SS-31

What SS-31 is

SS-31 is a lab-made peptide that has gone through human trials at Phase 2 and Phase 3. It has also been tested in many animal studies of aging and organ injury. The results are mixed. A number of the trials missed their main goals. Even so, in September 2025 the FDA gave it accelerated approval for one rare illness, Barth syndrome [18].

A peptide is a short chain of amino acids, the building blocks of protein. SS-31 has only four, so it is called a tetrapeptide. Its sequence is D-Arg-2′,6′-dimethylTyr-Lys-Phe-NH2. It dissolves in water. It goes by other names too: elamipretide, bendavia and MTP-131.

The “SS” stands for Szeto-Schiller. Peter Schiller and Hazel Szeto first described this family of peptides at Weill Cornell Medicine. SS-31 grew out of it [1].

SS-31 is built to reach mitochondria, the parts of a cell that make energy. At the body’s normal pH it has a net charge of 3+. It collects in the inner membrane of the mitochondrion because it interacts with cardiolipin. Cardiolipin is a phospholipid, a kind of fat molecule, and it exists only in mitochondria [3].

This sets SS-31 apart from older molecules aimed at mitochondria, like the triphenylphosphonium (TPP+) conjugates. Those need a membrane potential, an electrical charge across the membrane, to build up inside. SS-31 does not. So it can still get to cardiolipin in damaged mitochondria. In those, the proton gradient has collapsed [2]. Once bound to cardiolipin, it steadies the electron transport chain, the protein chain that makes energy. It brings back the making of ATP, the cell’s energy molecule. It also cuts reactive oxygen species (ROS), harmful forms of oxygen, in mitochondria [3][2].

Stealth BioTherapeutics owns elamipretide as a development compound. The company has run clinical programs in five areas [12][7][16][15]:

• Barth syndrome
• primary mitochondrial myopathy
• age-related macular degeneration (AMD)
• heart failure
• ischemia-reperfusion injury, the damage done when blood flow is cut off and then returns

The 2025 FDA decision covers Barth syndrome patients who weigh 30 kg or more. It was based on gains in knee muscle strength. The application had Priority Review and a Rare Pediatric Disease designation [18]. The clinical program behind it was TAZPOWER [12][13].

This guide is an overview for researchers. Everything in it is for research and education only.

How much research there is

Among peptides aimed at mitochondria, few have a fuller record of human testing than SS-31. The table lists the main clinical trials cited in this guide, along with one anchor animal study. It is a sample, not a full list.

Study	Type	People	Stage	Result
Reid Thompson 2021 (TAZPOWER)	Barth syndrome. Randomized crossover, Phase 2/3, then an open-label extension	12	Early clinical	Goals of the crossover part were missed. In the extension, six-minute walk distance and patient-reported measures got better [12]
Thompson 2024 (TAZPOWER, 168 weeks)	Barth syndrome. Open-label extension only	12	Early clinical	Across 168 weeks, heart and function effects held up [13]
Karaa 2020 (MMPOWER-2)	Primary mitochondrial myopathy. Randomized crossover, Phase 2	30	Early clinical	Six-minute walk distance was longer on the drug, but not by a statistically significant amount. Patient-reported fatigue improved [7]
Butler 2020 (PROGRESS-HF)	Heart failure (HFrEF). Randomized, placebo-controlled, Phase 2	71	Early clinical	Missed its main goal, which was left ventricular end-systolic volume [15]
Ehlers 2025 (ReCLAIM-2)	Dry AMD with geographic atrophy. Randomized, Phase 2	176	Early clinical	Both main goals were missed: low-luminance visual acuity and growth of geographic atrophy. There were signals on ellipsoid-zone attenuation [16]
Chiao 2020	Animal study in aged mice (heart)	n/a	Preclinical	Diastolic dysfunction and poor mitochondrial respiration were reversed [9]

How it might work

Most drugs are studied as keys that fit a receptor. SS-31 is studied as something that protects cardiolipin. So scientists explain it in terms of membranes and energy production. They do not use chains of cell signals.

Binding to cardiolipin

Cardiolipin is a double phospholipid. It has four acyl chains, which are fatty tails, and two phosphate head groups that carry a negative charge. Nearly all of it sits in the inner membrane of mitochondria.

Birk and colleagues did structural and biochemical tests on how SS-31 attaches to it [3]. They found two forces at work:

• Electrostatic pull. SS-31 has two positively charged amino acids, D-Arg and Lys.
• Hydrophobic (water-avoiding) contact, by way of the side chain of its dimethyltyrosine.

SS-31 picks cardiolipin over the other phospholipids in mitochondria. Cardiolipin forms a complex with a protein called cytochrome c. The same work showed that SS-31 changes the shape of that complex. The new shape favors passing electrons along. The old one favors peroxidase activity, which pushes a cell toward apoptosis, a form of planned cell death [3].

Steadying the electron transport chain

The respiratory chain works best when its parts are grouped into supercomplexes. In animal and cell models, SS-31 has been linked with keeping these groups assembled, above all Complexes I, III and IV. It has also been linked with keeping cytochrome c in contact with the inner membrane [3][2].

Scientists have also taken mitochondria out of aged or injured tissue and exposed them to SS-31. This has been tied to [8][9]:

• more state 3 respiration, a measure of active energy production
• faster ATP synthesis
• a respiratory control ratio that returned to normal
• ATP production that recovered in mitochondria from skeletal muscle, heart and kidney

Fewer reactive oxygen species

Cardiolipin can be peroxidized, which means damaged by oxygen. When that happens, cytochrome c lets go of the inner membrane. It then gains peroxidase activity, and that drives more fat oxidation and more apoptosis signals [2].

SS-31 sits on cardiolipin. In oxidative stress models this is reported to do three things [1][2]:

• cut the peroxidation of cardiolipin
• lower the hydrogen peroxide that mitochondria make
• block the opening of the mitochondrial permeability transition pore

The end result in these models is less ROS from mitochondria. Neurons, heart muscle cells and kidney tubule cells were protected from death by oxidation [1].

Reaching mitochondria that have lost their charge

SS-31 gets into mitochondria even when the potential across the inner membrane is not intact. The first Szeto-Schiller papers pointed this out as a special trait [1].

Older methods work differently. The matrix is the inner space of the mitochondrion. TPP+ conjugates use the electrochemical gradient to pile up positively charged compounds there. In failing or ischemic (blood-starved) mitochondria, that gradient has drained away. So those methods work less well exactly when they are needed most [2].

SS-31 instead binds cardiolipin directly. That is how it settles into the inner membrane. Its 3+ charge stays mostly in the head-group zone. It does not cross over into the matrix [3].

This also explains what published studies show about how the body handles it [4][2]:

• It is given by injection, into a vein or under the skin.
• It collects in tissues that are rich in mitochondria, such as skeletal muscle, kidney and heart.
• Rodents and humans have received it for medium-length periods. Compounds that must gather in the matrix often build up off-target toxicity. That did not appear here.

SS-31 aims straight at cardiolipin. That idea is why it has been tested in three settings: ischemia-reperfusion injury, primary mitochondrial disease, and the mitochondrial decline of aging [2][5][9].

What the studies found

Stealth BioTherapeutics has paid for a number of trials at Phase 2 and Phase 3. Next to them is an active body of animal research on aging and organ injury.

Barth syndrome (TAZPOWER)

Barth syndrome is rare. It is an X-linked disorder, one carried on the X chromosome. It comes from mutations in TAZ, the gene for tafazzin, an enzyme that cells need to remodel cardiolipin. People with it have heart muscle disease and skeletal muscle disease. They also have delayed growth and neutropenia, a low count of one type of white blood cell.

The TAZPOWER program tested elamipretide in this group.

• The core trial. Reid Thompson and colleagues reported it in 2021. It was a randomized, placebo-controlled phase 2/3 trial with 12 teen and adult participants. It used a crossover design. Each person gets both the drug and the placebo, at different times. An open-label extension came next, a phase in which everyone knowingly takes the drug [12].
• What it showed. The double-blind crossover part failed to meet its co-primary endpoints, its main goals. The open-label extension ran 36 weeks. It went along with gains in six-minute walk distance, in functional tests and in what patients reported [12].
• Longer follow-up. A 2024 paper gave 168 weeks of open-label extension data. Dosing went on for more than three years. Effects on patient-reported fatigue, exercise capacity and heart structure lasted through it [13].
• Comparison with untreated patients. A natural-history group is a set of patients tracked over time. In 2022, Hornby and colleagues set TAZPOWER participants on elamipretide against a separate group of this kind. Six-minute walk distance and motor function differed in favor of the drug [14].

Taken as a set, these studies backed the US regulatory filing. That filing led to the September 2025 accelerated approval.

Primary mitochondrial myopathy

PMM, short for primary mitochondrial myopathy, is a mixed group of genetic disorders that affect the respiratory chain.

• MMPOWER. Karaa and colleagues ran this randomized Phase 1/2 study in 36 adults who had PMM. Elamipretide was given into a vein, and the dose was stepped up. The six-minute walk test improved in line with dose, at the top dose of 0.25 mg/kg [6].
• MMPOWER-2. Karaa and colleagues reported this later trial in 2020. It was randomized and placebo-controlled, with a crossover design. Thirty adults received elamipretide under the skin for four weeks. Six-minute walk distance, the main goal, was 19.8 meters longer on the drug. That gap was not statistically significant. Patient-reported fatigue did improve [7].
• MMPOWER-3. This larger Phase 3 trial followed. It gave 218 adults the drug or a placebo for 24 weeks. Its primary endpoints were six-minute walk distance and fatigue. Neither was met [17]. The earlier dose-escalation and crossover results are the main early signs that the drug is active in PMM [6][7].

Age-related macular degeneration

A cell layer called the retinal pigment epithelium lies at the back of the eye. Geographic atrophy is a loss of patches of retina. One proposed cause of it, and of dry AMD, is that mitochondria in this layer stop working well.

Ehlers and colleagues reported the ReCLAIM-2 trial in 2025. It was a randomized Phase 2 study in 176 adults who had geographic atrophy and dry AMD. They received elamipretide under the skin for 48 weeks [16]. There were two primary endpoints. One was the change in low-luminance visual acuity, which is vision in dim light. The other was growth in the area of geographic atrophy. The trial missed both. Other analyses planned ahead of time found slower ellipsoid-zone attenuation, a sign of damage to light-sensing cells. More people on the drug also gained 10 or more letters of dim-light vision [16].

Heart failure

PROGRESS-HF was a Phase 2 trial that Butler and colleagues reported in 2020. It studied heart failure with reduced ejection fraction (HFrEF). In HFrEF the heart pumps out too little blood per beat. The trial randomized 71 patients to placebo or to four weeks of elamipretide under the skin [15].

The primary endpoint was how much left ventricular end-systolic volume changed. The trial missed it. Ejection fraction did not change either. Side effects tied to the drug were about as common as with placebo [15].

Aging in mice

• Muscle. Campbell and colleagues gave aged mice SS-31 (elamipretide) for eight weeks. Skeletal muscle had built up redox stress with age, and the treatment reversed it. Exercise tolerance rose to a level similar to that of young control mice [8].
• Heart. Chiao and colleagues gave SS-31 for eight weeks late in life, to mice aged 24 months. Diastolic function, the heart’s ability to relax and fill, was restored. The heart enlargement that comes with age was reversed, and mitochondrial respiration came back [9].
• SS-31 and NMN. Whitson and colleagues tested SS-31 and NMN in aged mice. The proteome is the full set of proteins. The two compounds arrived at overlapping gains in the heart’s mitochondrial proteome and in its metabolism. Their effects on function added together [10][11].
• Protein changes. A 2021 follow-up described how SS-31 reversed post-translational modifications of heart proteins that come with age. These are chemical changes made to proteins after they are built [11].

These models put SS-31 among the more repeatable protective treatments in the hearts of aged mice. Whether this carries over to humans is an open question.

Ischemia-reperfusion injury

Part of the first description of the Szeto-Schiller series was how it acted in reperfusion injury [1].

In people, the EMBRACE STEMI trial tested MTP-131 given into a vein. The patients had anterior ST-elevation myocardial infarction, a type of heart attack. They received it during primary percutaneous coronary intervention, the procedure that reopens the blocked artery [5].

The primary endpoints were about infarct size, the amount of heart muscle that died. It was measured two ways: with cardiac magnetic resonance, and with the area under the curve for creatine kinase. In the intention-to-treat group, neither showed a significant difference from placebo [5].

The program still shaped later work on mechanism, dosing and the choice of patients. It is one of only a few Phase 2 human data sets on mitochondria-targeted therapy in acute reperfusion.

Handling in the lab

SS-31 is a small peptide that dissolves in water. For lab work it is usually made up in a sterile, water-based buffer. Published studies in humans and rodents have given it into a vein or under the skin [6][7].

Stability matters. Repeated freezing and thawing is kept to a minimum. The pH and temperature are kept within the limits on the certificate of analysis that comes with the compound.

Everything described here is lab and in vitro research. This guide is for education. It gives no human doses, no protocols and no treatment use.

Legal status in the US

• FDA accelerated approval for one disease. In September 2025 the FDA granted accelerated approval to elamipretide. It covers Barth syndrome patients who weigh at least 30 kg. Priority Review and a Rare Pediatric Disease designation came first. The approval was based on gains in knee muscle strength. The FDA requires a further trial to confirm the benefit [18].
• Status can change. Current notices from the FDA give the latest status. That includes any confirming trials required after an accelerated approval. When this was written, the MHRA in the UK had not authorized elamipretide as a medicine.
• Owner. The compound belongs to Stealth BioTherapeutics.
• Sport. WADA, the World Anti-Doping Agency, does not name SS-31 on its Prohibited List. Broader WADA categories may still cover substances whose biological effects are similar. The current WADA List is the authority.

Limits of the research

SS-31 has a large body of evidence, and that evidence is mixed.

1. Missed main goals. A number of trials at Phase 2 and Phase 3 failed on their primary endpoints. What they reported were effects on secondary measures or in subgroups planned ahead of time.
2. Where the good news sits. A large share of the promising data comes from open-label extensions and from animal models of aging [12][15][16][9].
3. Three kinds of evidence. Reading the record means keeping three things apart: confirmed randomized results, longer-term open-label observations, and rodent data.

SS-31 has an accelerated approval for one rare disease. Most of its randomized trials missed their main goals, and its aging results come from mice.

References

Selected peer-reviewed references. Not exhaustive. All DOIs and PubMed identifiers verified at time of publication.

1. Zhao K, Zhao G-M, Wu D, Soong Y, Birk AV, Schiller PW, Szeto HH (2004). Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury. Journal of Biological Chemistry, 279(33), 34682–34690. DOI · PMID: 15178689
2. Szeto HH (2014). First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergetics. British Journal of Pharmacology, 171(8), 2029–2050. DOI · PMID: 24117165
3. Birk AV, Liu S, Soong Y, Mills W, Singh P, Warren JD, Seshan SV, Pardee JD, Szeto HH (2014). The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipin. British Journal of Pharmacology, 171(8), 2017–2028. DOI · PMID: 24134698
4. Szeto HH, Schiller PW (2014). Serendipity and the discovery of novel compounds that restore mitochondrial plasticity. Clinical Pharmacology & Therapeutics, 96(6), 672–683. DOI · PMID: 25188726
5. Gibson CM, Giugliano RP, Kloner RA, Bode C, Tendera M, Janénescu A, Możeńska O, Lewis BS, Goodell L, Davidson-Ray L, Ardissino D, Halabi AR, Budaj A, Goldstein P, Al-Hujaili AA, Murphy SA, Hamm C (2016). EMBRACE STEMI study: a Phase 2a trial to evaluate the safety, tolerability, and efficacy of intravenous MTP-131 on reperfusion injury in patients undergoing primary percutaneous coronary intervention. European Heart Journal, 37(16), 1296–1303. DOI · PMID: 26586786
6. Karaa A, Haas R, Goldstein A, Vockley J, Weaver WD, Cohen BH (2018). Randomized dose-escalation trial of elamipretide in adults with primary mitochondrial myopathy. Neurology, 90(14), e1212–e1221. DOI · PMID: 29500292
7. Karaa A, Haas R, Goldstein A, Vockley J, Cohen BH (2020). A randomized crossover trial of elamipretide in adults with primary mitochondrial myopathy. Journal of Cachexia, Sarcopenia and Muscle, 11(4), 909–918. DOI · PMID: 32096613
8. Campbell MD, Duan J, Samuelson AT, Gaffrey MJ, Merrihew GE, Egertson JD, Wang L, Bammler TK, Moore RJ, White CC, Kavanagh TJ, Voss JG, Szeto HH, Rabinovitch PS, MacCoss MJ, Qian W-J, Marcinek DJ (2019). Improving mitochondrial function with SS-31 reverses age-related redox stress and improves exercise tolerance in aged mice. Free Radical Biology & Medicine, 134, 268–281. DOI · PMID: 30597195
9. Chiao YA, Zhang H, Sweetwyne M, Whitson J, Ting YS, Basisty N, Pino LK, Quarles E, Nguyen NH, Campbell MD, Zhang T, Gaffrey MJ, Merrihew G, Wang L, Yue Y, Duan D, Granzier HL, Szeto HH, Qian W-J, Marcinek D, MacCoss MJ, Rabinovitch P (2020). Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice. eLife, 9, e55513. DOI · PMID: 32648542
10. Whitson JA, Bitto A, Zhang H, Sweetwyne MT, Coig R, Bhayana S, Shankland EG, Wang L, Bammler TK, Mills KF, Imai S, Conley KE, Marcinek DJ, Rabinovitch PS (2020). SS-31 and NMN: two paths to improve metabolism and function in aged hearts. Aging Cell, 19(10), e13213. DOI · PMID: 32779818
11. Whitson JA, Martin-Perez M, Zhang T, Gaffrey MJ, Merrihew GE, Sweetwyne MT, Pino LK, MacCoss MJ, Qian W-J, Villen J, Rabinovitch PS (2021). Elamipretide (SS-31) treatment attenuates age-associated post-translational modifications of heart proteins. GeroScience, 43(5), 2395–2412. DOI · PMID: 34480713
12. Reid Thompson W, Hornby B, Manuel R, Bradley E, Laux J, Carr J, Vernon HJ (2021). A phase 2/3 randomized clinical trial followed by an open-label extension to evaluate the effectiveness of elamipretide in Barth syndrome, a genetic disorder of mitochondrial cardiolipin metabolism. Genetics in Medicine, 23(3), 471–478. DOI · PMID: 33077895
13. Thompson WR, Hornby B, Dessel K, Manuel R, Bradley E, Laux J, Vernon HJ (2024). Long-term efficacy and safety of elamipretide in patients with Barth syndrome: 168-week open-label extension results of TAZPOWER. Genetics in Medicine, 26(7), 101138. DOI · PMID: 38602181
14. Hornby B, McClellan R, Buckley L, Carson K, Gooding T, Vernon HJ (2022). Natural history comparison study to assess the efficacy of elamipretide in patients with Barth syndrome. Orphanet Journal of Rare Diseases, 17(1), 336. DOI · PMID: 36056411
15. Butler J, Khan MS, Anker SD, Fonarow GC, Kim RJ, Nodari S, O’Connor CM, Pieske B, Pieske-Kraigher E, Sabbah HN, Senni M, Voors AA, Udelson JE, Carr J, Gheorghiade M, Filippatos G (2020). Effects of elamipretide on left ventricular function in patients with heart failure with reduced ejection fraction: the PROGRESS-HF Phase 2 trial. Journal of Cardiac Failure, 26(5), 429–437. DOI · PMID: 32068002
16. Ehlers JP, Hu A, Boyer D, Cousins SW, Waheed NK, Rosenfeld PJ, Brown D, Kaiser PK, Abbruscato A, Gao G, Heier J (2025). ReCLAIM-2: a randomized Phase 2 clinical trial evaluating elamipretide in age-related macular degeneration, geographic atrophy growth, visual function, and ellipsoid zone preservation. Ophthalmology Science, 5(1), 100628. DOI · PMID: 39605874
17. Karaa A, Bertini E, Carelli V, Cohen BH, Enns GM, Falk MJ, Goldstein A, Gorman GS, Haas R, Hirano M, Klopstock T, Koenig MK, Kornblum C, Lamperti C, Lehman A, Longo N, Molnar MJ, Parikh S, Phan H, Pitceathly RDS, Saneto R, Scaglia F, Servidei S, Tarnopolsky M, Toscano A, Van Hove JLK, Vissing J, Vockley J, Finman JS, Brown DA, Shiffer JA, Mancuso M (2023). Efficacy and safety of elamipretide in individuals with primary mitochondrial myopathy: the MMPOWER-3 randomized clinical trial. Neurology, 101(3), e238–e252. DOI · PMID: 37268435
18. US Food and Drug Administration (2025). FDA Grants Accelerated Approval to First Treatment for Barth Syndrome. FDA news release, September 19, 2025. Link