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MOTS-c

Also known as: Mitochondrial Open Reading Frame of the 12S rRNA-c, Mitochondrial-derived peptide type-c

Research Only

Molecular Formula

C101 H152 N28 O22 S2 Fr Ba

Molecular Weight

2,174.62 Da (Free Base; Acetate ~2,234.64 Da)

Half-Life

Unknown in humans (rapid proteolysis in human blood in vitro at 37°C; no human in-vivo PK data available)

Sequence

MRWQEMGYIFYPRKLR (H-Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg-OH)

Clinical Applications & Evidence

Mechanism of Action

In cellular and rodent models, MOTS-c translocates to the nucleus under metabolic stress. It inhibits the folate-methionine cycle, resulting in intracellular AICAR accumulation and non-canonical AMPK activation. Preclinical studies report enhanced GLUT4 membrane translocation, downregulation of myostatin signaling, competitive binding to Raptor (inhibiting mTORC1), and modulation of inflammatory cytokine expression (TNF-α, IL-6, IL-10). These mechanisms have not been clinically validated in human trials.

Investigated Uses

  • Prediabetes & overweight/obesity (Investigational — Phase 2a trial recruiting: NCT07505745; no results published)
  • Type 2 Diabetes mellitus (Preclinical — mouse models & endogenous level correlations)
  • NASH / MASH (Preclinical for native MOTS-c; Phase 1b clinical data exists only for engineered analog CB4211)
  • Sarcopenia & muscle atrophy (Preclinical rodent cachexia models)
  • Postmenopausal osteoporosis (Preclinical cell & ovariectomized rodent models)
  • Autoimmune disorders & T1D (Preclinical murine models)
  • Traumatic brain injury (Preclinical rodent models)
  • Longevity & healthspan (Preclinical animal models & endogenous gene variant associations)
Early Clinical / Animal Models

Regulatory & Safety Status

FDA Status

Research Only

WADA / Athletic Status

Prohibited at All Times (WADA S4.4.1)

Known Side Effects

Insufficient published human safety data for native MOTS-cFDA Briefing Document notes absent human PK, acute/repeat-dose toxicity, genotoxicity, and carcinogenicity studiesInjection site reactions (reported in Phase 1 trials of engineered analog CB4211)

Contraindications

  • WADA-tested athletes (Prohibited at all times under S4.4.1 Metabolic Modulators)
  • Pregnancy and breastfeeding (Trial exclusion criterion / population of unknown risk)
  • Active malignancy or history of cancer (Trial exclusion criterion / unknown risk)
  • Severe renal or hepatic impairment (Trial exclusion criterion / unknown risk)

Drug Interactions

  • AMPK-activating agents like Metformin (Theoretical overlapping mechanism; excluded in NCT07505745 trial protocol)
  • Glucose-lowering pharmaceuticals & GLP-1 RAs (Co-administration safety and pharmacokinetics unstudied in humans)

Citations & Clinical Trials

PubMed The Mitochondrial-Derived Peptide MOTS-c Promotes Metabolic Homeostasis (Cell Metabolism 2015) PubMed MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression (Cell Metabolism 2018) ClinicalTrials.gov Phase 2a MOTS-c Study in Prediabetes and Overweight/Obesity FDA FDA Briefing Document: MOTS-c — Pharmacy Compounding Advisory Committee (July 2026) GlobeNewswire / CohBar CohBar Announces Positive Topline Results from Phase 1a/1b Study of CB4211 Analog World Anti-Doping Agency WADA 2026 Prohibited List — S4.4.1 Metabolic Modulators