MOTS-C (Mitochondrial Open Reading Frame of the 12S rRNA Type-C) is a 16-amino acid peptide encoded by the mitochondrial genome. Discovered in 2015 by the Lee laboratory at USC, it represents a novel class of mitochondria-derived peptides (MDPs) studied for their roles in metabolic homeostasis, insulin sensitivity, and cellular energy regulation.
MOTS-C is one of several mitochondria-derived peptides (MDPs) that function as retrograde signalling molecules from the mitochondria to the nucleus and beyond. Its primary studied mechanism involves activation of AMP-activated protein kinase (AMPK), a master regulator of cellular energy homeostasis. MOTS-C appears to activate AMPK by inhibiting the folate-methionine cycle in the de novo purine biosynthesis pathway, leading to accumulation of the AMPK-activating metabolite AICAR (5-aminoimidazole-4-carboxamide ribonucleotide).
AMPK activation by MOTS-C triggers a cascade of metabolic effects: increased glucose uptake via GLUT4 translocation, enhanced fatty acid oxidation, inhibition of gluconeogenesis, and stimulation of mitochondrial biogenesis. In preclinical models, MOTS-C administration has been shown to improve insulin sensitivity in diet-induced obesity and age-related metabolic dysfunction models. The Lee laboratory demonstrated that MOTS-C can translocate to the nucleus under metabolic stress conditions, where it regulates gene expression through interaction with the antioxidant response element (ARE) and NRF2 signalling.
MOTS-C levels have been shown to decline with age in both humans and animal models, leading to interest in its role in ageing research. Circulating MOTS-C levels correlate with metabolic health markers, and exercise has been shown to increase endogenous MOTS-C production — positioning it as a potential molecular link between physical activity and metabolic adaptation.
The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance
Lee C, Zeng J, Drew BG, et al. · Cell Metabolism (2015)
Discovery paper identifying MOTS-C as a mitochondria-derived peptide that regulates metabolic homeostasis through AMPK activation, with demonstration of anti-obesity and insulin-sensitising effects in mice.
DOI: 10.1016/j.cmet.2015.02.009The mitochondrial-encoded peptide MOTS-c translocates to the nucleus to regulate nuclear gene expression in response to metabolic stress
Kim KH, Son JM, Benayoun BA, Lee C. · Cell Metabolism (2018)
Demonstrated that MOTS-C translocates from mitochondria to the nucleus under metabolic stress, where it interacts with ARE motifs to regulate adaptive gene expression — a novel retrograde signalling mechanism.
DOI: 10.1016/j.cmet.2018.06.008MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis
Reynolds JC, Lai RW, Woodhead JST, et al. · Nature Communications (2021)
Showed that exercise increases endogenous MOTS-C levels and that exogenous MOTS-C improves physical performance in aged mice, positioning MOTS-C as a molecular mediator of exercise-induced metabolic benefits.
DOI: 10.1038/s41467-020-20790-0A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c
Zempo H, Kim SJ, Fuku N, et al. · Aging (2021)
Identified a common mitochondrial DNA polymorphism (m.1382A>C) that alters MOTS-C structure and is associated with increased diabetes risk, linking endogenous MOTS-C variation to metabolic disease susceptibility.
DOI: 10.18632/aging.202529Add bacteriostatic water slowly along the vial wall. MOTS-C dissolves readily. Do not shake. Store reconstituted solution refrigerated and protect from light.
Use reconstitution calculatorLyophilised: store at or below 5 °C for up to 12 months. Reconstituted: refrigerate at 2–8 °C and use within 30 days. MOTS-C is a relatively small peptide but should still be protected from repeated freeze-thaw cycles.
MOTS-C is encoded by the mitochondrial genome (specifically the 12S rRNA gene), making it a mitochondria-derived peptide (MDP) rather than a nuclear-encoded peptide. It represents a novel class of retrograde signalling molecules that communicate metabolic status from mitochondria to the nucleus.
MOTS-C inhibits the folate-methionine cycle in the de novo purine biosynthesis pathway, leading to accumulation of AICAR (5-aminoimidazole-4-carboxamide ribonucleotide). AICAR is a well-established endogenous AMPK activator, providing an indirect but potent mechanism for AMPK stimulation.
Yes. Studies have shown that circulating MOTS-C levels decrease with age in both humans and animal models. This decline correlates with age-related metabolic dysfunction. Exercise has been shown to increase endogenous MOTS-C production, which may partly explain the metabolic benefits of physical activity.
Reynolds et al. (Nature Communications, 2021) demonstrated that exercise increases endogenous MOTS-C levels and that exogenous MOTS-C administration improved physical capacity in aged mice. MOTS-C is being studied as a potential molecular link between physical activity and systemic metabolic adaptation.
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