MOTS-c

Also known as: Mitochondrial ORF of the twelve S c

**Mechanism of Action** MOTS-c (Mitochondrial ORF of the Twelve S c) is a 16-amino-acid peptide encoded within the mitochondrial 12S rRNA gene. It acts primarily by activating AMP-activated protein kinase (AMPK), a master regulator of cellular energy homeostasis. This activation enhances insulin sensitivity, promotes glucose uptake, and stimulates fatty acid oxidation. MOTS-c also modulates nuclear gene expression related to metabolism and stress resistance, and it can translocate to the nucleus under metabolic stress, influencing adaptive responses such as mitochondrial unfolded protein response (UPRmt) and autophagy. **Key Research Findings** Preclinical studies in rodent models demonstrate that MOTS-c administration improves insulin sensitivity, reduces adiposity, and enhances exercise capacity. It reverses age-related metabolic decline, including insulin resistance and impaired glucose tolerance, by restoring AMPK signaling and mitochondrial function. In cell-based assays, MOTS-c suppresses oxidative stress and inflammation, and it extends lifespan in *C. elegans*. Notably, circulating MOTS-c levels decline with age in humans, suggesting a potential biomarker role, though direct human interventional data remain absent. **Clinical Relevance** MOTS-c is in preclinical development for metabolic disorders such as type 2 diabetes, obesity, and sarcopenia. Its ability to target mitochondrial-nuclear communication offers a novel approach to age-related metabolic dysfunction. However, no clinical trials have been completed, and safety, pharmacokinetics, and efficacy in humans are unestablished. The peptide’s stability and delivery remain challenges for therapeutic translation. For research purposes only — not medical advice.

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