MOTS-c vs elamipretide (SS-31): an encoded peptide and a designed one
MOTS-c and elamipretide (SS-31) are both filed as mitochondrial peptides, yet one is encoded in mitochondrial DNA and the other was designed and synthesised in a laboratory.[1],[2],[3],[4]
MOTS-c is a 16-residue peptide read from a short open reading frame in the 12S rRNA gene, while SS-31 is a synthetic tetrapeptide of alternating cationic and aromatic residues that binds the inner-membrane lipid cardiolipin.[3],[4],[5]
Origin, structure and the laboratory pathway linked to each are compared here, and no study outcome for one is placed beside one for the other.[1],[2]
Identity side by side
| Attribute | MOTS-c | Elamipretide (SS-31) |
|---|---|---|
| Also recorded as[1],[2] | Mitochondrial ORF of the 12S rRNA type-c | SS-31; MTP-131; Bendavia |
| Origin[3],[4] | Encoded by a 51-base-pair open reading frame in mitochondrial 12S rRNA | Synthetic; lead compound of the Szeto-Schiller peptide series |
| Length[3],[4] | 16 residues | 4 residues |
| Sequence detail in the cited text[6],[3],[4] | Motifs named: YIFY (8-11) and RKLR (13-16); full sequence shown only in a figure | D-Arg-2′,6′-dimethyl-Tyr-Lys-Phe-NH2 |
| Molecular formula (library)[1],[2] | C101H152N28O22S2 | C32H49N9O5 |
| CAS Registry Number[1],[2] | 1627580-64-6 | 736992-21-5 |
| Where it is made or found[3],[6],[4],[5] | Translated in the cytoplasm with the standard genetic code; found in mitochondria and the nucleus | Made by chemical synthesis; partitions into membranes and binds cardiolipin of the inner mitochondrial membrane |
| Target or pathway recorded[1],[3],[6],[2],[5] | No receptor; folate-methionine pathway, purine synthesis and AMPK in cells; nuclear gene regulation | Cardiolipin (inner mitochondrial membrane) |
| U.S. regulatory entry[7] | No entry in this library | Drugs@FDA, NDA 215244 |
Where does each peptide come from?
The identification paper found MOTS-c by scanning the human mitochondrial 12S rRNA for short open reading frames, and the name records that origin.[3]
Its full text adds that the peptide has to be translated in the cytoplasm with the standard genetic code, since reading the frame with the mitochondrial code gives back-to-back start and stop codons.[3]
Elamipretide is synthetic: it is the lead compound of the Szeto-Schiller series, tetrapeptides built on a motif of alternating cationic and aromatic side chains.[4]
Its published structure, D-Arg-2′,6′-dimethyl-Tyr-Lys-Phe-NH2, contains a D-amino acid and a dimethylated tyrosine, and the series carries a formal charge of +3 at neutral pH.[4]
Which pathway is each linked to in laboratory work?
In HEK293 cells that overexpressed MOTS-c, metabolomic profiling pointed to the folate-methionine pathway and de novo purine synthesis, with AICAR accumulating and AMPK activated.[3]
A 2018 cell study found MOTS-c in both mitochondria and the nucleus, saw it move into the nucleus under metabolic stress in an AMPK-dependent way, and found that swapping its YIFY core for alanines blocked that entry.[6]
For SS-31, a polarity-sensitive fluorescent analogue was used to show high-affinity binding to cardiolipin, the anionic phospholipid of the inner mitochondrial membrane.[5]
Biophysical work published in 2020 found that SS-31 sits in the membrane interfacial region with an affinity tied to surface charge, and that it alters the surface electrostatics of model and mitochondrial membranes.[4]
Neither peptide has a receptor on record: the MOTS-c cell work points to a metabolic pathway and to gene regulation in the nucleus, and the SS-31 work points to a membrane lipid.[1],[2]
What does the U.S. regulatory record say?
Only elamipretide has an entry in the library's regulatory table; MOTS-c has none, so no regulatory line is printed for it.[7]
An FDA approved drug product containing elamipretide (SS-31) exists. PepGenex research materials are not that product, are not FDA approved, and are not for human or veterinary use. Source: Drugs@FDA, Application NDA 215244. Checked 2026-09-24.
What does this comparison not establish?
No publication cited here studied MOTS-c and SS-31 side by side, so their shared mitochondrial label is a filing category rather than a finding.[3],[5]
The clinical records on the elamipretide profile and the mouse metabolite study on the MOTS-c profile stay on those pages and are not set against each other here.[2],[1]
Limitations
The MOTS-c pathway findings come from cultured human cells, and the SS-31 binding findings from model membranes, isolated mitochondria and a labelled analogue; none of them describes an effect in a person.[3],[6],[5],[4]
The 2020 membrane study discloses that one of its authors invented the SS peptides and holds financial interests in the company developing elamipretide.[4]
Compound profiles
References
- MOTS-c research profile, PepGenex Science (identity and records, with their sources).
- Elamipretide (SS-31) research profile, PepGenex Science (identity and records, with their sources).
- Lee C, Zeng J, Drew BG, et al. Cell Metab. 2015;21(3):443-454 (title withheld on this site; see the publication record). PMID 25738459 · DOI 10.1016/j.cmet.2015.02.009 · PMC4350682
- Mitchell W, Ng EA, Tamucci JD, et al. The mitochondria-targeted peptide SS-31 binds lipid bilayers and modulates surface electrostatics as a key component of its mechanism of action. J Biol Chem. 2020;295(21):7452-7469. PMID 32273339 · DOI 10.1074/jbc.RA119.012094 · PMC7247319
- Birk AV, Liu S, Soong Y, et al. The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipin. J Am Soc Nephrol. 2013;24(8):1250-1261. PMID 23813215 · DOI 10.1681/ASN.2012121216 · PMC3736700
- Kim KH, Son JM, Benayoun BA, et al.. The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress. Cell Metabolism 2018. PMID 29983246 · DOI 10.1016/j.cmet.2018.06.008 · PMC6185997
- Drugs@FDA, Application NDA 215244. Checked 2026-09-24