Compound research

MOTS-c: research overview

MOTS-c is a 16-amino-acid peptide encoded by a short open reading frame within the 12S rRNA gene of mitochondrial DNA. It has been studied in cultured cells and rodent models in connection with the folate cycle, AICAR accumulation and AMPK activation, and in observational human work measuring endogenous levels in skeletal muscle and blood.1, 3

MOTS-c

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Mechanism at a glance

Folate cycle and de novo purine synthesisReported to be inhibited by MOTS-c in cultured cells, with accumulation of AICAR.1
AMPKReported to be activated downstream of AICAR accumulation in cell studies; described as the central node of the proposed pathway.1, 6
Nucleus and NRF2Under glucose restriction, MOTS-c was reported to enter the nucleus and interact with NRF2 in cell studies.2
Skeletal muscleProposed main target tissue in mouse studies; endogenous MOTS-c was reported to increase with exercise in human muscle and blood.1, 3

The folate-AICAR-AMPK axis and the nuclear signalling role appear linked, as nuclear gene regulation by MOTS-c was reported to be AMPK-dependent in cell studies; whether these steps operate the same way in humans is still being investigated.1, 2, 6

What it is

MOTS-c stands for mitochondrial open reading frame of the 12S rRNA type-c. It is a 16-amino-acid peptide encoded within the mitochondrial 12S rRNA gene, where it was identified as a short open reading frame. It belongs to the mitochondrial-derived peptides, a group that also includes humanin and the small humanin-like peptides.1, 6

Conservation and detection

A sequence alignment across 14 species indicated that MOTS-c is highly conserved, especially in its first 11 residues. Endogenous MOTS-c has been reported in rodent tissues and in rodent and human plasma, measured with a MOTS-c-specific immunoassay.1

How it acts

Most mechanistic data come from cultured cells and mice. Evidence from these models should not be read as evidence in humans.1–3

Folate cycle and AMPK (in vitro)

In HEK293 cells, stable expression of MOTS-c, or exposure of the cells to synthetic MOTS-c, was reported to inhibit the folate cycle and the linked de novo purine synthesis. This was accompanied by accumulation of AICAR, an endogenous AMPK activator, and by AMPK activation.1

Nuclear signalling (in vitro)

Under metabolic stress such as glucose restriction, MOTS-c was reported to move into the nucleus. There it was associated with regulation of nuclear genes, including genes carrying antioxidant response elements, and with interaction with the transcription factor NRF2. This nuclear role was reported to depend on AMPK.2

Animal models

In mice, MOTS-c has been studied in models of age-related and high-fat-diet-induced insulin resistance and of diet-induced obesity, with skeletal muscle proposed as its main target tissue. A later study examined physical performance and skeletal-muscle gene expression in young, middle-aged and old mice.1, 3

Research status

The human work listed here measured the body's own (endogenous) MOTS-c. None of these studies tested the peptide itself in people.3–5

Human observational data

Exercise was reported to raise endogenous MOTS-c expression in human skeletal muscle and in circulation. A systematic review and meta-analysis of mitochondrial-derived peptides pooled measurements of circulating MOTS-c in people with diabetes and in people with obesity.3, 5

Measurement questions

A mass-spectrometry method developed for doping control could not confirm the plasma MOTS-c levels reported by a commercial ELISA. The authors noted considerable differences between the two methods, so published circulating values should be read with caution.4

Open questions

Reviews describe MOTS-c research in type 1 and type 2 diabetes and in ageing-related conditions as an area of continuing investigation.6

Published research at a glance

Animal model
Insulin resistance and diet-induced obesity models in mice, alongside folate-cycle, AICAR and AMPK experiments in cultured cells
[1]
In vitro
Nuclear translocation under glucose restriction and NRF2-linked regulation of nuclear genes in cells
[2]
Animal model
Physical performance and skeletal-muscle gene expression across age groups in mice, with accompanying observations of exercise-induced endogenous MOTS-c in human muscle and blood
[3]
In vitro
Analytical method: mass-spectrometry detection of MOTS-c in human plasma samples for doping control, compared with a commercial ELISA
[4]
Review
Systematic review and meta-analysis of mitochondrial-derived peptides, pooling circulating MOTS-c in diabetes and obesity
[5]
Review
MOTS-c and other mitochondrial-encoded peptides in diabetes and ageing-related disease
[6]

Published research at a glance
Type of evidence	What was examined	Source
Animal model	Insulin resistance and diet-induced obesity models in mice, alongside folate-cycle, AICAR and AMPK experiments in cultured cells	[1]
In vitro	Nuclear translocation under glucose restriction and NRF2-linked regulation of nuclear genes in cells	[2]
Animal model	Physical performance and skeletal-muscle gene expression across age groups in mice, with accompanying observations of exercise-induced endogenous MOTS-c in human muscle and blood	[3]
In vitro	Analytical method: mass-spectrometry detection of MOTS-c in human plasma samples for doping control, compared with a commercial ELISA	[4]
Review	Systematic review and meta-analysis of mitochondrial-derived peptides, pooling circulating MOTS-c in diabetes and obesity	[5]
Review	MOTS-c and other mitochondrial-encoded peptides in diabetes and ageing-related disease	[6]

Research status: A mass-spectrometry method for detecting MOTS-c in plasma has been developed for doping-control purposes and validated in line with the World Anti-Doping Agency's International Standard for Laboratories.4

Technical specifications

Molecular weight: 2174 Da
CAS number: 1627580-64-6

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). doi:10.1016/j.cmet.2015.02.009
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). doi:10.1016/j.cmet.2018.06.008
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). doi:10.1038/s41467-020-20790-0
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). doi:10.1002/rcm.8337
Zhou Q, Yin S, Lei X, et al. The correlation between mitochondrial derived peptide (MDP) and metabolic states: a systematic review and meta-analysis. Diabetology & Metabolic Syndrome (2024). doi:10.1186/s13098-024-01405-w
Kong BS, Lee C, Cho YM. Mitochondrial-Encoded Peptide MOTS-c, Diabetes, and Aging-Related Diseases. Diabetes & Metabolism Journal (2023). doi:10.4093/dmj.2022.0333

Literature summary compiled on 15 October 2026.