What is MOTS-c, the mitochondrial peptide?

MOTS-c is a small peptide, a chain of 16 amino acids. Its name is an acronym: mitochondrial open reading frame of the 12S rRNA-c, an open reading frame in the mitochondrial 12S rRNA gene, type c.

What sets it apart is its origin. Most proteins and peptides in the body are encoded in the DNA of the cell nucleus. MOTS-c is encoded in the DNA of the mitochondria, the small structures in the cell that produce energy and carry their own small genome.

MOTS-c was first described in 2015 by a research group at the University of Southern California (Lee et al., Cell Metab 2015, PMID 25738459). The researchers found a short sequence within the mitochondrial 12S rRNA gene that encodes a 16-amino-acid peptide and named it MOTS-c.

For decades mitochondrial DNA was thought to contain only a few genes, mainly for the work of the mitochondria themselves. Before MOTS-c, another peptide encoded in a short sequence of mitochondrial DNA had already been described: humanin. The existence of humanin led researchers to look for further such sequences, and that is how MOTS-c was found (Lee et al., Cell Metab 2015, PMID 25738459).

In the literature, MOTS-c and humanin belong to a group called mitochondrial-derived peptides. The term describes their origin, not any particular action.

MOTS-c is produced by the human body itself. Its levels can be measured in blood and muscle, and almost all research in humans to date is based on these measurements.

The first studies were done in cell cultures, with the aim of describing how the peptide works inside the cell.

• Metabolic pathways (Lee et al., Cell Metab 2015, PMID 25738459): in cells, inhibition of folate metabolism and of purine synthesis (purines are building blocks of DNA) was recorded, followed by activation of AMPK. AMPK is an enzyme that acts as the cell's "energy sensor": it is activated when available energy falls.
• Movement to the nucleus (Kim et al., Cell Metab 2018, PMID 29983246): in cells under metabolic stress, such as glucose restriction, MOTS-c moved from the mitochondria to the nucleus. There, regulation of the expression of many genes was recorded, including genes with antioxidant response elements, as well as interaction with the transcription factor NRF2. The movement depended on AMPK.

Most data on giving MOTS-c come from experimental models in mice and rats:

• Metabolic parameters (Lee et al., Cell Metab 2015, PMID 25738459): in mice that received MOTS-c, the insulin resistance linked to age or induced experimentally with a special diet did not develop. Skeletal muscle was described as the main target organ.
• Physical capacity (Reynolds et al., Nat Commun 2021, PMID 33473109): in mice of three ages, young (2 months), middle-aged (12 months) and old (22 months), improved physical capacity was measured after MOTS-c was given. In mice in which it was started late in life (23.5 months), greater physical capacity was recorded compared with control mice.
• Vascular response (Qin et al., Int J Cardiol 2018, PMID 29242099): in aortic segments from rats and mice, studied outside the body, prior exposure to MOTS-c was associated with a better vessel response to acetylcholine.

Results in animals do not carry over automatically to humans. Rodent metabolism, lifespan and physiology differ considerably.

A PubMed search on 26/10/2026 found no published study in which MOTS-c was given to humans. The human data concern something different: measurement of the levels of MOTS-c that the body itself produces, in blood or muscle. Most are observational studies, which record associations, not cause and effect.

Age: • In healthy men of three age groups (18–30, 45–55 and 70–81 years), blood MOTS-c levels were lower at older ages. In contrast, MOTS-c expression in the muscle of middle-aged and older men was about 1.5 times higher than in young men (D'Souza et al., Aging 2020, PMID 32182209).

Diabetes and metabolism: • In a cross-sectional study of 225 people (68 without a disorder, 33 with prediabetes, 31 and 93 with type 2 diabetes with good or poor control respectively), serum MOTS-c levels were lower in type 2 diabetes than in the control group. They correlated negatively with age, glycated haemoglobin (HbA1c) and glucose (Ramanjaneya et al., Front Endocrinol 2019, PMID 31214116). • In 125 participants without type 2 diabetes (91 men, 34 women) the picture was different: plasma MOTS-c levels were higher in the 26 people with metabolic syndrome and correlated positively with blood pressure, fasting glucose, triglycerides and waist circumference (Sequeira et al., Biochim Biophys Acta Gen Subj 2021, PMID 34419510).

Heart and kidneys: • In 40 patients who underwent coronary angiography without significant narrowing (20 with normal and 20 with impaired coronary endothelial function), plasma MOTS-c was lower in the group with impaired function (Qin et al., Int J Cardiol 2018, PMID 29242099). • A Greek team from Attikon University Hospital followed 121 patients with type 2 diabetes and coronary artery disease for 2 years. 22 had a serious cardiovascular event, and low MOTS-c levels were recorded as a predictor, with a relative risk of 3.8. The findings were confirmed in a second group of 90 patients (Ikonomidis et al., J Thromb Thrombolysis 2020, PMID 32052315). • In patients with stage 5 chronic kidney disease, MOTS-c levels were lower in both muscle and serum compared with people of the same age with normal kidney function (Liu et al., Am J Physiol Renal Physiol 2019, PMID 31432706).

Exercise: • Researchers from the original group recorded that exercise was associated with an increase in the body's own MOTS-c, in muscle and in blood (Reynolds et al., Nat Commun 2021, PMID 33473109). • In a randomised study with 10 people per group, after 45 minutes of cycling plasma MOTS-c levels showed only a trend to increase, without a statistically significant difference (von Walden et al., J Appl Physiol 2021, PMID 34351816). • In women after breast cancer, a 16-week programme of aerobic and resistance exercise was associated with an increase in MOTS-c in 24 non-Hispanic white women but not in 25 Hispanic women (Dieli-Conwright et al., Sci Rep 2021, PMID 34413391). • In another study, 8 weeks of moderate exercise did not change blood MOTS-c levels, either in healthy women or in women with polycystic ovary syndrome (Ramanjaneya et al., Clin Endocrinol 2019, PMID 31066084). • In 75 professional athletes, serum MOTS-c levels were lower than in 30 people who did not do sport (Alser et al., Rev Cardiovasc Med 2022, PMID 39077591).

Genetics: • A mitochondrial DNA variant (m.1382A>C), found in East Asian populations, changes one amino acid of MOTS-c. In an analysis of three population studies with 27,527 people, men with the variant had a higher prevalence of type 2 diabetes, while no difference was recorded in women (Zempo et al., Aging 2021, PMID 33468709).

The ClinicalTrials.gov registry (checked 26/10/2026) has two relevant entries:

• A randomised phase 2a trial with MOTS-c itself, company-sponsored, in adults with prediabetes, with insulin sensitivity as the main end point (NCT07505745). It is recruiting and has no results.
• A phase 1 trial with a modified analogue of MOTS-c (code CB4211), also company-sponsored, completed in 2021 (NCT03998514). No results are posted in the registry, and no publication of its results was found in PubMed. The sponsor had announced results in 2021 by press release and a scientific-meeting presentation, without a journal publication.

A registered trial does not predict its own result and does not show that MOTS-c is effective or safe for any use.

The World Anti-Doping Agency (WADA) names MOTS-c on its 2026 list of substances and methods, in force from 1 January 2026. It sits in class S4 (hormone and metabolic modulators), subsection S4.4.1, as an example of a substance that activates AMPK. Class S4 is among the substances the list covers at all times, in and out of competition. According to the US Anti-Doping Agency (USADA), MOTS-c was added by name to the 2025 list.

This concerns athletes who are subject to anti-doping rules. Inclusion of a substance on the list is not a judgement on whether or not it acts in humans.

Research on MOTS-c is at an early stage and has important gaps:

• No study of giving MOTS-c to humans has been published. Everything about giving it comes from cells and rodents.
• Human studies measure the levels of MOTS-c the body produces. An association, such as lower levels in type 2 diabetes, does not show that MOTS-c causes or prevents anything.
• The findings do not always agree. In people with type 2 diabetes levels were lower, while in people without diabetes with metabolic syndrome they were higher. Some exercise studies recorded an increase, others no change, and in professional athletes levels were lower.
• The studies are usually small, from 10 to a few hundred people, except for the genetic analyses.
• Blood MOTS-c is measured with immunoassays (ELISA), and in the studies cited here the method is not always the same, so values cannot be compared directly from study to study.
• Many of the studies cited here have as authors members of the group that first described the peptide, or its collaborators.
• It is not known whether the results in rodents, such as improved physical capacity, have a counterpart in humans.

A certificate of analysis records the identity of the substance, usually by mass spectrometry, its purity measured by HPLC, the laboratory that ran the analysis and the batch number it refers to. For a 16-amino-acid peptide such as MOTS-c, mass spectrometry confirms that the molecular mass matches the correct sequence. Published certificates are in the COA library.

The literature describes it as a peptide produced in cells and detected in blood, which is why some researchers discuss it as a possible signal circulating in the body. Its exact role in humans has not been established.

No. They are two different peptides. Both are encoded in mitochondrial DNA, but in different places. Humanin was described first; MOTS-c in 2015. More on the categories of peptides in the guide "What are peptides".

The levels of MOTS-c that the body produces have been measured in various groups of people. No study of giving MOTS-c to humans has been published; one phase 2a clinical trial is registered and under way (checked 26/10/2026).

In humans, the levels of MOTS-c that the body produces have been measured before and after exercise: an increase in some studies, no change in others. No study of giving MOTS-c to humans has been published, and findings in mice do not carry over automatically to humans.

• Lee C et al. Cell Metab. 2015. PMID 25738459 · DOI 10.1016/j.cmet.2015.02.009
• Kim KH et al. Cell Metab. 2018. PMID 29983246 · DOI 10.1016/j.cmet.2018.06.008
• Reynolds JC et al. Nat Commun. 2021. PMID 33473109 · DOI 10.1038/s41467-020-20790-0
• Qin Q et al. Int J Cardiol. 2018. PMID 29242099 · DOI 10.1016/j.ijcard.2017.12.001
• D'Souza RF et al. Aging (Albany NY). 2020. PMID 32182209 · DOI 10.18632/aging.102944
• Ramanjaneya M et al. Front Endocrinol (Lausanne). 2019. PMID 31214116 · DOI 10.3389/fendo.2019.00331
• Sequeira IR et al. Biochim Biophys Acta Gen Subj. 2021. PMID 34419510 · DOI 10.1016/j.bbagen.2021.129991
• Ikonomidis I et al. J Thromb Thrombolysis. 2020. PMID 32052315 · DOI 10.1007/s11239-020-02060-4
• Liu C et al. Am J Physiol Renal Physiol. 2019. PMID 31432706 · DOI 10.1152/ajprenal.00202.2019
• von Walden F et al. J Appl Physiol (1985). 2021. PMID 34351816 · DOI 10.1152/japplphysiol.00706.2019
• Dieli-Conwright CM et al. Sci Rep. 2021. PMID 34413391 · DOI 10.1038/s41598-021-96419-z
• Ramanjaneya M et al. Clin Endocrinol (Oxf). 2019. PMID 31066084 · DOI 10.1111/cen.14007
• Alser M et al. Rev Cardiovasc Med. 2022. PMID 39077591 · DOI 10.31083/j.rcm2305181
• Zempo H et al. Aging (Albany NY). 2021. PMID 33468709 · DOI 10.18632/aging.202529
• ClinicalTrials.gov: NCT07505745, NCT03998514 (checked 26/10/2026)
• USADA, "What's New on the 2025 WADA Prohibited List" (2024; checked 26/10/2026)
• CohBar, press release on the phase 1a/1b results of CB4211 (10/08/2021; checked 26/10/2026)
• WADA, 2026 list of substances and methods, class S4.4.1 (checked 26/10/2026)

An informational text summarising published research. It is not medical advice or usage guidance.