SS-31 and MOTS-c: a roundup of mitochondria-focused peptide research

Mitochondria are no longer studied only as the cell’s ATP factories. Two short peptides have become reference points for the research that treats them as signalling and membrane-biology targets: SS-31, a synthetic peptide built to reach the inner mitochondrial membrane, and MOTS-c, a peptide that the mitochondrial genome itself encodes. This roundup sets out what kind of research exists on each, how those studies were designed, what they report in which model, and where the evidence is thin. Findings are grouped by model type, because a finding in isolated mitochondria, a cell line, a mouse and a human trial answers different questions.

What are SS-31 and MOTS-c?

SS-31 belongs to the Szeto-Schiller (SS) peptides, named after Hazel Szeto and Peter Schiller, whose groups developed the series; the 2004 paper by Zhao and colleagues is the founding description of their mitochondrial targeting (Zhao et al., 2004). Its sequence is D-Arg-Dmt-Lys-Phe-NH2, where Dmt is 2′,6′-dimethyltyrosine and the C-terminus is amidated. PubChem lists the molecular formula as C32H49N9O5 and the molecular weight as about 639.8 g/mol, with CAS number 736992-21-5 and the synonyms elamipretide, MTP-131 and Bendavia. The design alternates aromatic and basic residues; the dimethyltyrosine was included for its radical-scavenging chemistry, and peptide analogues lacking it did not reproduce the mitochondrial findings in the original study (Zhao et al., 2004).

MOTS-c (mitochondrial open reading frame of the 12S rRNA type-c) is a 16-amino-acid peptide, MRWQEMGYIFYPRKLR, encoded by a short open reading frame inside the gene for the mitochondrial 12S ribosomal RNA. It was reported in 2015 by Changhan Lee, Pinchas Cohen and colleagues at the University of Southern California, following the earlier discovery of humanin, another peptide encoded in mitochondrial DNA (Lee et al., 2015). PubChem lists its molecular formula as C101H152N28O22S2 and its molecular weight as about 2174.6 g/mol (CAS 1627580-64-6).

Both molecular weights refer to the free peptide. Material supplied as a salt, such as an acetate, hydrochloride or trifluoroacetate, weighs more per mole of peptide, which matters when comparing a certificate of analysis with these reference values.

How do the two peptides differ?

The two are often mentioned together, but they come from opposite directions.

• Origin. SS-31 is a designed molecule with no natural counterpart. MOTS-c is endogenous: it is detected in tissues and in circulation, and its study begins with the question of what the body’s own peptide does (Lee et al., 2015; Reynolds et al., 2021).
• Where it acts. SS-31 research centres on the inner mitochondrial membrane and its phospholipid cardiolipin (Szeto, 2014). MOTS-c research centres on signalling outside the organelle: metabolic pathways in the cytoplasm and, under stress, gene regulation in the nucleus (Kim et al., 2018).
• Chemistry. SS-31 contains a D-amino acid and a non-natural residue (Dmt), choices usually made to resist proteases and to tune membrane interaction. MOTS-c is made of standard L-amino acids, as translated in the cell.
• Maturity of the literature. SS-31 has about two decades of preclinical work and a registered human trial programme under the name elamipretide. MOTS-c has about a decade of mostly cell and mouse work.

What has SS-31 research reported?

Isolated mitochondria and model membranes

The founding paper worked largely in isolated mitochondria. Zhao et al. (2004) reported that the SS peptides are cell-permeable and concentrate about 1,000-fold in the inner mitochondrial membrane. In isolated mitochondria they lowered reactive oxygen species production, inhibited the mitochondrial permeability transition and swelling, and prevented calcium-induced cytochrome c release.

Later work asked how the peptide binds. Using a polarity-sensitive fluorescent analogue, Birk et al. (2013) reported that SS-31 binds cardiolipin with high affinity and that the SS-31–cardiolipin complex inhibited the peroxidase activity of cytochrome c, an activity that oxidises cardiolipin and damages cristae membranes. Mitchell et al. (2020) then used biophysical measurements and molecular simulations on model bilayers and mitochondrial membranes. They found that SS-31 sits in the membrane interfacial region, with binding that scales with surface charge; that it did not destabilise lamellar bilayers even at the highest binding concentrations tested; that it altered lipid packing; and that it changed membrane surface electrostatics, including the distribution of calcium ions at the interface. Their proposed mechanism is broader than “cardiolipin binding” alone: SS-31 may act by tuning the surface charge of the membrane.

Cell models

In the 2004 study, the peptides lowered intracellular reactive oxygen species and cell death caused by the oxidant t-butyl hydroperoxide in cultured N2A neuronal cells, with half-maximal concentrations in the nanomolar range, and prevented mitochondrial depolarisation in cells exposed to the mitochondrial toxin 3-nitropropionic acid (Zhao et al., 2004).

Animal and ex vivo models

• Ex vivo heart. In an isolated-heart model of ischaemia and reperfusion, the peptides were associated with better contractile force after reperfusion, while analogues without dimethyltyrosine were not (Zhao et al., 2004).
• Rat kidney. In a rat model of renal ischaemia, pretreatment with SS-31 preserved mitochondrial cristae, prevented mitochondrial swelling and was associated with a faster return of ATP levels on reperfusion, along with preserved tubular barrier function (Birk et al., 2013).
• Aged mouse muscle. Siegel et al. (2013) compared young (5-month) and old (27-month) mice. One hour after a single exposure, measures of skeletal-muscle mitochondrial energetics in the old mice, taken in vivo by optical and phosphorus-31 magnetic resonance spectroscopy, moved towards the values of young animals; no change was seen in young muscle. Eight days of exposure was associated with greater whole-animal endurance capacity in the old mice.

A 2014 review by Szeto summarises a wider range of animal models of conditions linked to energy failure, and the clinical development programme as it stood then (Szeto, 2014).

What has MOTS-c research reported?

Cell models

In the 2015 discovery paper, the cellular actions of MOTS-c were traced to inhibition of the folate cycle and the de novo purine synthesis tethered to it, leading to activation of AMPK, the cell’s energy sensor (Lee et al., 2015). Kim et al. (2018) followed the peptide under metabolic stress. In cultured cells under metabolic stress such as glucose restriction, MOTS-c moved into the nucleus in an AMPK-dependent manner, regulated a broad set of nuclear genes, including genes with antioxidant response elements, and interacted with stress-responsive transcription factors such as NRF2. The authors present this as a case of a mitochondrial-encoded factor regulating the nuclear genome. Reynolds et al. (2021) added myoblast experiments in which MOTS-c was linked to adaptation to metabolic stress.

Mouse models

• Diet and age. Lee et al. (2015) identified skeletal muscle as the apparent primary target organ in mice. In their models, MOTS-c exposure prevented age-dependent and high-fat-diet-induced insulin resistance, as well as diet-induced obesity.
• Physical capacity across age. Reynolds et al. (2021) studied young (2-month), middle-aged (12-month) and old (22-month) mice and reported higher physical performance in MOTS-c-exposed animals in each age group. In mice whose intermittent exposure began late in life (23.5 months), the authors reported higher physical capacity and healthspan measures. Gene-expression work in the same study pointed to nuclear genes involved in metabolism and proteostasis.

Human observational data

The same 2021 paper measured endogenous MOTS-c in human volunteers and reported that exercise was followed by higher MOTS-c levels in skeletal muscle and in circulation (Reynolds et al., 2021). That is a measurement of the body’s own peptide around exercise, not a study of supplied MOTS-c.

What human trials exist for elamipretide?

Elamipretide is the only one of the two with a substantial registered trial programme. ClinicalTrials.gov lists about twenty interventional and expanded-access entries for it, covering primary mitochondrial myopathy, Barth syndrome, heart failure, age-related macular degeneration, Friedreich ataxia and other conditions (ClinicalTrials.gov, searched October 2026). The trials below are described by design only.

Trial	Phase and design	Population	Primary endpoints
MMPOWER (NCT02367014)	Phase I/II, multicentre, randomised, double-blind, placebo-controlled, dose-escalating	36 adults with genetically confirmed primary mitochondrial myopathy	Change in 6-minute walk distance after 5 days; exercise testing, symptom scores, biomarkers and pharmacokinetics as other measures
MMPOWER-3 (NCT03323749)	Phase 3, randomised 1:1, double-blind, placebo-controlled, 24 weeks	218 adults with genetically confirmed primary mitochondrial myopathy	Change in 6-minute walk distance and in a fatigue score on the Primary Mitochondrial Myopathy Symptom Assessment
TAZPOWER (NCT03098797)	Phase 2/3, randomised, double-blind, placebo-controlled crossover (two 12-week periods), then open-label extension	12 people with Barth syndrome	6-minute walk distance and a Barth syndrome symptom assessment scale

Sources: Karaa et al. (2018); Karaa et al. (2023); Thompson et al. (2021).

Two points about these trials matter for reading the literature fairly. First, the published MMPOWER-3 report states that the trial did not meet its primary endpoints (Karaa et al., 2023). Second, the TAZPOWER report states that neither primary endpoint was met in the randomised crossover part; the open-label extension that followed had no placebo arm, and eight people reached 36 weeks in it (Thompson et al., 2021).

Regulatory review. The US Food and Drug Administration reviewed elamipretide for Barth syndrome and on 19 September 2025 announced accelerated approval under the brand name Forzinity. Accelerated approval relies on a surrogate endpoint; the FDA’s announcement names knee-extensor muscle strength as that endpoint and states that the manufacturer must run a post-approval randomised, double-blind, placebo-controlled trial to verify it (FDA, 2025).

MOTS-c. A randomised, double-blind, placebo-controlled phase 2a study of MOTS-c in adults with prediabetes is registered as NCT07505745. Its record lists a planned enrolment of 120, a 12-week intervention period, and two primary endpoints: an oral glucose tolerance test-derived insulin sensitivity index (the Matsuda index) and the incidence of adverse events. It was recruiting in 2026, and no outcome data had been posted at the time of writing.

What are the open questions?

• One mechanism or several? For SS-31, the field has moved from “mitochondrial antioxidant” (2004) to “cardiolipin binder” (2013) to “modulator of membrane surface charge” (2020). Which of these explains a given finding in a given model is not settled, and the 2020 authors describe their proposed mechanisms as non-exclusive (Mitchell et al., 2020).
• Who did the work? Much of the SS-31 literature comes from the inventor’s laboratory and its collaborators; the 2020 paper declares that Szeto is the inventor of the peptides and has financial interests in the company developing them (Mitchell et al., 2020). The 2018 and 2021 MOTS-c papers declare that senior authors are consultants and shareholders of CohBar, Inc. (Kim et al., 2018; Reynolds et al., 2021). Independent replication is the obvious gap for both.
• Preclinical signal versus human trials. The strongest elamipretide trial in primary mitochondrial myopathy did not meet its primary endpoints, after the animal findings and the small phase I/II signal described above. Why they diverge is an open question, and a reason to read animal data on either peptide with care.
• What does endogenous MOTS-c do? Most mouse findings come from supplying synthetic peptide. How much the body’s own MOTS-c contributes to the same pathways, and how its levels vary between tissues and with age, is far less mapped.
• Small numbers. TAZPOWER randomised 12 people, and the aged-mouse studies use small groups. Barth syndrome is rare, so small trials are expected, but sample size limits what any single study can show.
• Translation of mouse ages and models. Mouse ages of 22–27 months are often regarded as “old”, and high-fat feeding as a model of human metabolic disease. How well these models carry over is a general caution for both literatures.

Researchers sourcing either peptide for laboratory work should check that the identity data on the certificate match the reference values above; EuroPeps, the publisher of this site, lists its research peptides at the EuroPeps research-peptide shop.