MOTS-c

MOTS-c is a 16-amino-acid mitochondrial-derived peptide (sequence MRWQEMGYIFYPRKLR; CAS 627580-64-6) encoded within an open reading frame of the mitochondrial 12S rRNA (MT-RNR1) gene. In preclinical models it acts primarily by activating AMP-activated protein kinase (AMPK), the cell's central energy sensor, in part by inhibiting the folate cycle (one-carbon metabolism) and the tethered de novo purine biosynthesis pathway, leading to accumulation of the endogenous AMPK activator AICAR. Under metabolic stress it translocates to the nucleus in an AMPK-dependent manner and modulates antioxidant-response (ARE/Nrf2) and stress-adaptive gene expression, enhancing glucose uptake, fatty-acid oxidation, and insulin sensitivity in skeletal muscle in animal and cell studies.

Human evidence

Largely animal and mechanistic (in vitro) studies plus observational human data (exercise-induced changes in endogenous levels, correlations with insulin sensitivity and obesity); no completed controlled human clinical trials of exogenous (administered) MOTS-c. The only registered human trial of a related molecule is for the MOTS-c analog CB4211, not the unmodified peptide.

Regulatory status

Not approved by the FDA for any indication and not a licensed medicine. In April 2026 the FDA removed MOTS-c (free base and acetate) from 503A compounding Category 2, and it is scheduled for review by the Pharmacy Compounding Advisory Committee (PCAC) at the July 23-24, 2026 meeting to consider eligibility for the Section 503A bulk drug substances list (Docket No. FDA-2026-N-2979). This review is pending and does not constitute approval. Not authorised as a medicine in the UK by the MHRA.

• —Studied in animal and cell models for metabolic regulation, including effects on insulin sensitivity, glucose uptake, and diet-induced obesity and insulin resistance.
• —Investigated as an 'exercise-mimetic,' with research into mitochondrial biogenesis, fatty-acid oxidation, and age-dependent physical and muscle decline.
• —Explored in aging and metabolic-disease research, including effects on inflammation and, in animal models, mitochondrial respiration and cardiac function in type 2 diabetes.
• —Examined in observational human exercise studies measuring how endogenous MOTS-c levels change with aerobic and resistance training.

• ⚠No completed human clinical trials of exogenous MOTS-c have characterized its safety profile; the published research literature does not establish a human safety, toxicity, or adverse-event profile.
• ⚠Most data derive from rodent studies and in vitro work; human evidence is limited to observational measurements of endogenous (naturally produced) peptide levels rather than administered doses.
• ⚠As an unapproved research compound, material sold outside regulated channels is not subject to pharmaceutical quality, purity, or sterility controls (the April 2026 removal from 503A Category 2 is a reclassification for review, not a safety determination or endorsement).
• ⚠Long-term effects, dosing, and drug interactions in humans have not been established in peer-reviewed clinical literature.