MOTS-c, the mitochondrial peptide, and SS-31: what the studies measured
· Novatheris
MOTS-c is a peptide the body makes itself from the DNA of the mitochondria, the part of the cell that produces energy. It was described in 2015 and has since become one of the most talked-about peptides in metabolism and aging research. The same goes for SS-31, another peptide tied to the mitochondria, but with a very different history. Here is what has been published on each one, with its source, and where the evidence ends.
What MOTS-c is: the mitochondrial peptide
MOTS-c is a chain of 16 amino acids. Its sequence is MRWQEMGYIFYPRKLR, its formula C101 H152 N28 O22 S2, and it weighs about 2174.6 Da.
The interesting part is where it comes from. Almost all peptides are made from the DNA in the cell's nucleus. MOTS-c comes from a stretch of mitochondrial DNA, inside a gene called 12S ribosomal RNA. A group described it in 2015 while searching for small sequences hidden in that DNA (Lee et al., 2015).
In that same work, in mice, the main target seemed to be muscle. The peptide slowed the folate cycle, a pathway the cell uses to build pieces of DNA, and that ended up activating AMPK, an enzyme that works as the cell's energy sensor.
What was seen in mice
Everything known about giving MOTS-c comes from mice. In the 2015 work, in mice on a high-fat diet, the treated animals gained less weight and handled glucose better than the untreated ones (Lee et al., 2015).
In 2021 another paper, also in mice, saw that exercise raises MOTS-c levels and that, in old mice, giving it improved physical capacity in the tests they ran (Reynolds et al., 2021).
These are mouse findings, with a route of administration that is not used in people. There is no published half-life in any species.
In people it has only been measured, never given
This is the point that most often gets lost. Every published human study measures the MOTS-c the body already makes. None of them gives it.
And the measured effect is weaker than what gets told. In a controlled exercise trial, humanin, another mitochondrial peptide, clearly rose after 45 minutes of cycling. MOTS-c only showed a trend. Resistance exercise moved neither, and blood levels were not related to VO2max, a measure of aerobic capacity (von Walden et al., 2021).
On clinical trials: a program with a MOTS-c-like molecule, called CB4211, finished its early phase in 2021 and never published results (NCT03998514). A phase 2a trial started recruiting in 2026 and has no results yet (NCT07505745). A finished program that was never published does not count as evidence.
The longevity idea is a question
It is often repeated that MOTS-c explains why some people in Japan live so long. That idea comes from a mitochondrial DNA variant, called m.1382A>C, found in populations of northeast Asia.
The paper that proposed it is short and has a question mark in its title (Fuku et al., 2015). The authors themselves say more research is needed. It is a hypothesis, not a finding.
What SS-31 is
SS-31 is a synthetic peptide of four pieces: D-Arg-Dmt-Lys-Phe-NH2. Its formula is C32 H49 N9 O5 and it weighs about 639.8 Da. It is also known as MTP-131, Bendavia or elamipretide.
Unlike almost every other peptide, it does not act on the surface of the cell. It goes straight to the inner membrane of the mitochondria and binds cardiolipin, a fat that helps hold together the machinery that produces energy there (Tung et al., 2025).
In old mice, SS-31 quickly improved the energy output of muscle mitochondria (Siegel et al., 2013). Another paper in old female mice, with several weeks of treatment, saw less oxidative stress and better exercise tolerance (Campbell et al., 2019).
SS-31 does have large trials, and almost none met their goals
Here SS-31 is unusual among research peptides: it has large, randomized, placebo-controlled trials. The problem is how they came out.
- In mitochondrial myopathy, the MMPOWER-3 trial, with 218 patients, met none of its primary endpoints (Karaa et al., 2023).
- In dry macular degeneration, the ReCLAIM-2 trial, with 176 patients, also missed both primary endpoints (Ehlers et al., 2024).
- In Barth syndrome, the placebo part of the TAZPOWER trial, with 12 patients, missed its primary endpoints (Reid Thompson et al., 2021). The improvements that do get reported come from the open part, with no placebo, and from a comparison with historical patients (Hornby et al., 2022).
The closest thing to healthy people is a study of 39 older adults, chosen because their mitochondria performed poorly. After a single administration, ATP production in muscle improved. But the effect was gone by day 7, and the muscle's resistance to fatigue did not improve (Roshanravan et al., 2021).
What is still unknown
For the notebook:
- For MOTS-c, there is no published clinical result.
- There is no published MOTS-c half-life in any species.
- SS-31 missed its primary endpoints in three controlled trials.
- SS-31 has never been tested in young, healthy people.
A 2026 sports medicine review places MOTS-c among the peptides with very little human safety data (Mendias and Awan, 2026).
How they are stored
Both come lyophilized, which means dry: a powder whose water was removed with cold and vacuum. They are kept at -20 °C, closed and away from bright light. Let the vial reach room temperature before opening it. Once reconstituted, it goes to 2 to 8 °C and for a short time.
Where to find them
Every batch of MOTS-c is sent to an outside laboratory. The report published today is from Freedom Diagnostics, for the 20 mg vial, and you can see it in full exactly as the laboratory issues it. The standard we ask for is +99.5% purity. Delivery takes 2 hours in the GAM and 24 hours in the rest of Costa Rica.
The MOTS-c page has its chemical data, the MOTS-c lab analysis has the batch report, and the SS-31 page has the data on the other peptide. For research use only.