Mitochondrial-derived peptide (MDP); AMPK activator / exercise mimetic
MOTS-c
Prohibitedaka Mitochondrial ORF of the 12S rRNA type-c, MOTS-c peptide
Identified by Lee and colleagues (2015, Cell Metabolism) as a mitochondrial-to-nucleus signalling peptide regulating metabolism. It has been investigated for obesity, insulin resistance and age-related decline, but only in laboratory and animal models; it is not an approved drug or recognized therapy.
Mechanism
In plain terms it is a signal made by mitochondria that shifts cells toward burning fuel more efficiently, mimicking some effects of exercise. Technically, under metabolic stress MOTS-c translocates from mitochondria to the nucleus; it inhibits the folate cycle and tethered de novo purine biosynthesis, raising AICAR levels, which activates AMP-activated protein kinase (AMPK). AMPK activation upregulates GLUT4 and glucose uptake in skeletal muscle, alters fatty-acid metabolism, and MOTS-c further modulates stress-adaptive nuclear gene expression (Lee et al., 2015; Reynolds et al., 2021).
Regulatory Status by Region
- United States (FDA)Not approved for any indication; an experimental peptide with no FDA-approved therapeutic use, and not an approved/compoundable drug substance. On July 23, 2026, the FDA Pharmacy Compounding Advisory Committee voted 7-5, with two abstentions, to recommend MOTS-c (for obesity and osteoporosis) for the Section 503A Bulk Drug Substances List; the vote is advisory and non-binding, and the FDA had not made a final decision as of publication.
- Australia (TGA)Not on the ARTG; an unapproved experimental substance with no approved indication.
- European Union (EMA)No EMA marketing authorization; not an approved medicine in the EU.
- WADAProhibited at all times under Section S4.4 (Metabolic Modulators), 4.4.1 Activators of AMP-activated protein kinase (AMPK); MOTS-c is explicitly named. No therapeutic use exemption is available because there is no approved therapeutic use.
Key Studies
- The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance (opens in a new tab) (Lee C, Zeng J, Drew BG, et al. Cell Metab. 2015;21(3):443-454. PMID 25738459 (preclinical: mice/cell models))
- MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis (opens in a new tab) (Reynolds JC, Lai RW, Woodhead JST, et al. Nat Commun. 2021;12(1):470. PMID 33473109 (mouse studies; human exercise observational data))
Related Clinical Trials
- Comparison of the Effects of General Anesthesia and Combined Spinal-Epidural Anesthesia on Ferroptosis, Humanin and MOTS-c Levels in Renal TransplantationN/A · Recruiting
- MOTS-c for Improving Insulin Sensitivity in Adults With Prediabetes and Overweight/ObesityPhase 2 · Recruiting
- The Cardiovascular Effect of GLP-1 Agonist, SGLT2 Inhibitor and Their CombinationN/A · Recruiting
- Cohort Of DEafness-gene ScreeningN/A · Active Not Recruiting
- Platelet Reactivity, B-amyloid, MOTS-c and Mortality of Type II Diabetics With CADN/A · Unknown
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Latest research
- Mitochondrial-derived peptides (MDPs) activated by physical exercise as therapeutic targets for metabolic disorders: A systematic review. (opens in a new tab)
Physiology international · Aug 25, 2026
- MOTS-c in sepsis-induced cardiomyopathy: Mechanisms and translational potential. (opens in a new tab)
European journal of pharmacology · Aug 23, 2026
- MOTS-c is a mitochondrial-encoded interferon-linked host defense peptide. (opens in a new tab)
eLife · Aug 18, 2026
- Mitochondria-derived peptide hydrogel augments mitochondrial transplantation for promoting cardiac repair via macrophage metabolic reprogramming. (opens in a new tab)
Bioactive materials · Aug 14, 2026
Common Questions
- What is MOTS-c?
- MOTS-c is a 16-amino-acid peptide encoded within the mitochondrial 12S rRNA gene that activates the cellular energy sensor AMPK and improves insulin sensitivity in animal models. The evidence base is essentially preclinical (mouse and rat studies) plus human observational data showing that exercise raises endogenous MOTS-c; there are no completed, published human efficacy trials. It is prohibited in sport by WADA as an AMPK-activating metabolic modulator.
- Is MOTS-c approved for medical use?
- MOTS-c is not approved for medical use and is prohibited in one or more regulatory or anti-doping frameworks. United States (FDA): Not approved for any indication; an experimental peptide with no FDA-approved therapeutic use, and not an approved/compoundable drug substance. On July 23, 2026, the FDA Pharmacy Compounding Advisory Committee voted 7-5, with two abstentions, to recommend MOTS-c (for obesity and osteoporosis) for the Section 503A Bulk Drug Substances List; the vote is advisory and non-binding, and the FDA had not made a final decision as of publication. European Union (EMA): No EMA marketing authorization; not an approved medicine in the EU. Australia (TGA): Not on the ARTG; an unapproved experimental substance with no approved indication.
- How does MOTS-c work?
- In plain terms it is a signal made by mitochondria that shifts cells toward burning fuel more efficiently, mimicking some effects of exercise. Technically, under metabolic stress MOTS-c translocates from mitochondria to the nucleus; it inhibits the folate cycle and tethered de novo purine biosynthesis, raising AICAR levels, which activates AMP-activated protein kinase (AMPK).
- Is MOTS-c legal in Australia?
- MOTS-c in Australia (TGA): Not on the ARTG; an unapproved experimental substance with no approved indication.
- Is MOTS-c banned in sport?
- MOTS-c under the World Anti-Doping Agency (WADA) code: Prohibited at all times under Section S4.4 (Metabolic Modulators), 4.4.1 Activators of AMP-activated protein kinase (AMPK); MOTS-c is explicitly named. No therapeutic use exemption is available because there is no approved therapeutic use.