What Is MOTS-c?
MOTS-c is a 16-amino-acid peptide (sequence: MRWQEMGYIFYPRKLR) encoded by a short open reading frame within the mitochondrial 12S ribosomal RNA gene (MT-RNR1). Molecular weight: 2174.6 Da. Highly conserved across 14 species.[1]
Before 2015, MT-RNR1 was considered a structural RNA gene — not a protein-coding region. Its identification as a peptide-hormone source was unexpected, and MOTS-c became one of the first peptides known to originate from the mitochondrial genome rather than the nuclear genome.[1]
The peptide belongs to a class called mitochondrial-derived peptides (MDPs). Two other MDP classes exist: humanin (from the 16S rRNA region, MT-RNR2) and the small humanin-like peptides SHLP1–6 (also from MT-RNR2). MOTS-c is structurally and functionally distinct from both — see MOTS-c vs humanin for the disambiguation.
Endogenous MOTS-c circulates in human plasma. Levels respond to exercise: stationary cycling induced an 11.9-fold increase in skeletal muscle MOTS-c expression and a 1.5–1.6-fold rise in circulating plasma levels in healthy young males, with return toward baseline within four hours post-exercise.[2][3]
What Does MOTS-c Do?
MOTS-c activates AMPK via the folate-AICAR axis. The peptide inhibits the folate cycle and linked de novo purine biosynthesis, causing accumulation of AICAR — an endogenous AMPK activator. Activated AMPK drives increased glucose uptake in skeletal muscle, enhanced fatty acid oxidation, and suppressed hepatic lipid accumulation.[1][17]
Under metabolic stress, MOTS-c translocates from the cytoplasm to the nucleus within 30 minutes in an AMPK-dependent manner, where it interacts with NRF2 and upregulates antioxidant response element (ARE) genes including NQO1 and HO-1.[4]
A 2024 study identified CK2alpha as a direct molecular binding partner for MOTS-c in skeletal muscle. The peptide binds CK2alpha with a dissociation constant of approximately 1 nM, activating it to promote glucose uptake and prevent muscle atrophy.[12]
For the complete MOTS-c mechanism of action, see the research page. The primary tissue targets are skeletal muscle, liver, and adipose tissue. Cardiac, bone, and immune effects have been reported in secondary studies.[10][14][20]
MOTS-c and WADA Prohibition
PROHIBITED IN SPORT
WADA S4.4.1 — Prohibited at All Times
MOTS-c is prohibited at all times under the WADA Prohibited List, Section S4.4.1: Activators of AMP-activated protein kinase (AMPK) / Metabolic Modulators. This classification covers both in-competition and out-of-competition use.
Note on category: some sources misreport the classification as WADA S2 (Peptide Hormones and Related Substances). The correct category is S4.4.1. This distinction matters for anti-doping proceedings.
USADA confirms MOTS-c has no approved medical use in any jurisdiction as of 2025. No Therapeutic Use Exemption (TUE) pathway exists.
Athletes subject to anti-doping testing must treat MOTS-c as prohibited under all circumstances.
Is MOTS-c Naturally Occurring?
Yes. MOTS-c is an endogenous peptide produced by human mitochondria in skeletal muscle and other tissues. Exercise elevates circulating and intramuscular MOTS-c in healthy adults.[3]
The WADA prohibition applies to the exogenous synthetic analog administered as a research chemical — not to the naturally circulating peptide the body produces. Exogenous and endogenous MOTS-c are structurally identical; the prohibition targets administration, not presence.
MOTS-c in Supplements
USADA warns that MOTS-c may appear in dietary supplements without clear labeling. Athletes should treat any supplement carrying mitochondria-support or AMPK-activator language with caution given the S4.4.1 prohibition and the lack of mandatory pre-market approval requirements for supplements in most jurisdictions.
For MOTS-c side effects and safety signals from the available literature, see the dedicated page.
FDA Approval Status of MOTS-c
REGULATORY STATUS
No FDA-Approved Indication
MOTS-c has no FDA-approved indication. It is not an approved drug in any jurisdiction as of 2025. Compounding pharmacies are prohibited from manufacturing MOTS-c products under FDA guidelines.
CB-4211, a MOTS-c analog developed for obesity, entered early human trials, but peer-reviewed Phase 2 results have not been published. Human interventional trial data for the native 16-amino-acid sequence are absent.
For the full MOTS-c clinical trial status, see the research page.
MOTS-c and TUE Applications
USADA states that MOTS-c has no approved medical use and therefore no TUE would be granted. Athletes subject to anti-doping testing should treat it as prohibited under all circumstances, with no exemption pathway currently available.