MOTS-c (mitochondrial open reading frame of the 12S rRNA type-c) is a short peptide encoded not in the nuclear genome but within mitochondrial DNA. Since it was first described in 2015, MOTS-c has become one of the most frequently discussed mitochondrial-derived peptides in metabolic research, and searches for "mots c" and "mots c peptide uk" have grown alongside the published literature. This guide sets out what the molecule is, where it came from, what the research has examined so far and how it relates to other compounds studied in mitochondrial and metabolic laboratories.
For laboratory research use only. Not for human or veterinary use. See our research use only policy.
At a glance: MOTS-c identity
- Name: MOTS-c
- Synonyms: Mitochondrial open reading frame of the 12S rRNA-c, MOTS-c peptide
- Sequence: Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg (MRWQEMGYIFYPRKLR)
- Molecular formula: C101H152N28O22S2
- Molecular weight: 2174.6 g/mol
- CAS number: 1627580-64-6
- Form: Lyophilised powder
- Purity: >99% (HPLC)
- Storage: 2-8°C, dark, upright, do not freeze. Keep sealed until use.
What is MOTS-c?
MOTS-c is a 16-residue peptide. Its coding sequence is a short open reading frame located within the gene for the mitochondrial 12S ribosomal RNA (MT-RNR1). For decades, the human mitochondrial genome was thought to encode only 13 proteins, all of them components of the oxidative phosphorylation machinery, along with the ribosomal and transfer RNAs needed to make them. The identification of small open reading frames inside mitochondrial rRNA genes changed that picture, and MOTS-c is one of the most thoroughly characterised examples.
MOTS-c belongs to a group now referred to as mitochondrial-derived peptides (MDPs). The first member of this group to be reported was humanin, identified in the early 2000s from an open reading frame in the 16S rRNA region. A family of small humanin-like peptides (SHLP1 to SHLP6) followed. MOTS-c differs from these in that its open reading frame sits in the 12S rRNA gene rather than the 16S gene.
Why mitochondrial-derived peptides attracted interest
Mitochondria have long been studied as the site of cellular energy production. The discovery that they may also encode short signalling peptides opened a separate line of enquiry: the possibility that mitochondria communicate with the nucleus and with other tissues through peptide messengers. In the research literature this concept is often described as "retrograde signalling" or, when signals act between tissues, as part of a wider mitochondrial stress-response network. MOTS-c has been one of the main molecules used to investigate that idea experimentally.
Translation and the genetic code question
Mitochondria use a slightly different genetic code from the cytoplasm. One question raised by the original authors was whether the MOTS-c open reading frame is translated inside the mitochondrion or exported and translated by cytoplasmic ribosomes. The 2015 description by Lee and colleagues proposed cytoplasmic translation, based partly on how the sequence reads under each code. The precise route of biosynthesis remains a topic that later papers have continued to discuss.
Structure and physicochemical properties
At 16 amino acids, MOTS-c is a relatively small linear peptide with a free N-terminus and C-terminus in its native form. Several features are worth noting for laboratory work:
- Basic residues. The sequence contains three arginines and one lysine, giving the peptide a net positive charge at physiological pH. Basic peptides of this size can show affinity for glass and some plastics, which is relevant when preparing low-concentration solutions.
- Oxidation-sensitive residues. Two methionines (positions 1 and 6) and one tryptophan (position 3) are present. Methionine can oxidise to methionine sulfoxide, and tryptophan is sensitive to light and oxidation. This is one reason storage away from light and minimising air exposure matter.
- Aromatic content. Tryptophan and two tyrosines give the peptide measurable UV absorbance at around 280 nm, which can be used for concentration estimates by spectrophotometry.
- Hydrophobic patch. The Tyr-Ile-Phe-Tyr stretch in the middle of the sequence is relatively hydrophobic, which can influence solubility and retention behaviour on reversed-phase HPLC.
For a synthetic peptide of this length, identity is typically confirmed by mass spectrometry against the calculated molecular weight, and purity by reversed-phase HPLC. Our guide on how to read a peptide certificate of analysis explains what those two measurements show and what they do not.
A short history of MOTS-c research
2015: first description
MOTS-c was first reported by Lee and colleagues in Cell Metabolism in 2015, from the laboratory of Pinchas Cohen at the University of Southern California. The authors identified the open reading frame, raised antibodies against the peptide, detected it in tissues and plasma of rodents, and investigated its activity in cell culture and in mice. In cultured cells they reported effects on the folate-methionine pathway and on de novo purine biosynthesis, with downstream accumulation of the intermediate AICAR and activation of AMP-activated protein kinase (AMPK). In mouse experiments, the paper examined skeletal muscle as a principal target tissue and reported changes in markers of insulin sensitivity in diet-induced models.
2018: nuclear translocation
A 2018 study by Kim and colleagues, also in Cell Metabolism, reported that MOTS-c could translocate to the nucleus in cultured cells under metabolic stress, such as glucose restriction or oxidative stress. Once in the nucleus, the peptide was reported to interact with chromatin and to be associated with changes in the expression of genes linked to antioxidant response elements, in a manner involving the transcription factor NRF2. This work was influential because it offered experimental support for the idea that a mitochondrially encoded peptide could act directly on nuclear gene regulation.
2021: exercise models
In 2021, Reynolds and colleagues reported in Nature Communications that MOTS-c levels in skeletal muscle and circulation changed in response to exercise in human volunteers, and that administration of MOTS-c to mice of different ages was associated with changes in physical capacity measures in those rodent models. The human element of that study was observational, measuring endogenous peptide levels, and did not involve giving the peptide to people.
Other areas of investigation
Beyond these core papers, MOTS-c has been investigated in rodent and cell models relating to bone metabolism, vascular function, inflammation signalling and ageing biology. Association studies have also measured circulating MOTS-c in different human populations, and a naturally occurring variant of the MOTS-c sequence (m.1382A>C, which changes a lysine to a glutamine) has been studied in genetic association work in East Asian cohorts. These are largely early-stage findings and many have not been independently replicated.
Proposed mechanisms examined in the literature
Research papers have explored several mechanistic threads. It is worth presenting them as hypotheses that were investigated, not as settled biology.
Folate-methionine pathway and AICAR
The original 2015 paper reported that MOTS-c influenced the folate-methionine pathway in cultured cells, which was associated with a reduction in purine biosynthesis flux and accumulation of AICAR (5-aminoimidazole-4-carboxamide ribonucleotide). AICAR is itself a well-known experimental AMPK activator, so this offered a plausible link between MOTS-c and AMPK signalling in the models examined.
AMPK signalling
AMP-activated protein kinase is a central energy sensor in cells. Many of the downstream observations in MOTS-c papers, including changes in glucose uptake in muscle cells, were interpreted in terms of AMPK activation. Later work has examined whether other pathways contribute, and the relative importance of AMPK across tissues and experimental conditions is still discussed.
Nuclear signalling and stress response
The 2018 nuclear translocation work placed MOTS-c within the broader field of mitonuclear communication. In that study, the peptide's nuclear entry was reported to depend on AMPK and to be associated with stress-response gene expression. This line of research connects MOTS-c to studies of how cells coordinate mitochondrial and nuclear gene programmes under stress.
How MOTS-c fits into wider mitochondrial research
MOTS-c is one of several compounds that laboratories use to probe mitochondrial function from different angles. Comparing them is useful because they act at very different points:
- SS-31 (elamipretide) is a synthetic tetrapeptide designed to associate with cardiolipin in the inner mitochondrial membrane. It has been studied for its interaction with membrane structure and electron transport, rather than as a signalling peptide. See our overview of SS-31 (elamipretide), the mitochondria-targeting tetrapeptide.
- NAD+ and its precursors sit at the heart of cellular redox chemistry and are substrates for sirtuins and PARPs. Research on NAD+ metabolism overlaps with MOTS-c work through shared interest in AMPK and energy sensing. Our article on NAD+ vs NMN and the NAD+ pathway covers the biochemistry.
- 5-Amino-1MQ is a small-molecule inhibitor of nicotinamide N-methyltransferase (NNMT), an enzyme that links methyl-donor metabolism with NAD+ salvage. Read more in 5-Amino-1MQ: an NNMT inhibitor in metabolic research.
- AOD 9604 is a modified fragment of the C-terminal region of human growth hormone, studied in rodent models of lipid metabolism. It works through quite different biology from mitochondrial peptides, and is covered in AOD 9604: the hGH fragment 176-191 explained.
Taken together, these compounds allow researchers to examine metabolism at the level of membrane structure, cofactor supply, enzyme regulation and peptide signalling. They are not interchangeable, and conclusions drawn from one model do not transfer automatically to another.
Limitations of the current evidence
Anyone reviewing the MOTS-c literature should be aware of several limitations:
- Predominantly preclinical. Most mechanistic data come from cell culture and rodent studies. Rodent physiology, particularly in energy metabolism, differs from human physiology in important ways.
- Measurement challenges. Quantifying endogenous MOTS-c in plasma or tissue relies on immunoassays and, increasingly, mass spectrometry. Different methods have produced different concentration ranges, which complicates comparison between studies.
- Replication. Several reported findings come from a small number of research groups. Independent replication across laboratories is still building.
- Peptide stability. Short linear peptides are generally susceptible to proteolysis in biological matrices, so in vitro and in vivo conditions may not be directly comparable.
None of the published work establishes any effect of MOTS-c in humans, and MOTS-c is not an approved medicine in the UK or elsewhere.
Handling and storage in the laboratory
MOTS-c is supplied as a lyophilised powder. In common with most research peptides, the dry solid is considerably more stable than any solution. General good practice includes:
- Keeping sealed vials at 2-8°C, protected from light, and avoiding repeated temperature changes.
- Allowing a vial to reach room temperature before opening, so that condensation does not form on the cold powder.
- Minimising air exposure, given the oxidation-prone methionine and tryptophan residues.
- Recording the date of receipt and opening in the laboratory log.
Our article on how to store lyophilised peptides covers moisture, light and temperature in more detail. For information on the laboratory solvents commonly kept alongside peptides, see bacteriostatic water vs sterile water vs acetic water.
Purity and identity testing
Our MOTS-c is specified at >99% purity by HPLC. Purity figures should always be read alongside the analytical method and the identity confirmation. A high HPLC figure tells you what proportion of UV-absorbing material elutes as the main peak, while mass spectrometry confirms that the main species has the expected molecular weight of 2174.6 g/mol. For a broader explanation, see our research peptides UK buyer's guide.
Regulatory position in the UK
MOTS-c is sold by Compound Cave strictly as a laboratory research material. It is not a medicine, food supplement or cosmetic ingredient, and is not supplied for human or veterinary use. For an informational overview of how research chemicals are regarded under UK medicines law, see are peptides legal in the UK.
View MOTS-c in the catalogue.
Frequently asked questions
What does MOTS-c stand for?
MOTS-c stands for mitochondrial open reading frame of the 12S rRNA type-c. The name reflects where the peptide's coding sequence sits: inside the mitochondrial gene for 12S ribosomal RNA.
How long is the MOTS-c peptide?
MOTS-c is 16 amino acids long, with the sequence MRWQEMGYIFYPRKLR. Its molecular formula is C101H152N28O22S2 and its molecular weight is 2174.6 g/mol.
When was MOTS-c discovered?
MOTS-c was first described in 2015 by Lee and colleagues in Cell Metabolism, from the laboratory of Pinchas Cohen. Subsequent papers in 2018 and 2021 extended the work to nuclear signalling and exercise models.
Is MOTS-c the same as humanin?
No. Both are mitochondrial-derived peptides, but humanin is encoded in the 16S rRNA region and MOTS-c in the 12S rRNA region. They have different sequences and have been investigated in different experimental contexts.
Is MOTS-c an approved medicine?
No. MOTS-c is not approved as a medicine in the UK or elsewhere. The material supplied by Compound Cave is for laboratory research use only and is not for human or veterinary use.
How should lyophilised MOTS-c be stored?
Sealed vials should be kept at 2-8°C, in the dark and upright, and should not be frozen. Keep the vial sealed until use and let it reach room temperature before opening to avoid condensation.
References
- Lee C, Zeng J, Drew BG, et al. (2015). Cell Metabolism, 21(3), 443-454. Original description of MOTS-c.
- Kim KH, Son JM, Benayoun BA, Lee C. (2018). Cell Metabolism, 28(3), 516-524. Nuclear translocation of MOTS-c under metabolic stress.
- Reynolds JC, Lai RW, Woodhead JST, et al. (2021). Nature Communications, 12, 470. MOTS-c in exercise and ageing models.
- Hashimoto Y, Niikura T, Tajima H, et al. (2001). Proceedings of the National Academy of Sciences USA, 98(11), 6336-6341. Identification of humanin.
- Cobb LJ, Lee C, Xiao J, et al. (2016). Aging (Albany NY), 8(4), 796-809. Small humanin-like peptides (SHLPs).
MOTS-c remains an active subject of mitochondrial research. Its identity is well defined, while much of its biology is still being investigated in preclinical models.
For laboratory research use only. Not for human or veterinary use. See our research use only policy.