MOTS-c

Overview

MOTS-c — Mitochondrial Open reading frame of the Twelve S rRNA type-c — is a sixteen-residue peptide studied in research on metabolic regulation, insulin sensitivity and exercise physiology. It is the only compound in this catalogue that is not encoded by nuclear DNA, and that distinction is not a curiosity: it is the reason the peptide is scientifically interesting.

Chemical identity

• Sequence: Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg
• CAS number: 1627580-64-6
• Molecular formula: C₁₀₁H₁₅₂N₂₈O₂₂S₂
• Molecular weight: 2174.6 g/mol
• Classification: Mitochondrial-derived peptide (MDP)
• Length: 16 residues, all standard L-amino acids
• Appearance: White lyophilised powder

At 2,175 g/mol the molecule is past the point where a two-dimensional depiction stays legible at article width, so the sequence above is the more useful representation. The two sulfur atoms in the formula are the methionines at positions 1 and 6 — relevant to handling, as noted below.

Unlike most peptides in this catalogue, MOTS-c contains no engineered modifications: no D-amino acids, no unnatural residues, no C-terminal amidation, no acylation. It is a naturally occurring human sequence reproduced as written.

A peptide encoded outside the nucleus

Essentially every protein in a human cell is transcribed from nuclear DNA. Mitochondria are the exception: they carry their own small circular genome, a remnant of the bacterial ancestor from which they descend, and it encodes a handful of proteins involved in oxidative phosphorylation.

MOTS-c is encoded within that mitochondrial genome — specifically within the gene for the 12S ribosomal RNA, in a short open reading frame that had not been recognised as coding for anything. It was identified in 2015 by Changhan Lee, Pinchas Cohen and colleagues, who were examining the mitochondrial genome for previously unannotated peptide-coding sequences.

The finding matters beyond one peptide. It implies that the mitochondrial genome encodes regulatory molecules as well as respiratory machinery, and that mitochondria participate in cellular signalling as senders rather than only as responders.

Mitochondrial-derived peptides as a class

MOTS-c belongs to a small group of peptides encoded in mitochondrial DNA, collectively termed mitochondrial-derived peptides. Humanin, identified earlier, came from the 16S rRNA region and is studied largely in cytoprotection and neurobiology. A further set, the small humanin-like peptides, were identified subsequently.

The group is small, recently characterised, and still being mapped — which is worth knowing when reading the literature, because the field is young enough that the picture is actively changing rather than settled.

Mechanism of action

MOTS-c does not work the way most peptides in this catalogue do. There is no cell-surface receptor that it agonises; its reported mechanism is metabolic and indirect.

Published work describes it as acting on the folate–methionine cycle, inhibiting a step in folate-dependent one-carbon metabolism. The consequence is accumulation of AICAR, an intermediate of purine biosynthesis and a known activator of AMP-activated protein kinase. AMPK is the cell’s principal low-energy sensor: when activated it shifts metabolism toward catabolic, energy-generating pathways and away from anabolic ones.

So the reported chain runs from a peptide, through inhibition of a biosynthetic cycle, to accumulation of a metabolite, to activation of a kinase — rather than from ligand to receptor to second messenger. That indirectness is unusual and is part of what makes the compound a distinctive research tool.

It also places MOTS-c alongside the other compounds here that act on cellular energy metabolism without a receptor of their own. 5-Amino-1MQ inhibits an enzyme to preserve substrate for NAD⁺ synthesis; MOTS-c inhibits a different enzyme to accumulate a metabolite that activates AMPK. Different targets, but the same shape of mechanism — changing the concentration of something the cell already makes, rather than supplying a signal.

Retrograde signalling

A subsequent line of work established something further: under metabolic stress, MOTS-c translocates from the mitochondrion into the cell nucleus, where it associates with regulatory regions of nuclear DNA and influences expression of stress-response genes.

That is retrograde signalling — information flowing from mitochondrion to nucleus, the opposite of the usual direction in which the nucleus directs mitochondrial biogenesis. A peptide encoded in one genome physically relocating to regulate the other is a striking mechanism, and it is the finding that moved MOTS-c from a metabolic curiosity to a subject of sustained interest.

Exercise and metabolic research

Two research threads dominate the literature.

The first is metabolic regulation. The original characterisation reported effects on insulin sensitivity and glucose handling in mouse models, including under high-fat-diet conditions, which established the compound’s association with metabolic homeostasis.

The second concerns exercise. MOTS-c expression has been reported to respond to physical activity, and later work examined its relationship to skeletal muscle function and age-related physical decline. This has made it a compound of interest in exercise physiology and ageing research, where the question is less about administering it than about understanding what endogenous MOTS-c signalling does.

A further strand concerns human genetic variation: a polymorphism in the MOTS-c coding region has been reported at differing frequencies between populations and examined in relation to metabolic and longevity phenotypes. That work is population-genetic rather than interventional, and is worth reading separately from the animal literature.

Handling, reconstitution and storage

• Lyophilised storage: sealed, refrigerated, protected from light. Freeze for long-term storage.
• Methionine oxidation is the main degradation route. This sequence carries two methionines, and methionine is among the most oxidation-prone residues. Minimise headspace air in opened vials, and avoid oxidising conditions in diluents.
• Reconstitution: add diluent slowly down the vial wall, allow to dissolve undisturbed, do not shake.
• After reconstitution: refrigerate, protect from light, minimise freeze–thaw cycles. The single tryptophan adds mild photosensitivity on top of the methionine concern.
• Concentration: our peptide reconstitution calculator converts vial quantity, diluent volume and syringe size into concentration per unit.

Purity and analytical verification

MOTS-c is, analytically, one of the more straightforward compounds in this catalogue — and for an instructive reason.

Several peptides here have failure modes that a certificate cannot detect. A D-amino acid substituted for its L-form leaves the molecular mass unchanged. A hydrolysed conjugation linker looks nearly identical to an intact one. MOTS-c has none of these vulnerabilities, because it has no engineered features to get wrong: it is sixteen standard L-residues in a natural sequence. There is no stereochemistry to invert, no unnatural residue to substitute with a cheaper one, no modification to omit.

What remains is ordinary synthesis quality, which HPLC purity and mass confirmation address well. Methionine oxidation adds sixteen mass units per event and appears as a resolvable variant, so a mass figure also reports on how the material has been stored.

For this compound, a standard certificate genuinely tells you what you need.

References

• Lee C, Zeng J, Drew BG, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metabolism, 2015. PMID 25738459
• Kim KH, Son JM, Benayoun BA, Lee C. The mitochondrial-encoded peptide MOTS-c translocates to the nucleus to regulate nuclear gene expression in response to metabolic stress. Cell Metabolism, 2018. PMID 29983246
• Reynolds JC, Lai RW, Woodhead JST, et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nature Communications, 2021. PMID 33473109

Summary

MOTS-c is a sixteen-residue mitochondrial-derived peptide, CAS 1627580-64-6, molecular formula C₁₀₁H₁₅₂N₂₈O₂₂S₂, molecular weight 2,174.6 g/mol. It is encoded within the mitochondrial genome rather than the nucleus — unique among the compounds in this catalogue — and was identified in 2015 within the 12S rRNA gene. Its reported mechanism is indirect, running through inhibition of the folate–methionine cycle to AICAR accumulation and AMPK activation, and it has been shown to translocate to the nucleus under metabolic stress to influence nuclear gene expression. Research centres on metabolic regulation and on exercise physiology and ageing.

For laboratory research use only. Not for human consumption. This material is not a drug, food, or cosmetic and may not be sold or used for any purpose other than in vitro or non-human laboratory research.