What is MOTS-c?

MOTS-c is a peptide of 16 amino acids whose gene sits in an unusual place. Nearly every peptide your body makes is written in the nuclear genome; MOTS-c is written in the mitochondrial genome, in a short open reading frame hidden inside the gene for the 12S ribosomal RNA (MT-RNR1). That is what its name spells out: mitochondrial open reading frame of the 12S rRNA type-c. Lee and colleagues described it in 2015 as a peptide that regulates insulin sensitivity and metabolic homeostasis, with skeletal muscle as its apparent primary target organ Lee C et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab 2015. PMID 25738459. Most of what has been claimed about it since traces back to that paper and the few that followed.

Why the address matters takes one sentence of background. Mitochondrial DNA is a small circular genome that had been described as encoding 37 genes: 22 transfer RNAs, 2 ribosomal RNAs and 13 messenger RNAs, all of them parts of the machinery that keeps the organelle running Lee C et al. MOTS-c: a novel mitochondrial-derived peptide regulating muscle and fat metabolism. Free Radic Biol Med 2016. PMID 27216708. A peptide that comes out of one of those ribosomal RNA genes is a different kind of thing: a signal, sent by the mitochondrion, that acts on the rest of the cell and on the body. MOTS-c was the second such peptide identified, after humanin, and the 2015 paper closed by suggesting that mitochondria may actively regulate metabolism through peptides encoded in their own genome Lee C et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab 2015. PMID 25738459. That is the sense in which we group it under mitochondrial peptides: a peptide made from the mitochondrial genome, not merely one that acts on mitochondria.

What the 2015 paper showed is specific and worth stating precisely. In cells, MOTS-c inhibited the folate–purine pathway, the coupled reactions that build purines from folate-carried carbon, and the block led to activation of AMPK, the enzyme cells use to sense low energy Lee C et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab 2015. PMID 25738459. Later reviews name the intermediate: the block lets AICAR accumulate, and AICAR is what switches AMPK on, so the route is usually written folate–AICAR–AMPK Wan W et al. Mitochondria-derived peptide MOTS-c: effects and mechanisms related to stress, metabolism and aging. J Transl Med 2023. PMID 36670507. In mice, MOTS-c treatment protected against the insulin resistance that develops with age and with a high-fat diet, and against the obesity that diet induces Lee C et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab 2015. PMID 25738459. Both findings come from cell culture and from mice.

Two later papers extended the story. In 2018 Kim and colleagues showed that under metabolic stress, in the form of glucose restriction, MOTS-c moves into the nucleus and regulates a broad set of nuclear genes, including ones carrying antioxidant response elements, in a way that depends on AMPK; in the nucleus it interacted with the stress-responsive transcription factor NRF2 Kim KH et al. The mitochondrial-encoded peptide MOTS-c translocates to the nucleus to regulate nuclear gene expression in response to metabolic stress. Cell Metab 2018. PMID 29983246. In 2021 Reynolds and colleagues reported that in people, exercise induces the body's own MOTS-c in skeletal muscle and in the bloodstream, and that in mice given MOTS-c, physical performance was higher at young (2 months), middle (12 months) and old (22 months) age, with intermittent treatment started late in life increasing physical capacity and healthspan Reynolds JC et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun 2021. PMID 33473109. Note what the human part of that paper measured: endogenous MOTS-c rising after exercise, not the effect of injecting it.

That distinction is the whole human evidence picture. What exists in people is observational: exercise raises circulating MOTS-c Reynolds JC et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun 2021. PMID 33473109; plasma levels fall with age Zheng Y et al. MOTS-c: a promising mitochondrial-derived peptide for therapeutic exploitation. Front Endocrinol (Lausanne) 2023. PMID 36761202; and a variant in the mitochondrial region that encodes it, specific to Northeast Asian populations, has been proposed as one possible contributor to the longevity of Japanese people Fuku N et al. The mitochondrial-derived peptide MOTS-c: a player in exceptional longevity? Aging Cell 2015. PMID 26289118. No randomised trial of exogenous MOTS-c in humans has been published, and the 2023 review by Zheng and colleagues records that no effective method of applying it in the clinic has been developed Zheng Y et al. MOTS-c: a promising mitochondrial-derived peptide for therapeutic exploitation. Front Endocrinol (Lausanne) 2023. PMID 36761202. On status, one statement covers it: no MOTS-c product holds a marketing authorisation in the European Union.

MOTS-c is often filed next to NAD+ under the word mitochondrial, and the two are not the same kind of molecule. NAD+ is a coenzyme, a carrier of electrons in the reactions that make ATP; it is not a peptide and does not act as a signal, as what is NAD+ explains. The pairing is useful precisely because it shows the difference between a message sent by mitochondria and a component they use, which is how we set the two out at MOTS-c vs NAD+. Our two mitochondrial pens are sold together as the Metabolic Reset set; no published study has given the two compounds together, in animals or in people.

What we supply is MOTS-C 32: 32 mg of MOTS-c already in solution in a 3 ml pre-loaded multi-dose pen. Every batch is tested by an independent lab for identity by mass spectrometry, purity by HPLC and sterility. The certificate for your batch shows the HPLC purity percentage and the concentration of the cartridge (mg/ml and total mg per 3 ml); you reach it by scanning the QR code on the pen or from the certificate index, as a plain PDF with no account needed.