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MOTS-c

Also identified as Mitochondrial ORF of the 12S rRNA type-c

Mitochondrial-derived peptide

Molecular weight
2174.6
Molecular formula
C101H152N28O22S2
CAS
1627580-64-6
Published studies reviewed
3

FOR RESEARCH USE ONLY. NOT FOR HUMAN OR VETERINARY USE. NOT FOR HUMAN CONSUMPTION.

Compounds described on this site are supplied solely for laboratory research. They are not offered for human or veterinary use or for clinical use, and they are not intended to diagnose, mitigate, cure or prevent any disease.

MOTS-c is a peptide encoded in mitochondrial DNA rather than the nuclear genome, which places it among the mitochondrial-derived peptides. Three publications are reviewed: two laboratory studies and a 2019 metabolomics study of plasma markers in mice. Every finding comes from sequence work, cultured cells or mouse plasma, and no human study is included.

At a glance

Also identified as
Mitochondrial ORF of the 12S rRNA type-c
Class
Mitochondrial-derived peptide
Target or mechanism
The 2019 mouse study recorded here characterises the compound by the plasma metabolite pathways that changed after it was given to mice.
Evidence types represented
in vitro, animal
Published studies reviewed
3
Last reviewed
2026-09-24

Overview

MOTS-c is a peptide encoded in mitochondrial DNA rather than in the nuclear genome — one of a small group of such peptides, which is what "mitochondrial-derived peptide" means.

One of the three publications recorded on this page, a 2019 study, used an unbiased metabolomics approach to ask what MOTS-c does to plasma markers in diet-induced obese mice. It found three metabolic pathways reduced — sphingolipid metabolism, monoacylglycerol metabolism and dicarboxylate metabolism — and notes that those same pathways are raised in obese and type 2 diabetes models.

Everything in the last paragraph happened in mice. No human study is recorded on this page, and the mouse figures do not transfer to a person by being described carefully.

Nothing here is a statement about the research material PepGenex supplies.

Mechanism under investigation

The 2019 mouse study recorded here characterises the compound by the plasma metabolite pathways that changed after it was given to mice. None of the three publications recorded here identifies a receptor.

Scope of the published work

Areas investigated
  • Plasma metabolite profile
  • Insulin sensitivity in animal models
Models used
  • Diet-induced obese mice

Of the three publications recorded here, two are represented by laboratory (in vitro) findings and one by findings in mice; no human study is represented. What they report comes from sequence analysis, cultured cells and mouse plasma, and does not establish anything about a person. Nothing on this page is a statement about the research material PepGenex supplies.

Limitations

Evidence represented on this page: in vitro and animal. No human research is represented. The page reviews 3 published studies, and each figure is reported for the study that published it; results are not pooled across studies.

Common questions

What is MOTS-c?

MOTS-c is a peptide encoded in mitochondrial DNA rather than in the nuclear genome — one of a small group of such peptides, which is what "mitochondrial-derived peptide" means.

How does MOTS-c work, according to the published research?

The 2019 mouse study recorded here characterises the compound by the plasma metabolite pathways that changed after it was given to mice. None of the three publications recorded here identifies a receptor.

  • In HEK293 cells, MOTS-c translocated to the nucleus following metabolic stress in an AMPK-dependent manner. In the nucleus it regulated a broad range of genes, including genes with antioxidant response elements, and interacted with the stress-responsive transcription factor NFE2L2/NRF2. (Kim et al., 2018, PMID 29983246)
  • In HEK293 cells stably overexpressing MOTS-c, unbiased metabolomic profiling pointed to the folate–methionine pathway and the directly tethered de novo purine biosynthesis pathway as its target; endogenous AICAR accumulated to levels more than 20-fold higher than in control cells. The authors report that these cellular actions lead to AMPK activation. (Lee et al., 2015, PMID 25738459)

What has published research on MOTS-c found, and what are its limits?

This page records 3 publications, reporting laboratory (in vitro) work in 2, animal work in 1. Each is listed with its identifier under References.

No human study is represented on this page.

Evidence represented on this page: in vitro and animal.

No human research is represented.

The page reviews 3 published studies, and each figure is reported for the study that published it; results are not pooled across studies.

Of the three publications recorded here, two are represented by laboratory (in vitro) findings and one by findings in mice; no human study is represented. What they report comes from sequence analysis, cultured cells and mouse plasma, and does not establish anything about a person. Nothing on this page is a statement about the research material PepGenex supplies.

Is MOTS-c approved by the U.S. FDA?

This page cites no FDA approval record for MOTS-c; PepGenex Science states a U.S. regulatory status only where a sourced record exists.

PepGenex research materials are not FDA approved and are not for human or veterinary use.

What risks have published studies of MOTS-c reported?

No human study is recorded on this page, so it reports no adverse events in people. Laboratory and animal findings are not a measure of risk in people.

Published research

Grouped by the kind of study. Select one to narrow what is shown below.

Laboratory (in vitro)(2)

Laboratory (in vitro)

The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress

Kim KH, Son JM, Benayoun BA, et al., Cell Metabolism, 2018;28(3):516-524.e7

published

  • In resting HEK293 cells, EGFP-tagged MOTS-c localised to both mitochondria and the nucleus. Replacing its hydrophobic core (residues 8-11, YIFY) with alanines prevented nuclear entry, whereas replacing its basic cluster (residues 13-16, RKLR) with alanines did not.
  • In HEK293 cells, MOTS-c translocated to the nucleus following metabolic stress in an AMPK-dependent manner. In the nucleus it regulated a broad range of genes, including genes with antioxidant response elements, and interacted with the stress-responsive transcription factor NFE2L2/NRF2.
View publication →
Laboratory (in vitro)

The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance

Lee C, Zeng J, Drew BG, et al., Cell Metabolism, 2015;21(3):443-454

published

  • An in silico search of the human mitochondrial 12S rRNA identified a 51-base-pair short open reading frame with a strong Kozak sequence, translating into a 16-amino-acid peptide the authors named MOTS-c (mitochondrial open-reading-frame of the twelve S rRNA type-c; GenBank accession KP715230). Sequence alignment across 14 species showed the first 11 residues to be highly conserved.
  • In HEK293 cells stably overexpressing MOTS-c, unbiased metabolomic profiling pointed to the folate–methionine pathway and the directly tethered de novo purine biosynthesis pathway as its target; endogenous AICAR accumulated to levels more than 20-fold higher than in control cells. The authors report that these cellular actions lead to AMPK activation.
View publication →

Preclinical (animal)(1)

Preclinical (animal)

The mitochondrial-derived peptide MOTS-c is a regulator of plasma metabolites and enhances insulin sensitivity

Kim SJ, Miller B, Mehta HH, et al., Physiological Reports, 2019;7(13):e14171

published

An unbiased metabolomics study of plasma markers in diet-induced obese mice given MOTS-c, examining whether the compound changes the plasma markers associated with metabolic dysfunction.

  • Three metabolic pathways were reduced in the mice given MOTS-c: sphingolipid metabolism, monoacylglycerol metabolism and dicarboxylate metabolism. The publication notes that these same pathways are raised in obese and type 2 diabetes models.
  • The publication reports that MOTS-c improves insulin sensitivity and increases beta-oxidation in these mice, and proposes the three pathways above as the route by which it does so.
Context

A metabolomics study answers a question of the form “what changed in the blood, and along which pathways” — which is mechanistic information, and useful as such. It is not a measurement of whether anything improved for the animal, and it is three steps removed from a measurement of whether anything would improve for a person.

Limitations

There is no human study on this page. This study's measurements were made in diet-induced obese mice, and the distance between a mouse model of metabolic dysfunction and a person is the reason mouse findings are recorded at their own evidence tier rather than alongside human ones.

View publication →

Compared with related compounds

Classification, structure, recorded targets, evidence types and FDA status only, each read from the two compounds' own pages. These comparisons do not compare study results.

MOTS-c and Elamipretide (SS-31)

Peptides studied in mitochondrial research: one encoded in mitochondrial DNA, one synthetic and recorded at cardiolipin.

MOTS-cElamipretide (SS-31)
ClassificationMitochondrial-derived peptideMitochondria-targeting tetrapeptide
StructureFormula C101H152N28O22S2Formula C32H49N9O5
Targets recordedNo target recorded on its pageCardiolipin (inner mitochondrial membrane)
Evidence types representedin vitro, animalhuman
Status with the U.S. FDANot shown (no Drugs@FDA application record verified for this page)An FDA approved drug product containing elamipretide (SS-31) exists. Source: Drugs@FDA, Application NDA 215244.

References

Published studies reviewed (3)

  1. The mitochondrial-derived peptide MOTS-c is a regulator of plasma metabolites and enhances insulin sensitivity — Kim SJ, Miller B, Mehta HH, et al., Physiological Reports, 2019;7(13):e14171
    DOI 10.14814/phy2.14171 · PMID 31293078 · PMC6640593
  2. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance — Lee C, Zeng J, Drew BG, et al., Cell Metabolism, 2015;21(3):443-454
    DOI 10.1016/j.cmet.2015.02.009 · PMID 25738459 · PMC4350682
  3. The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress — Kim KH, Son JM, Benayoun BA, et al., Cell Metabolism, 2018;28(3):516-524.e7
    DOI 10.1016/j.cmet.2018.06.008 · PMID 29983246 · PMC6185997

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