Written and reviewed by Peptide.Express Editorial Team||
SS-31 vs MOTS-c in Mitochondrial Research
SS-31 and MOTS-c both appear in mitochondrial research, and they are not interchangeable. SS-31 is a synthetic tetrapeptide that binds the phospholipid cardiolipin. MOTS-c is a 16-residue peptide encoded in mitochondrial DNA and studied as an AMPK signal. For in-vitro laboratory research use only. Not for human or veterinary use.
Not the same experimental probe
SS-31 is a probe of inner-membrane structure. MOTS-c is a probe of a metabolic signal that originates in the mitochondrion. One binds a lipid. The other has no identified cell-surface receptor on this site. A protocol that swaps them changes the question being asked.
SS-31 and cardiolipin
SS-31, international nonproprietary name elamipretide, is D-Arg-2',6'-dimethyltyrosine-Lys-Phe-NH2. Older papers also use the development code MTP-131. The N-terminal arginine is the D-enantiomer and the C-terminus is an amide. Identity: formula C32H49N9O5, average mass 639.8 Da, CAS 736992-21-5, PubChem CID 11764719.
The binding partner is cardiolipin in the inner mitochondrial membrane, not a peptide receptor. The cationic side chains meet the phosphate headgroups, and the dimethyltyrosine inserts into the acyl region. Birk and colleagues reported that interaction (Journal of the American Society of Nephrology, 2013). Paradies and colleagues review cardiolipin as an organizer of respiratory supercomplexes (Biochimica et Biophysica Acta, 2014).
The alternating aromatic-cationic pattern is the structural reason, already stated on the SS-31 compound guide, that accumulation does not require an intact membrane potential. This page does not treat that binding as a stand-in for a functional result.
MOTS-c and AMPK
MOTS-c (mitochondrial open reading frame of the 12S rRNA type-c) is translated from a short open reading frame in MT-RNR1, the mitochondrial 12S ribosomal RNA gene. Sequence MRWQEMGYIFYPRKLR. Formula C101H152N28O22S2, average mass 2,174.6 Da, CAS 1627580-64-6, PubChem CID 146675088.
Lee and colleagues described an indirect route to AMPK: interference with the folate-methionine cycle, accumulation of AICAR, then AMPK activation (Cell Metabolism, 2015). The same report describes nuclear translocation under metabolic stress. No cell-surface receptor is identified. This page stops at that mechanism.
Reynolds and colleagues report MOTS-c as exercise-induced (Nature Communications, 2021). That paper is not a comparison with SS-31. Functional endpoints from it are not restated here.
What an experiment can separate
An SS-31 design that tests the proposed mechanism reads cardiolipin oxidation, respirasome organization on blue native PAGE, or mitochondrial respiration. A MOTS-c design reads AMPK phosphorylation or nuclear localization. One shared readout cannot assign the result to either molecule.
No head-to-head study of SS-31 against MOTS-c is cited on this site. NAD+ is a third tool, a dinucleotide coenzyme rather than a peptide. The compound guides compare each of these peptides with NAD+ separately. This draft does not repeat that comparison.
Identity comparison
The figures below are chemical identity from the compound records on this site. They are not lot assays and not potency values.
| Attribute | SS-31 | MOTS-c |
|---|---|---|
| Class | Synthetic tetrapeptide | Mitochondrial-encoded 16-mer |
| Sequence | D-Arg-Dmt-Lys-Phe-NH2 | MRWQEMGYIFYPRKLR |
| Origin | Szeto-Schiller series, fully synthetic | Open reading frame in MT-RNR1 |
| Formula | C32H49N9O5 | C101H152N28O22S2 |
| Average mass | 639.8 Da | 2,174.6 Da |
| CAS | 736992-21-5 | 1627580-64-6 |
| PubChem CID | 11764719 | 146675088 |
| Target named here | Cardiolipin | No cell-surface receptor identified |
| Pathway named here | Inner-membrane lipid binding | AICAR accumulation, then AMPK |
Questions
Does SS-31 bind the same target as MOTS-c?
No. SS-31 binds cardiolipin in the inner mitochondrial membrane. MOTS-c has no identified cell-surface receptor on this site and is studied through AMPK signaling. They are different molecules with different assays. Research use only.
Is MOTS-c encoded in mitochondrial DNA?
Yes. MOTS-c is translated from a short open reading frame in MT-RNR1, the mitochondrial 12S ribosomal RNA gene. The sequence used on this site is MRWQEMGYIFYPRKLR, average mass 2,174.6 Da, CAS 1627580-64-6. Research use only.
Is there a published head-to-head of SS-31 and MOTS-c?
Not in the references this site holds for either compound. Birk 2013 and Paradies 2014 concern cardiolipin. Lee 2015 and Reynolds 2021 concern MOTS-c. None of those papers is a comparison of the two peptides. Research use only.
Does Peptide.Express supply SS-31 or MOTS-c for human use?
No. Both are supplied for in-vitro laboratory research only. Not for human or veterinary use.
References
Titles are quoted verbatim from PubMed. Cited findings include studies of related compounds in humans or animals; they are not evidence of effects from the research materials on this site, and they are not dosing or use guidance.
- Birk AV, Liu S, Soong Y, Mills W, Singh P, Warren JD, Seshan SV, Pardee JD, Szeto HH. "The Mitochondrial-Targeted Compound SS-31 Re-Energizes Ischemic Mitochondria by Interacting with Cardiolipin." Journal of the American Society of Nephrology, 2013. PMID 23813215.SS-31 interaction with cardiolipin
- Paradies G, Paradies V, De Benedictis V, Ruggiero FM, Petrosillo G. "Functional Role of Cardiolipin in Mitochondrial Bioenergetics." Biochimica et Biophysica Acta (Bioenergetics), 2014. PMID 24183692.Cardiolipin in mitochondrial bioenergetics
- Lee C, Zeng J, Drew BG, et al. "The Mitochondrial-Derived Peptide MOTS-c Promotes Metabolic Homeostasis and Reduces Obesity and Insulin Resistance." Cell Metabolism, 2015. PMID 25738459.MOTS-c mechanism report. Endpoints in the title are not restated on this page.
- Reynolds JC, Lai RW, Woodhead JST, et al. "MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis." Nature Communications, 2021. PMID 33473109.MOTS-c reported as exercise-induced. Functional endpoints are not restated here.