MOTS-c: Mitochondrial Research, Human Evidence & Metabolism

Overview

MOTS-c stands for mitochondrial open reading frame of the 12S rRNA type-c. It is a 16-amino-acid peptide described in 2015 as a mitochondrial-derived peptide. The usual one-letter sequence is MRWQEMGYIFYPRKLR.^1,9

This hub does not argue that MOTS-c is an “exercise mimetic,” or that it improves metabolism in people. The editorial thesis is narrower: three evidence layers that are often collapsed must stay separate.

• Preclinical administration: the peptide is given to cells or mice.
• Human endogenous or observational measurement: MOTS-c the body already makes is measured.
• Human clinical administration: investigational MOTS-c is given to participants.

As of 1 September 2026, the third layer exists as a registered, recruiting Phase 2a trial. No results are posted. An ongoing trial is not a clinical result.⁶

What MOTS-c is

FDA’s substance record represents the sequence as Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg. That chemical identity is not a clinical indication and not a use instruction.⁹

The full definition is in What Is MOTS-c.

What “mitochondrial-derived peptide” means

“Mitochondrial-derived peptide” — often abbreviated MDP — names a conceptual family. It includes short peptides associated with the mitochondrial genome, among them MOTS-c and, in other literature, humanin. The category describes origin, not a shared clinical effect.^1,4

Membership in that family does not make MOTS-c a medicine, and it does not make every MDP equivalent. Each sequence has its own evidence map.

How it was discovered

Lee and colleagues described MOTS-c in Cell Metabolism in 2015. The paper identified a short open reading frame associated with mitochondrial 12S rRNA, the 16-amino-acid peptide, and a metabolic research line with a skeletal-muscle emphasis, folate and purine metabolism findings, and AMPK activation in models.¹

Evidence map

MOTS-c and exercise

Exercise can be associated with changes in endogenous MOTS-c that circulates or is measured in muscle. That is a physiological measurement. It is different from giving MOTS-c to a mouse and measuring physical capacity.^3,4

Reynolds and colleagues (2021) mix both kinds of work in one paper: mouse experiments and human exercise-related observations. The paper does not turn mouse administration into a human treatment trial.³

The detail is in MOTS-c and exercise.

MOTS-c and metabolism

The 2015 preclinical base raised a hypothesis of metabolic homeostasis and insulin sensitivity in mouse models. That hypothesis is not a clinical result.¹

Human cohorts that measure circulating MOTS-c — for example a 2024 multicenter hemodialysis study with 94 patients — treat the peptide as a biomarker. They did not administer MOTS-c.⁵

The metabolic line and the current trial are in metabolism and insulin.

Current Phase 2a trial

NCT07505745, short name MOTS-MET, is a randomized, double-blind, placebo-controlled Phase 2a trial. The registered name is MOTS-c for Improving Insulin Sensitivity in Adults With Prediabetes and Overweight/Obesity. Study start is 2 February 2026. The last update posted that we use is 1 April 2026. Estimated enrollment is 120. Estimated primary completion is 14 February 2027; estimated study completion is 17 May 2028.⁶

That means controlled human administration is now being formally studied. It does not mean MOTS-c works, that insulin sensitivity improves, that safety is established, that weight loss is demonstrated, or that metabolic efficacy is established.⁶

The human inventory is in MOTS-c in humans.

FDA 2026

MOTS-c is not an FDA-approved drug. On 23 July 2026, the Pharmacy Compounding Advisory Committee evaluated MOTS-c free base and MOTS-c acetate. The uses evaluated were obesity and osteoporosis.^8,7

FDA’s briefing noted a lack of sufficient clinical safety information, a lack of human data from drug products containing MOTS-c-related bulk drug substances, and a lack of information needed to assess immunogenic safety risk. A recruiting trial can exist at the same time as that reading: a trial record is not trial results.^7,6

A published vote tally from a law firm describes an advisory recommendation of 7 yes, 5 no, and 2 abstentions. That is a non-binding advisory committee recommendation. It is not FDA approval, it does not legalize MOTS-c, and it does not place MOTS-c on the final 503A list.¹⁰

The detail is in FDA, compounding, and WADA status.

WADA 2026

On the 2026 WADA Prohibited List, MOTS-c appears under S4.4 metabolic modulators, specifically among AMPK activators. Under that framework it is prohibited at all times. This page reports status only. It does not provide a detection window, a washout period, or an athlete protocol.^11,12

What we do not know

• What NCT07505745 will show; the registry has not posted results.⁶
• Whether the insulin-sensitivity hypothesis holds in people after the peptide is administered.^1,6
• How FDA will resolve, in a final rule, the 503A nomination of MOTS-c-related bulk substances.⁷
• MOTS-c is not established as an exercise mimetic, an obesity treatment, or a human metabolic therapy. Those phrases are marketing or hypothesis, not an established scientific classification.

Explore research

Six pages cover distinct intents: definition; AMPK and mitochondrial mechanisms; exercise; metabolism and insulin; the human inventory; and FDA/WADA status.

Analytical documentation

A certificate of analysis describes lot identity and purity. It does not demonstrate metabolic efficacy. See the MOTS-c certificate archive and, if you are looking for the research material, the product page.