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MOTS-c is a 16-amino-acid peptide encoded in mitochondrial DNA, and in research it has mainly been studied for how it affects cell metabolism and insulin action, in cells and mice [G1]. Other studies tracked it moving into the cell nucleus under stress [G2], and looked at heart, blood-vessel, bone and infection models in animals [G5, G6, G7, G8]. The work in people in this overview is observational, and the trial registry lists no trial results [G4, G5, G11].
What is MOTS-c?
The name is short for "mitochondrial open reading frame of the 12S rRNA-c" [G1]. Mitochondria, the cell's energy-producing structures, carry a small set of genes of their own. One of them, 12S rRNA, is part of the machinery mitochondria use to make proteins. A short stretch inside that gene codes for MOTS-c [G1].
Lee et al. described the peptide in 2015 [G1]. Their paper cites humanin as an earlier peptide found encoded in mitochondrial DNA [G1]. Researchers now group these molecules as "mitochondrial-derived peptides" [G9, G10].
Lee et al. detected MOTS-c in mouse and rat tissues, and in human and rodent blood [G1]. Their experiments used synthetic MOTS-c, as well as cells engineered to make more of it [G1].
What is MOTS-c used for?
In research, MOTS-c has mainly been studied for how it changes metabolism inside cells, and for insulin action in mice [G1]. The research areas, in plain terms:
- Metabolism inside lab-grown cells. The work centred on the folate cycle, a chain of reactions cells use to make DNA building blocks [G1].
- Moving into the nucleus. Kim et al. tracked whether MOTS-c entered the cell's nucleus, its control centre, when cells were under stress, and which genes changed [G2].
- Insulin action in mice. Clamp tests and glucose uptake into muscle were the measures [G1].
- Heart and blood vessels. Models included mice whose main artery, the aorta, was surgically narrowed [G8], and blood-vessel rings from rats and mice [G5].
- Bone. Bone loss was measured in mice after their ovaries were removed [G6].
- Infection. Mice infected with MRSA, an antibiotic-resistant bacterium, were studied alongside immune cells called macrophages [G7].
- Physical tests in mice. Reynolds et al. put mice through a treadmill test and a rotating-rod (rotarod) test [G3]. - Genetics in people. A gene variant that changes one amino acid of MOTS-c was studied in large groups of people of Japanese descent [G4].
- Levels in people. MOTS-c in muscle and blood was measured in 10 young men around a cycling session [G3].
MOTS-c research areas at a glance
| Area | What researchers looked at | Models | How strong the evidence is |
|---|---|---|---|
| Cell metabolism | The folate cycle, purine (DNA building-block) production, a molecule called AICAR and the energy-sensing enzyme AMPK [G1] | Human HEK293 cells; rat muscle cells [G1] | Lab cell studies |
| Gene control in the nucleus | Whether MOTS-c entered the nucleus under stress, and which genes changed [G2] | Human HEK293 and HepG2 cells [G2] | Lab cell studies |
| Insulin action | Clamp tests and glucose uptake into muscle [G1] | Mice on a high-fat diet; 12-month-old mice [G1] | Animal studies |
| Heart | Heart ultrasound and tissue scarring after the aorta was narrowed [G8] | Mice; heart-derived cells [G8] | One animal study |
| Bone | Bone measured by micro-CT scans; formation of bone-resorbing cells [G6] | Mice after ovary removal; cell culture [G6] | One animal study |
| Infection and immune cells | Bacterial load and inflammatory messengers; bacterial killing by macrophages [G7] | Mice infected with MRSA; macrophages [G7] | One animal study |
| Physical tests in mice | Treadmill and rotating-rod (rotarod) tests [G3] | Mice [G3] | Animal studies |
| Genetics in people | A variant that changes one amino acid of MOTS-c, and type 2 diabetes prevalence [G4] | Three population cohorts, n = 27,527 [G4] | Observational (association) |
| MOTS-c levels in people | MOTS-c in muscle and blood before and after a cycling session [G3] | 10 young men [G3] | One small study measuring levels |
| Trials in people | Registry check for interventional studies [G11] | One completed phase 1 study of an analogue [G9, G11]; one phase 2a study of MOTS-c listed as recruiting [G11] | No trial results posted [G11] |
Evidence levels describe the study types in the sources listed; they are not a grading by the sources' authors.
How is MOTS-c thought to work?
The folate–AICAR–AMPK route. In human and rat cells, Lee et al. observed that MOTS-c inhibited the folate cycle and the linked pathway that builds purines [G1]. The enzymes the paper names are MTR, in the folate cycle, and GART and ATIC, in the purine pathway [G1]. In cells engineered to overproduce MOTS-c, AICAR, a molecule partway along that pathway, built up to more than 20 times control levels [G1]. AMPK, an enzyme that senses a cell's energy status, was switched on [G1]. A later review summarises MOTS-c as acting mainly through this pathway [G10].
Insulin measures in mice. Lee et al. reported higher insulin-stimulated glucose disposal in mice given MOTS-c, and named skeletal muscle as the apparent main target organ [G1].
The nucleus. Kim et al. put HEK293 cells under three kinds of stress: glucose restriction, serum deprivation and oxidative stress [G2]. Under each, MOTS-c moved into the nucleus, in as little as 30 minutes [G2]. Blocking AMPK stopped the move [G2]. Under glucose restriction, MOTS-c in the nucleus regulated a broad range of genes, including genes with antioxidant response elements [G2]. In a pull-down test (co-immunoprecipitation), it came down together with NRF2, a protein that switches on stress-response genes [G2].
Findings in other animal and tissue models.
- Heart: in mice with a narrowed aorta, Zhong et al. reported a smaller decline in heart function and less remodelling (structural change in the heart) with MOTS-c, with AMPK activation in heart tissue [G8].
- Blood vessels: in rat and mouse aortic rings, MOTS-c had no direct effect on vessel tone, but rings given it beforehand responded more strongly to acetylcholine, a messenger used to test the vessel lining [G5].
- Bone: Ming et al. reported less bone loss in ovary-removed mice given MOTS-c [G6]. In cells, it inhibited the formation of osteoclasts, the cells that break down bone, and an AMPK blocker partly removed that effect [G6].
- Infection: in mice infected with MRSA, Zhai et al. reported lower bacterial load in mice given MOTS-c [G7].
- Physical tests: Reynolds et al. reported that mice given MOTS-c ran longer on a treadmill test than control mice [G3]. Open questions. Protein modelling predicted that MOTS-c binds Raptor, part of a cell-growth signalling complex called mTORC1; this is a prediction, not a measured binding [G9]. One review lists what is still unknown: how MOTS-c's genetic message leaves the mitochondria, how it targets genes in the nucleus, and why it acts differently in different tissues [G10].
What kind of studies are these?
Cell studies test a compound on cells in a dish. Animal studies test it in a whole living animal, not a person. Observational studies in people measure something, such as a blood level or a gene, and look for links; they cannot show cause. Trials give a compound to people and compare it with a placebo.
Most of the work cited here is in cells and mice [G1, G2, G6, G7, G8]. In 40 people having an X-ray test of the heart's arteries (coronary angiography), plasma MOTS-c was lower in the group whose blood-vessel lining responded poorly, and it correlated with measures of that lining's function [G5]. In 27,527 people of Japanese descent, type 2 diabetes was more common in men carrying a mitochondrial DNA variant that changes one amino acid of MOTS-c, but not in women carrying it [G4]. In 10 young men, MOTS-c levels in muscle rose after a cycling session; blood levels rose during and after it, then returned to baseline after a rest [G3]. Kong et al. describe clinical trials of MOTS-c as "ongoing and currently limited" [G9]. A search of the ClinicalTrials.gov registry in October 2026 listed a completed phase 1 study of a MOTS-c analogue and a phase 2a, randomised, placebo-controlled study of MOTS-c listed as recruiting. Neither record listed results [G9, G11]. Several of the studies came from one university group, and authors of five of the papers declared consulting or shareholding ties to a company [G1, G2, G3, G4, G9] that sponsored a registered trial of a MOTS-c analogue [G9, G11].
For the same kind of map of another research peptide, see how the KPV research is laid out.
Sources
- [G1] Lee C, Zeng J, Drew BG, et al. Cell Metab. 2015;21(3):443–454. doi:10.1016/j.cmet.2015.02.009. PMID 25738459. PMC4350682.
- [G2] Kim KH, Son JM, Benayoun BA, Lee C. Cell Metab. 2018;28(3):516–524.e7. doi:10.1016/j.cmet.2018.06.008. PMID 29983246. PMC6185997.
- [G3] Reynolds JC, Lai RW, Woodhead JST, et al. Nat Commun. 2021;12:470. doi:10.1038/s41467-020-20790-0. PMID 33473109. PMC7817689.
- [G4] Zempo H, Kim SJ, Fuku N, et al. Aging (Albany NY). 2021;13(2):1692–1717. doi:10.18632/aging.202529. PMID 33468709. PMC7880332.
- [G5] Qin Q, Delrio S, Wan J, et al. Int J Cardiol. 2018;254:23–27. doi:10.1016/j.ijcard.2017.12.001. PMID 29242099.
- [G6] Ming W, Lu G, Xin S, et al. Biochem Biophys Res Commun. 2016;476(4):412–419. doi:10.1016/j.bbrc.2016.05.135. PMID 27237975.
- [G7] Zhai D, Ye Z, Jiang Y, et al. Mol Immunol. 2017;92:151–160. doi:10.1016/j.molimm.2017.10.017. PMID 29096170.
- [G8] Zhong P, Peng J, Hu Y, Zhang J, Shen C. J Cell Mol Med. 2022;26(21):5369–5378. doi:10.1111/jcmm.17551. PMID 36156853. PMC9639045.
- [G9] Kong BS, Lee C, Cho YM. Diabetes Metab J. 2023;47(3):315–324. doi:10.4093/dmj.2022.0333. PMID 36824008. PMC10244198.
- [G10] Wan W, Zhang L, Lin Y, et al. J Transl Med. 2023;21:36. doi:10.1186/s12967-023-03885-2. PMID 36670507. PMC9854231.
- [G11] ClinicalTrials.gov, searches for "MOTS-c" and "CB4211", accessed 26 October 2026; NCT03998514 (https://clinicaltrials.gov/study/NCT03998514); NCT07505745 (https://clinicaltrials.gov/study/NCT07505745).
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