MOTS-c: a mitochondrial-encoded peptide in metabolic research

Abstract illustration of a mitochondrion with folded inner membranes

Prepared by: Research Desk. Sources are linked for verification.

Published 19 October 2026

At a glance

Type: 16-amino-acid peptide encoded by mitochondrial DNA
Discovered: reported in 2015 by Changhan Lee, Pinchas Cohen and colleagues
Research stage: mainly cell and mouse studies; human data are observational
Regulatory status: not an approved medicine; prohibited in sport by WADA since 2025

What MOTS-c is

MOTS-c stands for "mitochondrial open reading frame of the 12S rRNA-c". It is a short peptide whose coding sequence sits inside the gene for the mitochondrial 12S ribosomal RNA. Its sequence is Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg. MOTS-c belongs to a small family of "mitochondrial-derived peptides" that also includes humanin.

The discovery was notable because it suggested that the mitochondrial genome, long thought to encode only a handful of proteins for energy production, also encodes signalling peptides that act elsewhere in the cell and body.

Research history

Lee et al. (2015) in Cell Metabolism reported the short open reading frame within the 12S rRNA gene and showed that the encoded peptide influenced insulin sensitivity and metabolic balance in mice. The authors identified skeletal muscle as its main target organ.

Later work by the same research community expanded the picture. Kim et al. (2018) reported that MOTS-c moves into the cell nucleus under metabolic stress and influences nuclear gene expression. Reynolds et al. (2021) in Nature Communications studied physical capacity in mice of different ages and reported that exercise raised MOTS-c levels in human skeletal muscle and blood.

Mechanisms studied in preclinical work

Folate cycle and AMPK. In cells, MOTS-c was reported to inhibit the folate cycle and the linked de novo purine synthesis pathway. This led to accumulation of AICAR, an intermediate that activates AMP-activated protein kinase (AMPK), a central energy sensor.
Nuclear signalling. Under glucose restriction, MOTS-c was found in the nucleus, where it interacted with stress-responsive transcription factors such as NRF2 and influenced genes with antioxidant response elements.
Mouse metabolism and physical capacity. In mice given MOTS-c, researchers reported resistance to diet-induced insulin resistance and obesity, and higher physical capacity in older animals.

These are findings in cells and mice. They do not show what MOTS-c does in people.

The published research landscape

Human research on MOTS-c is mostly observational. Studies have measured circulating MOTS-c levels in different groups of people and compared them with metabolic measures, exercise or disease status. Observational associations of this kind cannot show cause and effect.

We found no published large randomised controlled trials of MOTS-c in humans. Most of the mechanistic literature comes from a relatively small group of laboratories, and independent replication is still building.

Regulatory status

United States. MOTS-c is not an FDA-approved drug and has no FDA marketing authorisation.
Sport. Since the 2025 list, WADA's Prohibited List names MOTS-c as an example of an AMPK activator under S4.4.1 (metabolic modulators), prohibited at all times.
Elsewhere. We found no marketing authorisation from any major regulator as of 19 October 2026.

Open research questions

How MOTS-c leaves the mitochondrion. The peptide is encoded in mitochondrial DNA, but there is debate over whether it is translated inside mitochondria or in the cytoplasm, and how it reaches the nucleus and the bloodstream.
Receptors and targets. No dedicated cell-surface receptor has been confirmed. Most proposed mechanisms act inside the cell, through the folate cycle and AMPK.
Genetic variation. A common variant in the mitochondrial sequence that encodes MOTS-c, found mainly in some East Asian populations, changes one amino acid. Researchers have studied whether it is associated with metabolic traits.
Replication. Independent laboratories repeating the key mouse findings with well-characterised material would strengthen the field.
Assays. Standardised, validated methods for measuring MOTS-c in blood and tissue are still being developed.

Key terms

Short open reading frame (sORF). A short stretch of DNA that can be read as a small protein or peptide.
AMPK. AMP-activated protein kinase, an enzyme that senses cellular energy status.
Mitochondrial-derived peptides. Peptides encoded within mitochondrial DNA, a family that includes humanin and MOTS-c.

Limitations of the evidence

Most evidence is from mice and cultured cells.
Human studies are observational and measure natural levels, not the effect of giving the peptide.
Measuring MOTS-c accurately in blood is technically difficult, and assays differ between laboratories.

Where researchers source it

Purita is a store that lists MOTS-c for laboratory research use only. Its product page carries the label "For Research Use Only. Not for human or animal administration."

Purita product page

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