MOTS-c
Mitochondria-derived peptide (MDP) encoded within the mitochondrial 12S rRNA gene. Synthesised in the mitochondrial matrix and secreted into circulation, MOTS-c translocates to the nucleus under metabolic stress where it activates AMPK signalling. Studied for insulin sensitivity regulation, folate cycle modulation via AICAR, and exercise-associated metabolic pathway research.
Mechanism of Action
MOTS-c (Mitochondrial Open reading frame of the twelve S rRNA type-c) is a 16-amino-acid peptide with the sequence MRWQEMGYIFYPRKLR, encoded by a small open reading frame (sORF) within the mitochondrial 12S rRNA gene. This genomic location — within the mitochondrial genome rather than the nuclear genome — makes MOTS-c a member of the emerging class of mitochondria-derived peptides (MDPs), which also includes humanin and SHLPs. MDPs are believed to function as intracellular and endocrine signalling molecules communicating mitochondrial status to other cellular compartments and distant tissues.
Under metabolic stress conditions, MOTS-c translocates from the mitochondrial matrix to the cytoplasm and then to the nucleus, where it has been found to regulate gene expression programs related to energy metabolism. The primary downstream effector identified is AMPK (AMP-activated protein kinase). MOTS-c activates AMPK, a master metabolic sensor that responds to cellular energy status by promoting ATP-producing pathways (fatty acid oxidation, glycolysis, mitochondrial biogenesis) and inhibiting ATP-consuming anabolic pathways. AMPK activation promotes: glucose uptake in skeletal muscle via GLUT4 translocation, fatty acid oxidation, and mitophagy.
MOTS-c is also studied for its interaction with the folate cycle through AICAR (5-aminoimidazole-4-carboxamide ribonucleotide). AICAR is an endogenous metabolite of the purine synthesis pathway and a well-known endogenous AMPK activator. MOTS-c has been described as modulating the folate cycle in a manner that elevates AICAR production, potentially providing an indirect mechanism for AMPK activation alongside its direct nuclear activities. Circulating MOTS-c levels have been studied in aging and exercise contexts, with exercise-induced secretion from skeletal muscle identified as a potential mechanism for some of exercise’s beneficial metabolic effects.
Key Research Findings
- Lee et al. originally identified and characterised MOTS-c as a mitochondria-derived peptide with metabolic regulatory functions, establishing the nuclear translocation mechanism and downstream AMPK activation. Lee et al., Cell Metabolism, 2015.
- Insulin sensitivity improvement in mice fed a high-fat diet was described in the same Cell Metabolism publication, with MOTS-c administration improving glucose tolerance and reducing obesity-associated metabolic dysfunction. Lee et al., Cell Metabolism, 2015.
- Age-related decline in circulating MOTS-c levels has been described in published work, with supplementation studies in aged mice showing improved metabolic parameters consistent with AMPK pathway restoration. Lee and Cohen research group, mitochondrial-derived peptide ageing literature.
- Exercise-induced MOTS-c release from skeletal muscle has been identified as a potential mechanism linking physical activity to systemic metabolic improvement, positioning MOTS-c as a candidate exercise-mimetic research tool compound. Reynolds et al., Nature Communications, 2021 (exercise-induced MOTS-c).
- Lifespan extension in Drosophila models has been described in published work; mechanistic research in higher organism models examining the longevity relevance of MOTS-c continues. Lee and Cohen research group, MOTS-c longevity literature.
Citations last reviewed: 1 October 2026
As Supplied by BasedPeps
Researcher FAQ
What is MOTS-c?
MOTS-c is a 16-amino-acid peptide encoded within the mitochondrial genome’s 12S rRNA gene — a member of the class of mitochondria-derived peptides (MDPs). It is synthesised in the mitochondrial matrix, secreted into circulation, and studied for nuclear translocation under metabolic stress where it activates AMPK signalling to regulate glucose uptake, fatty acid oxidation, and mitochondrial biogenesis.
What makes MOTS-c a mitochondria-derived peptide?
MOTS-c is encoded by a small open reading frame within the mitochondrial 12S rRNA gene — part of a class of peptides (MDPs) translated from the mitochondrial genome. Most proteins are nuclear-encoded and imported into mitochondria; MOTS-c is unusual in being synthesised within the mitochondrial matrix. It can be secreted into the cytoplasm and bloodstream, functioning as an intracellular and endocrine signalling molecule communicating mitochondrial status.
How does AMPK activation work in MOTS-c research?
AMPK is a master energy sensor activated when cellular AMP:ATP ratio rises. MOTS-c translocates to the nucleus under metabolic stress and activates AMPK signalling, which then promotes glucose uptake in skeletal muscle via GLUT4 translocation, fatty acid oxidation, mitochondrial biogenesis, and autophagy — metabolic effects relevant to insulin sensitivity and longevity research. The folate cycle/AICAR pathway provides an indirect AMPK activation mechanism also under study.
How is MOTS-c stored and reconstituted?
Supplied as lyophilised powder, stored at −20 °C. Reconstitution in sterile bacteriostatic water is standard. Reconstituted solution stored at 2–8 °C and used within 28 days per experimental protocol.
Does BasedPeps provide purity documentation?
Yes. Every BasedPeps lot includes a third-party Certificate of Analysis documenting HPLC purity (≥99%) and mass spectrometric identity confirmation. Certificates of Analysis are available per batch on request.
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Research-grade mitochondria-derived peptide. Third-party HPLC and mass spectrometry verification per lot. Certificate of Analysis available on request. Dispatched from Riga, Latvia within 24 hours.
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