawn and FDA lists it as 'nominated but withdrawn' (page current as of Apr 22, 2026)

References (5)

MOTS-c

Overview.

The molecule, decoded.

How it works.

What the research shows

What to know first.

Reported side effects

Cautions

Where it stands.

More in Metabolic