What Is MOTS-c? The Mitochondria-Encoded Peptide

MOTS-c is a 16-amino-acid peptide encoded inside mitochondrial DNA, not in the nuclear genome. Its name stands for “mitochondrial open reading frame of the 12S rRNA type-c”. Identified in 2015, it belongs to a small class of mitochondria-derived peptides that appear to act as signals from mitochondria to the rest of the cell.

For laboratory research use only. The compounds discussed are not approved for human or veterinary use and are not drugs, foods or cosmetics. This article summarises published research and is not medical advice.

Key points

16 residues; C₁₀₁H₁₅₂N₂₈O₂₂S₂, ~2174.6 g/mol.
Encoded by a short open reading frame within the mitochondrial 12S rRNA gene.
Mechanism described: inhibits the folate cycle and de novo purine synthesis, activating AMPK.
Skeletal muscle is described as its primary target organ.
Translocates to the nucleus under stress, where it influences gene expression.

Quick facts

Property	Value
Length	16 amino acids
Formula / weight	C₁₀₁H₁₅₂N₂₈O₂₂S₂, ~2174.6 g/mol
Genomic origin	Mitochondrial DNA, 12S rRNA region
Peptide family	Mitochondria-derived peptides (with humanin, SHLPs)
Year described	2015
Sulfur-containing residues	Two (reflected in the S₂ in its formula)

Our MOTS-c research peptide is supplied in 10, 20 and 40 mg vials with lot-level HPLC and MS data.

Discovery

The existence of peptides encoded in mitochondrial DNA was suggested by humanin, found in a short open reading frame in the mitochondrial genome. Lee and colleagues searched for more and identified MOTS-c within the 12S rRNA region. In their study, its cellular actions inhibited the folate cycle and the de novo purine biosynthesis tethered to it, leading to AMPK activation. In mice, MOTS-c treatment prevented age-dependent and high-fat-diet-induced insulin resistance as well as diet-induced obesity (Lee et al., 2015). The authors proposed that mitochondria actively regulate metabolic homeostasis using peptides encoded in their own genome.

Exercise and physical capacity

A 2021 study examined MOTS-c as a regulator of age-dependent physical decline (Reynolds et al., 2021):

Finding	System
Enhanced physical performance	Young (2 mo.), middle-aged (12 mo.) and old (22 mo.) mice
Regulation of nuclear genes related to metabolism and proteostasis	Mouse tissue
Effects on skeletal muscle metabolism and myoblast adaptation to metabolic stress	Cells and tissue
Increased physical capacity and healthspan with late-life intermittent treatment (from 23.5 mo., 3×/week)	Mice
Exercise induced endogenous MOTS-c expression in skeletal muscle and circulation	Humans

The human component of that work is observational: exercise raised endogenous MOTS-c. The treatment findings are from mice.

MOTS-c in human studies

A review describes MOTS-c as colocalised with mitochondria in various tissues, present in plasma, and declining with age, and notes that under stress it translocates to the nucleus where it regulates a range of genes (Mohtashami et al., 2022). Human association data are more nuanced than a simple decline. In people without diabetes or cardiovascular disease, plasma MOTS-c and SHLP2 were positively associated with android and liver fat (Sequeira et al., 2021). Circulating concentrations therefore reflect more than age alone, which complicates their use as a simple biomarker.

Where MOTS-c sits among longevity research targets

Target	Type	Main described mechanism
MOTS-c	Mitochondria-encoded peptide	Folate cycle inhibition, AMPK activation
NAD+	Nucleotide coenzyme	Redox plus sirtuin/PARP/CD38 cosubstrate (Covarrubias et al., 2021)
Humanin	Mitochondria-encoded peptide	Cytoprotective signalling

Comparisons are covered in NAD+ vs MOTS-c and MOTS-c vs tesamorelin.

Handling in the lab

Store lyophilized powder at −20 °C, sealed and protected from light.
Water-soluble; reconstitute with bacteriostatic or sterile water and swirl gently (method).
The peptide contains sulfur-containing residues, so limit air exposure; watch for +16 Da oxidation species by MS.
Keep solutions at 2–8 °C; avoid repeated freeze–thaw (storage guide).
Calculate concentrations with the peptide reconstitution calculator; 10 mg in 2 mL gives 5 mg/mL, about 2.3 mM at 2174.6 g/mol.

Open questions

What is MOTS-c’s pharmacokinetic profile, including half-life? We did not find a published human study.
How does a mitochondria-encoded peptide reach the nucleus, and what controls that translocation?
Why do plasma levels associate positively with liver and android fat if MOTS-c improves metabolic measures in mice?

Related research

Frequently asked questions

What is MOTS-c?

MOTS-c (mitochondrial open reading frame of the 12S rRNA type-c) is a 16-amino-acid peptide encoded within mitochondrial DNA rather than the nuclear genome. It was identified in 2015 as a regulator of insulin sensitivity and metabolic homeostasis.

How does MOTS-c work?

In the original study its cellular actions inhibited the folate cycle and the de novo purine biosynthesis tethered to it, leading to AMPK activation. Skeletal muscle appeared to be its primary target organ.

Is MOTS-c related to exercise?

Yes. A 2021 study reported that exercise induces endogenous MOTS-c expression in human skeletal muscle and in circulation, and that MOTS-c treatment enhanced physical performance in young, middle-aged and old mice.

Do MOTS-c levels change with age?

Reviews report that MOTS-c is found in plasma and that levels decline with age, though circulating levels also associate with body fat distribution in human studies.

What is MOTS-c's molecular weight?

About 2174.6 g/mol (C101H152N28O22S2) according to PubChem.

References

Lee C, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015. PMID: 25738459 https://pubmed.ncbi.nlm.nih.gov/25738459/
Reynolds JC, et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun. 2021. PMID: 33473109 https://pubmed.ncbi.nlm.nih.gov/33473109/
Mohtashami Z, et al. MOTS-c, the Most Recent Mitochondrial Derived Peptide in Human Aging and Age-Related Diseases. Int J Mol Sci. 2022. PMID: 36233287 https://pubmed.ncbi.nlm.nih.gov/36233287/
Sequeira IR, et al. Plasma mitochondrial derived peptides MOTS-c and SHLP2 positively associate with android and liver fat in people without diabetes. Biochim Biophys Acta Gen Subj. 2021. PMID: 34419510 https://pubmed.ncbi.nlm.nih.gov/34419510/
Covarrubias AJ, et al. NAD(+) metabolism and its roles in cellular processes during ageing. Nat Rev Mol Cell Biol. 2021. PMID: 33353981 https://pubmed.ncbi.nlm.nih.gov/33353981/
PubChem Compound Summary for CID 146675088, MOTS-c. National Center for Biotechnology Information. https://pubchem.ncbi.nlm.nih.gov/compound/146675088