MOTS-c: A Research Overview of the Mitochondrial-Derived Peptide
By The Bionova Club Team
Research use only. Bionova products are sold strictly for in-vitro and laboratory research by qualified professionals. They are not drugs, food, or cosmetics, are not approved by the FDA, and are not for human or veterinary use. Nothing in this article is medical advice or a claim about effects in people.
Disclosure: Bionova Club sells MOTS-c, linked below.
Most of the proteins that work inside mitochondria are encoded in the cell nucleus. Mitochondria have their own small genome, but for decades it was thought to encode only a fixed set of genes. MOTS-c challenged that picture. It is a 16-amino-acid peptide encoded by a short open reading frame hidden inside a mitochondrial ribosomal RNA gene, and it is one of a small group of molecules now called mitochondrial-derived peptides.
This overview covers what MOTS-c is, how it was discovered, why its genetics are unusual, and what cell-based research has examined.
What is MOTS-c?
MOTS-c stands for "mitochondrial open reading frame of the twelve S rRNA type-c." It was reported in 2015 by Changhan Lee, Pinchas Cohen and colleagues at the University of Southern California as a 16-amino-acid peptide encoded within the mitochondrial 12S rRNA gene (Lee et al., 2015, Cell Metabolism).
- Sequence: MRWQEMGYIFYPRKLR (Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg)
- Peptide length: 16 amino acids
- Molecular formula: C₁₀₁H₁₅₂N₂₈O₂₂S₂
- Molecular weight: ~2,174.6 g/mol
- Encoded in: Mitochondrial DNA, within the 12S rRNA gene
- Open reading frame: 51 base pairs
- First described: 2015
- Bionova format: MOTS-c 40 mg, lyophilized (40 mg per vial, from the label)
Sequence, formula and weight are from PubChem (CID 146675088). The formula matches the one on Bionova's product page.
How MOTS-c was discovered
A small genome with hidden genes
Human mitochondrial DNA is a small circular genome. It has been described as encoding 37 genes: 22 transfer RNAs, 2 ribosomal RNAs and 13 messenger RNAs (Lee et al., 2016, Free Radical Biology & Medicine). The first sign that it might encode more came with humanin, a signaling peptide encoded by a short open reading frame in mitochondrial DNA. Humanin's discovery suggested that other short open reading frames might be hiding in mitochondrial DNA (Lee et al., 2015).
Searching the 12S rRNA gene
Lee and colleagues ran a computational search of the human 12S rRNA sequence for short open reading frames. They found one of 51 base pairs with a strong Kozak sequence, translating into a 16-amino-acid peptide. They named it MOTS-c and deposited it in GenBank under accession KP715230 (Lee et al., 2015).
The same study reported that the peptide sequence is highly conserved across 14 species, especially its first 11 residues. Using a MOTS-c-specific ELISA, the authors detected the peptide in several rodent tissues and in rodent and human plasma samples.
Why MOTS-c's genetics are unusual
Mitochondria use a slightly different genetic code from the rest of the cell. According to the discovery paper, reading the MOTS-c open reading frame with the mitochondrial code would produce tandem start and stop codons, not a peptide. Translation therefore has to happen in the cytoplasm, using the standard genetic code (Lee et al., 2015).
That makes MOTS-c a peptide whose gene sits in mitochondrial DNA but whose message is read by the cell's main protein-synthesis machinery. It is one reason the peptide has drawn attention as an example of communication between mitochondria and the nucleus.
What has MOTS-c research examined?
Mitochondrial-derived peptides as a class
MOTS-c and humanin are the founding members of the mitochondrial-derived peptide (MDP) group. A 2016 review by the discovery team discusses MDPs as a new class of mitochondrial-encoded signaling molecules (Lee et al., 2016).
Nuclear translocation and AMPK
The "MOTS-c AMPK" search term refers mainly to a 2018 cell-culture study. Kim and colleagues reported that, under glucose restriction, MOTS-c moved from the cytoplasm into the nucleus. That translocation depended on AMP-activated protein kinase (AMPK). Once in the nucleus, MOTS-c was associated with changes in the expression of many nuclear genes, including genes with antioxidant response elements, and interacted with the transcription factor NRF2 (Kim et al., 2018, Cell Metabolism).
The authors framed the finding as evidence that mitochondrial and nuclear genomes cross-regulate each other. Put simply, a peptide encoded in mitochondrial DNA was shown to act on gene expression in the nucleus in cultured cells.
Reading the literature carefully
The MOTS-c literature is young, dating only from 2015. Most of it uses cultured cells and rodent models. Cell and animal findings are hypothesis-generating; they are not demonstrations of effects in people. MOTS-c is not approved by the FDA as a drug.
MOTS-c and NAD+
MOTS-c and NAD+ often appear together in searches about mitochondria, but they are very different molecules. MOTS-c is a 16-residue peptide. NAD+ is a small-molecule coenzyme, not a peptide at all. Our guide to NAD+ in the lab covers NAD+ chemistry and handling. For background on what counts as a peptide, see What are peptides? A primer for researchers. Single-compound research peptides are listed in the research peptides category.
Storage notes for lyophilized MOTS-c
- Keep it sealed, cold and dry. Store the lyophilized powder in its original sealed vial, away from light and moisture.
- Warm before opening. Let a sealed vial reach room temperature before opening so moisture does not condense on the powder.
- Follow the label. Store as directed on the product label.
Key takeaways
- MOTS-c is a 16-amino-acid peptide (MRWQEMGYIFYPRKLR) encoded by a 51-base-pair open reading frame in the mitochondrial 12S rRNA gene.
- It was reported in 2015 and, with humanin, defines the class of mitochondrial-derived peptides.
- Its open reading frame is translated in the cytoplasm using the standard genetic code.
- In a 2018 cell study, MOTS-c moved into the nucleus under glucose restriction in an AMPK-dependent way and was associated with changes in nuclear gene expression.
- Bionova's MOTS-c vial is labeled 40 mg. It is a research material only and is not approved for human use.
Frequently asked questions
What is the MOTS-c peptide?
MOTS-c is a 16-amino-acid peptide encoded in mitochondrial DNA, within the 12S rRNA gene. Its name stands for "mitochondrial open reading frame of the twelve S rRNA type-c."
What is a mitochondrial-derived peptide?
A mitochondrial-derived peptide is a short peptide encoded by a small open reading frame in mitochondrial DNA. Humanin and MOTS-c are the best-known examples.
When was MOTS-c discovered?
MOTS-c was first reported in 2015 by researchers at the University of Southern California.
What is the connection between MOTS-c and AMPK?
In a 2018 cell-culture study, MOTS-c's movement into the nucleus under glucose restriction depended on AMPK, an enzyme that senses the cell's energy status.
Is MOTS-c the same as NAD+?
No. MOTS-c is a peptide. NAD+ is a small-molecule coenzyme, not a peptide.
How should lyophilized MOTS-c be stored?
Keep the sealed vial cold, dry and away from light, let it reach room temperature before opening, and store it as directed on the product label.
Shop for your research: MOTS-c for laboratory research. Use code CLUB10 at checkout for 10% off.
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 Metab. 2015. https://pubmed.ncbi.nlm.nih.gov/25738459/
- Lee C, Kim KH, Cohen P. MOTS-c: A novel mitochondrial-derived peptide regulating muscle and fat metabolism. Free Radic Biol Med. 2016. https://pubmed.ncbi.nlm.nih.gov/27216708/
- 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 Metab. 2018. https://pubmed.ncbi.nlm.nih.gov/29983246/
- PubChem. MOTS-c, CID 146675088 (sequence, formula and weight). https://pubchem.ncbi.nlm.nih.gov/compound/146675088
For laboratory research use only. Not for human consumption.