Mitochondrial
MOTS-c vs SS-31: Research Comparison
MOTS-c and SS-31 are both peptides studied in mitochondrial research, with different targets. MOTS-c is a 16-amino-acid peptide encoded in mitochondrial DNA, linked to the energy-sensing enzyme AMPK. SS-31 (elamipretide) is a synthetic four-amino-acid peptide that binds cardiolipin, a lipid in the inner mitochondrial membrane.
Side-by-side comparison
| Attribute | MOTS-c | SS-31 |
|---|---|---|
| What it is | Natural 16-amino-acid peptide encoded in mitochondrial DNA | Synthetic four-amino-acid peptide (D-Arg-Dmt-Lys-Phe-NH2) |
| Target | Linked to AMPK activation via the folate cycle | Binds cardiolipin on the inner mitochondrial membrane |
| Main models studied | Cells and mice | Cells, isolated mitochondria, animals and human trials |
| Human data | Observational studies; a modified version completed a phase 1 trial with no results posted | Phase 3 trial in primary mitochondrial myopathy and a small trial in Barth syndrome both missed their primary goals |
| Licensed status | Not licensed | US accelerated approval for Barth syndrome (September 2025); not authorised in the EU |
Detailed analysis
MOTS-c was described in 2015 (Lee et al., 2015). In cell and mouse studies it inhibits the folate cycle and the linked pathway that makes purines, which leads to activation of AMPK. In people, published studies so far are observational. A modified version, CB4211, completed a phase 1 trial in 2021 with no results posted.
SS-31 is one of the Szeto-Schiller peptides and was developed as a medicine by Stealth BioTherapeutics. It enters cells and gathers at the inner mitochondrial membrane, where it binds cardiolipin; in cell, mitochondria and animal studies this was linked to more stable membrane folds and less production of reactive oxygen species (Mitchell et al., 2020). A phase 3 placebo-controlled trial in 218 adults with primary mitochondrial myopathy did not meet its primary goals (Karaa et al., 2023), and a 12-person trial in Barth syndrome also missed its primary goals (Thompson et al., 2021). In September 2025 the US FDA granted it accelerated approval for Barth syndrome, based on knee muscle strength, and requires a further trial to confirm the result.
The material supplied here is not the licensed medicine.
Key differences
- ·MOTS-c is linked to AMPK signalling; SS-31 binds cardiolipin in the inner mitochondrial membrane.
- ·SS-31 has phase 3 human trial data; MOTS-c human data are observational.
- ·SS-31 has US accelerated approval for one rare disorder; MOTS-c is not licensed.
Research summary
MOTS-c evidence is mostly cell and mouse work (Lee et al., 2015). SS-31 has extensive cell and animal work and human trials with mixed results (Karaa et al., 2023), plus a US accelerated approval for Barth syndrome that still needs confirming. Supplied for laboratory research use only.