MOTS-c: the mitochondrial-derived peptide in published research

In short: MOTS-c is a 16-amino-acid peptide encoded within the 12S ribosomal RNA gene of mitochondrial DNA, first described in 2015. The published evidence is mostly cell and rodent work, plus human studies that measured circulating levels. No placebo-controlled trial of MOTS-c in people has published results. MOTS-c has no ARTG entry and is named on the WADA Prohibited List.

This review summarises what the published studies on MOTS-c measured and reported, labelled by study type. If you are new to the difference between cell, animal and human evidence, our guide to how to read a peptide study explains the labels used here. For a side-by-side look at a synthetic mitochondria-targeted peptide, see MOTS-c vs SS-31 compared.

Key facts

Property	Value
Name and synonyms	MOTS-c; mitochondrial open reading frame of the 12S rRNA-c; UniProt entry A0A0C5B5G6 (MOTSC_HUMAN) 12
Sequence and length	MRWQEMGYIFYPRKLR (Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg), 16 amino acids 12
Encoding gene	MT-RNR1 (mitochondrial 12S ribosomal RNA) 12
Molecular formula	C101H152N28O22S2 13
Molecular weight	2174.6 g/mol 13
CAS number	1627580-64-6 13
PubChem CID	146675088
Compound class	Mitochondrial-derived peptide 11
Evidence base	Cell and animal studies; human observational and genetic association studies; no published results from a placebo-controlled trial of MOTS-c in people
WADA status	Named in section S4.4.1 (metabolic modulators: activators of AMPK) of the 2026 Prohibited List, prohibited at all times 14
TGA status	No entry in the Australian Register of Therapeutic Goods (ARTG search, 28 September 2026) 18

What is MOTS-c?

MOTS-c is a short peptide whose coding sequence sits in mitochondrial DNA rather than in the DNA of the cell nucleus. Mitochondria are the compartments inside cells that produce most of the cell’s chemical energy, and they carry a small genome of their own.

The name stands for “mitochondrial open reading frame of the 12S rRNA type-c”. An open reading frame is a stretch of genetic code that can be read, from a start signal to a stop signal, into a chain of amino acids. In a 2015 cell and mouse study, Lee et al. reported a 51-base-pair short open reading frame within the mitochondrial 12S ribosomal RNA gene that encodes a 16-amino-acid peptide, which they named MOTS-c 1.

MOTS-c belongs to a small group called mitochondrial-derived peptides. A 2022 narrative review by Miller et al. counted eight published members: humanin, MOTS-c and six small humanin-like peptides (SHLP1 to SHLP6) 11. The mitochondrial peptide SS-31 is sometimes discussed alongside MOTS-c, but it is a synthetic compound with a different origin; our SS-31 (elamipretide) research review covers it separately.

How is MOTS-c structured?

MOTS-c is a linear chain of 16 amino acids with the sequence MRWQEMGYIFYPRKLR, recorded in UniProt under the gene MT-RNR1 12. PubChem lists its molecular formula as C101H152N28O22S2 and its molecular weight as 2174.6 g/mol 13.

Illustration: a short peptide chain shown as linked beads, not the exact structure of MOTS-c.

Three structural points are worth noting:

• Where it is translated. Lee et al. reported that translation of MOTS-c must occur in the cytoplasm, using the standard genetic code, because reading the same sequence with the mitochondrial genetic code produces back-to-back start and stop signals 1.
• Nuclear look-alikes. Fragments of mitochondrial DNA also exist in the nuclear genome. Lee et al. searched these copies and reported that none encoded a peptide identical to MOTS-c 1.
• A human sequence variant. In a 2021 study, Zempo et al. described an Asian-specific mitochondrial DNA variant (m.1382A>C) that changes lysine to glutamine at position 14 of MOTS-c, written K14Q 7.

The sequence contains two methionine residues. When Knoop et al. built a mass spectrometry test for MOTS-c, they included two oxidation products of the peptide in the assay 10.

What mechanisms have researchers studied?

Researchers have mainly studied how MOTS-c relates to folate metabolism, the energy-sensing enzyme AMPK and gene expression in the nucleus.

• Folate and purine metabolism. In human cell lines, Lee et al. reported that MOTS-c altered folate-methionine metabolism and blocked the linked pathway that builds purines (a class of DNA and RNA building blocks). This led to a build-up of AICAR, an intermediate of purine synthesis, to more than 20 times control levels in cells engineered to produce extra MOTS-c 1.
• AMPK activation. AMPK (AMP-activated protein kinase) is an enzyme that responds to low cellular energy. Lee et al. linked the AICAR build-up to AMPK activation 1. Later studies in ovariectomised mice and in bone cell cultures also reported AMPK activation with MOTS-c 3 5.
• Movement into the nucleus. In a 2018 cell study, Kim et al. reported that MOTS-c moved into the nucleus during metabolic stress, such as glucose restriction, in an AMPK-dependent manner. There it regulated a broad range of genes, including those with antioxidant response elements, and interacted with the transcription factor NRF2 2.
• Immune cell signalling. In a 2021 study in non-obese diabetic (NOD) mice, Kong et al. reported that MOTS-c changed T cell behaviour through T cell receptor and mTORC1 signalling 6. Zhai et al. reported changes in macrophage signalling, including reduced MAPK phosphorylation, in a mouse infection model 4.

These are proposed mechanisms from cell and rodent experiments. None has been confirmed in people.

What does the published research include?

The MOTS-c literature is mostly cell and rodent studies, a set of human studies that measured MOTS-c in blood, one large genetic association study and an analytical method paper. The table lists representative studies; it is not exhaustive.

Study	Study type	Model	What was measured	Reported finding
Lee 2015	Cell and mouse study	Human cell lines (HEK293, HeLa); mice fed a high-fat diet; middle-aged mice	Metabolites, AMPK activity, insulin sensitivity, body weight	Authors reported that MOTS-c treatment prevented diet-induced and age-dependent insulin resistance, and diet-induced obesity, in mice
Kim 2018	Cell study	Human cell lines (HEK293, HepG2) under glucose restriction, serum deprivation or oxidative stress	Location of MOTS-c in the cell; nuclear gene expression	MOTS-c moved to the nucleus under metabolic stress and regulated genes with antioxidant response elements
Ming 2016	Mouse and cell study	Ovariectomised mice (a model of oestrogen loss); osteoclast cultures	Bone structure by micro-CT; osteoclast formation	Authors reported less bone loss and reduced osteoclast formation; an AMPK inhibitor partly blocked the effect on osteoclasts
Zhai 2017	Mouse and cell study	Mice infected with MRSA (a drug-resistant bacterium); macrophages	Survival, bacterial load, cytokines	Authors reported higher survival, lower bacterial load and lower pro-inflammatory cytokines than controls
Lu 2019	Mouse study	Ovariectomised mice	Fat mass, insulin resistance, brown fat activity	Authors reported less fat accumulation and insulin resistance, with AMPK pathway activation
Kong 2021	Mouse study with human samples	NOD mice (a model of autoimmune diabetes); serum and T cells from people with type 1 diabetes	High blood glucose, islet immune cell infiltration, T cell activity	Authors reported less hyperglycaemia in mice; people with type 1 diabetes had lower serum MOTS-c than healthy controls
Zempo 2021	Human genetic association study with mouse and cell work	Three cohorts, 27,527 people; high-fat-fed mice	Type 2 diabetes prevalence by K14Q genotype	Males, but not females, with the C allele had a higher prevalence of type 2 diabetes
Du 2018	Human case-control study	40 children and adolescents with obesity, 57 controls	Circulating MOTS-c and metabolic markers	MOTS-c was lower in the obesity group, a difference seen in males but not females
Cataldo 2018	Human cross-sectional study	10 lean and 10 obese adults	Plasma MOTS-c and insulin sensitivity indices	Plasma MOTS-c was similar in both groups; associations with insulin sensitivity held only in lean participants
Knoop 2019	Analytical method validation	Human plasma	LC-MS detection of MOTS-c compared with a commercial ELISA	ELISA values of 45.9 to 218.5 ng/mL in 20 healthy people were not confirmed by LC-MS; the authors reported considerable differences between the methods

Registered human trials

Two interventional trials are registered on ClinicalTrials.gov:

• NCT03998514. A phase 1a/1b, randomised, double-blind, placebo-controlled study of CB4211 in healthy non-obese adults and adults with non-alcoholic fatty liver disease. Its primary endpoints were adverse events, laboratory tests, vital signs and ECGs; secondary endpoints were pharmacokinetic measures (how the body absorbs and clears the compound). It is listed as completed in April 2021, with no results posted 16. Miller et al. describe CB4211 as a MOTS-c analogue, a modified version of the peptide rather than MOTS-c itself 11.
• NCT07505745. A phase 2a, randomised, double-blind, placebo-controlled, parallel-group trial of MOTS-c in adults with prediabetes and overweight or obesity, with an estimated 120 participants at a site in China. Its primary endpoints are change in an insulin sensitivity index derived from an oral glucose tolerance test (the Matsuda index) and treatment-emergent adverse events. It was recruiting when checked, with primary completion estimated for February 2027 15.

What are the limits of the evidence?

The main limit is that almost all findings about what MOTS-c does come from cells and rodents, and no placebo-controlled trial of MOTS-c in people has published results.

• Preclinical evidence only for effects. Every finding in the table about bone, fat tissue, infection or insulin sensitivity after MOTS-c exposure comes from cell or rodent models. Our explainer on why most peptide research is preclinical covers why these results cannot be applied to people.
• Human studies are observational. The human studies measured MOTS-c levels or genotypes and looked for associations. They cannot show cause and effect, and some were small: Cataldo et al. studied 20 adults 9.
• Measurement disagreement. Reported blood levels vary widely between methods. Du et al. reported group means of roughly 470 to 560 ng/mL 8, while Cataldo et al. reported means of about 0.5 ng/mL 9. Knoop et al. could not confirm ELISA-measured levels using mass spectrometry 10.
• Concentration of the foundational work. The discovery paper and several follow-up studies share authors from one research group, including Lee and Cohen 1 2 6 7. In the discovery paper, one author reported being a stockholder of and consultant to CohBar, Inc., and another a consultant 1; the 2018 nuclear translocation paper disclosed a consultancy and shareholding in the same company 2. The 2022 review states that UCLA licensed intellectual property on MOTS-c to CohBar 11.
• Varied models. Studies used different species, disease models, preparations and durations, so their results cannot be pooled or ranked against each other.

What is MOTS-c’s regulatory and anti-doping status in Australia?

MOTS-c has no entry in the ARTG, and it is named on the 2026 WADA Prohibited List.

• TGA. A search of the Australian Register of Therapeutic Goods on 28 September 2026 returned no entry for MOTS-c 18. The TGA’s advisory of 13 April 2026 defines unapproved peptide products as goods not included in the ARTG and names BPC-157, GHK-Cu, TB-500, retatrutide and CJC-1295 as examples; MOTS-c is not among them 17.
• WADA. The 2026 Prohibited List, in force from 1 January 2026, names “mitochondrial open reading frame of the 12S rRNA-c (MOTS-c)” under S4.4.1, activators of AMPK, within S4 hormone and metabolic modulators. Section S4 is listed as prohibited at all times, in and out of competition 14.
• Detection. Knoop et al. developed and validated a liquid chromatography-mass spectrometry test for MOTS-c in plasma for doping control purposes 10.

Our page on research peptides and anti-doping status sets MOTS-c alongside other compounds. Australian athletes can check Sport Integrity Australia for current guidance.

How is MOTS-c characterised in the lab?

A synthetic MOTS-c sample is usually characterised for identity, purity and peptide content, with results reported on a certificate of analysis.

• Identity. Mass spectrometry measures the mass of the molecule and compares it with the value expected from the sequence. PubChem gives a monoisotopic mass of 2173.108 Da for MOTS-c 13. Because the sequence contains two methionines, oxidised forms, each about 16 Da heavier per added oxygen atom, are a known species to look for 10.
• Purity. Reversed-phase HPLC separates the peptide from related impurities such as truncated or incomplete sequences. Our guide to what an HPLC purity percentage tells you explains how the figure is calculated.
• Peptide content and counter-ions. Synthetic peptides are usually supplied as salts. PubChem lists a trifluoroacetate salt form of MOTS-c among its synonyms 13. See net peptide content vs gross weight and acetate vs TFA salts.
• Sealed storage. Lyophilised (freeze-dried) material in a sealed vial is covered in our guide to storing lyophilised peptides.

Illustration: an HPLC chromatogram on a lab monitor, used to assess peptide purity.

Batch reports for our own material are published on the COA library and can be checked with the COA verification tool.

Frequently asked questions

Is MOTS-c encoded in mitochondrial DNA?

Yes. Lee et al. reported in 2015 that MOTS-c is encoded by a 51-base-pair short open reading frame inside the mitochondrial 12S ribosomal RNA gene, MT-RNR1 1. They also reported that the peptide is translated in the cytoplasm using the standard genetic code, because the mitochondrial code would read the same sequence as adjacent start and stop signals. UniProt records the peptide under entry A0A0C5B5G6 12.

What is the amino acid sequence and molecular weight of MOTS-c?

MOTS-c has 16 amino acids with the sequence MRWQEMGYIFYPRKLR, according to UniProt entry A0A0C5B5G6 12. PubChem (CID 146675088) lists the molecular formula C101H152N28O22S2, a molecular weight of 2174.6 g/mol and CAS number 1627580-64-6 13. A salt form, such as a trifluoroacetate salt, has a higher total mass than the free peptide, which is one reason certificates of analysis report net peptide content.

Has MOTS-c been tested in human clinical trials?

No placebo-controlled trial of MOTS-c in people has published results. ClinicalTrials.gov lists a completed phase 1a/1b study of CB4211, described in a 2022 review as a MOTS-c analogue, with no results posted 16 11. A phase 2a placebo-controlled trial of MOTS-c in adults with prediabetes was recruiting in 2026 15. Published human studies so far measured circulating MOTS-c or genotypes 8 9.

Is MOTS-c on the WADA Prohibited List?

Yes. The 2026 WADA Prohibited List names MOTS-c in section S4.4.1, activators of the AMP-activated protein kinase (AMPK), under S4 hormone and metabolic modulators, which are prohibited at all times 14. A validated mass spectrometry detection method for MOTS-c in plasma was published for doping control in 2019 10. See our anti-doping status table for other compounds.

Is MOTS-c included in the Australian Register of Therapeutic Goods?

No. A search of the ARTG on 28 September 2026 returned no entry for MOTS-c 18. The TGA’s April 2026 advisory defines unapproved peptide products as goods that are not included in the ARTG, and says such products have not been evaluated by the TGA 17. This article describes regulatory status only.

How is the identity of a MOTS-c sample confirmed?

Identity is usually confirmed by mass spectrometry, which compares the measured mass with the mass expected from the sequence MRWQEMGYIFYPRKLR. PubChem lists a monoisotopic mass of 2173.108 Da 13. Purity is assessed separately by HPLC. Our guide to mass spectrometry identity testing explains how the two results fit together on a certificate of analysis.

References

1. 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;21(3):443-454. doi:10.1016/j.cmet.2015.02.009. PMID: 25738459. PMCID: PMC4350682. [cell and mouse study]
2. Kim KH, Son JM, Benayoun BA, et al. The mitochondrial-encoded peptide MOTS-c translocates to the nucleus to regulate nuclear gene expression in response to metabolic stress. Cell Metabolism. 2018;28(3):516-524.e7. doi:10.1016/j.cmet.2018.06.008. PMID: 29983246. PMCID: PMC6185997. [cell study]
3. Ming W, Lu G, Xin S, et al. Mitochondria related peptide MOTS-c suppresses ovariectomy-induced bone loss via AMPK activation. Biochemical and Biophysical Research Communications. 2016;476(4):412-419. doi:10.1016/j.bbrc.2016.05.135. PMID: 27237975. [mouse and cell study]
4. Zhai D, Ye Z, Jiang Y, et al. MOTS-c peptide increases survival and decreases bacterial load in mice infected with MRSA. Molecular Immunology. 2017;92:151-160. doi:10.1016/j.molimm.2017.10.017. PMID: 29096170. [mouse and cell study]
5. Lu H, Wei M, Zhai Y, et al. MOTS-c peptide regulates adipose homeostasis to prevent ovariectomy-induced metabolic dysfunction. Journal of Molecular Medicine (Berlin). 2019;97(4):473-485. doi:10.1007/s00109-018-01738-w. PMID: 30725119. [mouse study]
6. Kong BS, Min SH, Lee C, et al. Mitochondrial-encoded MOTS-c prevents pancreatic islet destruction in autoimmune diabetes. Cell Reports. 2021;36(4):109447. doi:10.1016/j.celrep.2021.109447. PMID: 34320351. PMCID: PMC10083145. [mouse study with human samples]
7. Zempo H, Kim SJ, Fuku N, et al. A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c. Aging (Albany NY). 2021;13(2):1692-1717. doi:10.18632/aging.202529. PMID: 33468709. PMCID: PMC7880332. [human genetic association study with mouse and cell work]
8. Du C, Zhang C, Wu W, et al. Circulating MOTS-c levels are decreased in obese male children and adolescents and associated with insulin resistance. Pediatric Diabetes. 2018;19(6):1058-1064. doi:10.1111/pedi.12685. PMID: 29691953. [human case-control study]
9. Cataldo LR, Fernández-Verdejo R, Santos JL, et al. Plasma MOTS-c levels are associated with insulin sensitivity in lean but not in obese individuals. Journal of Investigative Medicine. 2018;66(6):1019-1022. doi:10.1136/jim-2017-000681. PMID: 29593067. [human cross-sectional study]
10. Knoop A, Thomas A, Thevis M. Development of a mass spectrometry based detection method for the mitochondrion-derived peptide MOTS-c in plasma samples for doping control purposes. Rapid Communications in Mass Spectrometry. 2019;33(4):371-380. doi:10.1002/rcm.8337. PMID: 30394592. [analytical method validation]
11. Miller B, Kim SJ, Kumagai H, et al. Mitochondria-derived peptides in aging and healthspan. Journal of Clinical Investigation. 2022;132(9):e158449. doi:10.1172/JCI158449. PMID: 35499074. PMCID: PMC9057581. [narrative review]
12. UniProt. A0A0C5B5G6 (MOTSC_HUMAN): Mitochondrial-derived peptide MOTS-c. https://www.uniprot.org/uniprotkb/A0A0C5B5G6/entry. Accessed 28 September 2026.
13. PubChem. Mots-c, compound summary, CID 146675088. https://pubchem.ncbi.nlm.nih.gov/compound/146675088. Accessed 28 September 2026.
14. World Anti-Doping Agency. Prohibited List 2026 (in force 1 January 2026). https://www.wada-ama.org/en/prohibited-list. Accessed 28 September 2026.
15. ClinicalTrials.gov. NCT07505745: MOTS-c in adults with prediabetes and overweight/obesity (phase 2a). https://clinicaltrials.gov/study/NCT07505745. Accessed 28 September 2026.
16. ClinicalTrials.gov. NCT03998514: A phase 1a/1b study of CB4211 in healthy non-obese subjects and subjects with nonalcoholic fatty liver disease. https://clinicaltrials.gov/study/NCT03998514. Accessed 28 September 2026.
17. Therapeutic Goods Administration. Understanding your responsibilities when importing, compounding and supplying unapproved peptide products (safety advisory, 13 April 2026). https://www.tga.gov.au/safety/safety-monitoring-and-information/safety-alerts/understanding-your-responsibilities-when-importing-compounding-and-supplying-unapproved-peptide-products. Accessed 28 September 2026.
18. Therapeutic Goods Administration. Australian Register of Therapeutic Goods (ARTG) search. https://www.tga.gov.au/resources/artg. Accessed 28 September 2026.