# MOTS-c: The Mitochondrial-Derived Peptide — Research Record > MOTS-c is a 16-amino-acid mitochondrial-derived peptide studied across rodent and human models for metabolic regulation, exercise mimicry, and aging biology. Literature digest, cited. ## 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). 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 [12]. ## MOTS-c and WADA Prohibition 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: the correct WADA category is S4.4.1, not S2. USADA confirms MOTS-c has no approved medical use in any jurisdiction as of 2025. No Therapeutic Use Exemption (TUE) pathway exists. ## 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. ## FDA Approval Status of MOTS-c 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. ## References [1] Lee C, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metabolism. 2015;21(3):443-454. DOI: 10.1016/j.cmet.2015.02.009 PMID: 25738459 [2] Reynolds JC, et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nature Communications. 2021;12(1):773. DOI: 10.1038/s41467-020-20790-0 PMID: 33473109 [3] Reynolds JC, et al. [Human exercise data.] Nature Communications. 2021;12(1):773. PMID: 33473109 [4] Kim KH, et al. The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus. Cell Metabolism. 2018;28(3):516-524. DOI: 10.1016/j.cmet.2018.06.008 PMID: 29983246 [12] Kumagai H, et al. MOTS-c modulates skeletal muscle function by directly binding and activating CK2. iScience. 2024;27(11):111212. DOI: 10.1016/j.isci.2024.111212 PMID: 39559755 [17] Wan W, et al. Mitochondria-derived peptide MOTS-c: effects and mechanisms related to stress, metabolism and aging. Journal of Translational Medicine. 2023;21(1):36. DOI: 10.1186/s12967-023-03885-2 PMID: 36670507 --- Calibrated from the peer-reviewed record — a machined-instrument digest of the MOTS-c literature, not a clinic, not a vendor, not a prescription.