MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA Type-c)
MOTS-c | Mitochondrial-Derived Peptide
Mechanism of Action
MOTS-c is a 16-amino-acid peptide encoded by the mitochondrial genome within the 12S rRNA gene. Discovered by Changhan David Lee and Pinchas Cohen at the University of Southern California in 2015, it was one of the first mitochondrial-derived peptides (MDPs) identified with significant metabolic regulatory activity. Its discovery challenged the longstanding view that the mitochondrial genome encodes only 13 proteins, 22 tRNAs, and 2 rRNAs.
MOTS-c's primary mechanism involves activation of the AMPK (AMP-activated protein kinase) pathway, the master cellular energy sensor. It inhibits the folate cycle and de novo purine biosynthesis, leading to accumulation of AICAR (an endogenous AMPK activator). This AMPK activation promotes glucose uptake, fatty acid oxidation, and mitochondrial biogenesis — effects that closely mimic the metabolic benefits of exercise. Lee et al. showed that MOTS-c treatment prevented age-dependent and high-fat-diet-induced insulin resistance in mice.
Remarkably, MOTS-c can translocate to the nucleus during metabolic stress, where it regulates nuclear gene expression through interaction with the antioxidant response element (ARE). This represents a novel form of mitochondrial-nuclear communication (retrograde signaling). MOTS-c levels decline with age in human plasma, and exercise has been shown to acutely increase circulating MOTS-c levels, linking it to the molecular mechanisms underlying exercise benefits.
Key Research Findings
- Lee et al. (2015) discovered MOTS-c and demonstrated it regulates insulin sensitivity and metabolic homeostasis through AMPK activation via folate cycle inhibition.
- Kim et al. (2018) showed MOTS-c translocates to the nucleus during metabolic stress to regulate adaptive gene expression via the ARE, establishing a new mitochondria-to-nucleus signaling pathway.
- Reynolds et al. (2021) demonstrated MOTS-c improves physical performance in young and old mice, with aged mice showing particularly robust responses.
- D'Souza et al. (2020) found circulating MOTS-c levels increase with exercise and decline with age in human subjects.
References
Dosage in Research
Mouse studies used 5-15 mg/kg IP daily or every other day. Human dosing protocols are not yet established. The peptide has been administered both systemically and locally in preclinical models.
Storage & Handling
Store lyophilized powder at -20C. Reconstituted solution should be refrigerated at 2-8C and used within 14 days. Protect from light.
Frequently Asked Questions
What is MOTS-c?
MOTS-c is a 16-amino-acid peptide encoded by the mitochondrial genome, discovered in 2015. It is one of the first identified mitochondrial-derived peptides with significant metabolic regulatory activity, acting as an endogenous 'exercise mimetic' through AMPK activation.
Why is MOTS-c called an exercise mimetic?
MOTS-c activates AMPK and produces metabolic effects that closely resemble exercise: improved glucose uptake, enhanced fatty acid oxidation, and increased mitochondrial biogenesis. Exercise increases circulating MOTS-c levels, and MOTS-c treatment improves physical performance in aged mice.
How does MOTS-c signal from mitochondria to the nucleus?
During metabolic stress, MOTS-c physically translocates from the cytoplasm to the nucleus, where it interacts with the antioxidant response element (ARE) to regulate gene expression. This represents a novel mechanism of mitochondrial-nuclear communication.
Source MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA Type-c) for your research
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