SS-31, also known as elamipretide, is a short synthetic peptide (a chain of just four amino acids) that accumulates in the inner membrane of mitochondria — the cell's “power plants” — and binds there to a lipid called cardiolipin. It is an exception among “research peptides”: it went through a full clinical development programme and in September 2025 was approved in the USA as a medicine (Forzinity) for a rare genetic disease, Barth syndrome. At the same time, in most other applications — above all mitochondrial myopathy and heart failure — large trials showed no benefit. In this review we explain in plain terms how SS-31 is meant to work, what animal and human studies have shown, and why approval in one disease does not mean the compound “optimises mitochondria” in healthy people.
What SS-31 is
SS-31 belongs to the family of so-called Szeto–Schiller peptides (hence the abbreviation SS), developed in the early 2000s by the team of Hazel Szeto and Peter Schiller. The first paper, from 2004 (Zhao et al.), described them as “cell-permeable peptide antioxidants” that home to the inner mitochondrial membrane and concentrate there more than a thousand-fold. The compound was later developed by the company Stealth BioTherapeutics under the names MTP-131 and elamipretide; the approved medicine is called Forzinity. All these names refer to the same molecule.
How it works — cardiolipin and the mitochondrial “scaffold”
A mitochondrion has two membranes. The inner one is folded into ridges (cristae) that carry the complexes of the respiratory chain — the “production line” for energy, ATP. Cardiolipin is an unusual lipid found only in this membrane: it maintains the shape of the cristae and glues the respiratory complexes together into larger assemblies. When cardiolipin becomes oxidised, the cristae fall apart, ATP production drops, and the protein cytochrome c, instead of carrying electrons, starts to act as an enzyme that destroys the membrane. Birk et al. (2013) used a fluorescent analogue to show that SS-31 binds cardiolipin with high affinity, inhibits that destructive activity of cytochrome c, and protects the cristae in rat kidneys during ischaemia, so that ATP recovers faster. Hence the term “cardiolipin stabiliser” — SS-31 acts at the source, on the structure of the membrane, rather than “sweeping up” radicals circulating in the cell. The original 2004 paper, however, also attributed scavenging properties to it, linked to the unusual amino acid dimethyltyrosine: analogues lacking that amino acid did not inhibit radical production. The two descriptions are not mutually exclusive — cardiolipin binding is now regarded as the main mechanism, and the statement “SS-31 is not an antioxidant” is a simplification.
Structure and origin
Elamipretide is a tetrapeptide, a chain of four amino acids arranged alternately: aromatic, basic, aromatic, basic; one of them is the aforementioned dimethyltyrosine, which does not occur in natural proteins. This pattern gives the molecule a positive charge and “stickiness” towards negatively charged cardiolipin, while allowing it to pass easily through cell membranes — Karaa et al. (2018) describe it as an “aromatic-cationic tetrapeptide that readily penetrates cell membranes and transiently localizes to the inner mitochondrial membrane”. In clinical trials it was given intravenously by infusion or subcutaneously in daily injections.
What was studied — cells and animals
The animal literature is extensive: models of kidney and heart ischaemia, heart failure in dogs, diabetes, injury. For a reader interested in ageing, the most striking work is that of Siegel et al. (2013). Old, 27-month-old mice were given a single dose of SS-31, and within an hour measurements taken in the living animal showed that the efficiency of ATP production in muscle had returned to the level of young, 5-month-old mice; in young animals the same injection changed nothing. After an hour the muscles of old mice were more fatigue-resistant, and eight days of treatment increased the endurance of the whole animal. It is a spectacular result — but it concerns mice and was measured in hours and days, not years.
Human data — mitochondrial myopathy
The main clinical target of elamipretide was primary mitochondrial myopathy (PMM) — a group of genetic diseases in which damaged mitochondria cause muscle weakness and rapid fatigue. The early MMPOWER study (Karaa et al., 2018) in 36 patients was encouraging: after five days of two-hour intravenous infusions, those receiving the highest dose walked on average 64.5 m farther in the six-minute walk test, versus 20.4 m in the placebo group (p = 0.053, borderline significance), and the dose-response relationship was significant (p = 0.014). On that basis the pivotal phase 3 trial was designed. MMPOWER-3 (Karaa et al., 2023) enrolled 218 patients with genetically confirmed PMM who for 24 weeks received subcutaneous elamipretide, 40 mg as a daily injection, or placebo. The result was unequivocal: the difference in walking distance was −3.2 m (95% CI −18.7 to 12.3; p = 0.69), and in the fatigue score −0.07 points (p = 0.37). The trial met neither of its two primary endpoints, and the authors classified it as Class I evidence that elamipretide does not improve walking distance or fatigue in this disease. The drug was, at the same time, well tolerated. An important lesson: a “borderline” result in a small study did not survive confrontation with a large one.
Human data — Barth syndrome and FDA approval
Barth syndrome is an ultra-rare X-linked genetic disease in which a defect in the TAZ gene disrupts the structure of cardiolipin in the inner mitochondrial membrane — precisely the lipid SS-31 binds to; the disease affects the heart and muscles. The TAZPOWER trial (Reid Thompson et al., 2021) was small: 12 patients received elamipretide and placebo in alternation, 12 weeks each. In that blinded part neither of the two primary endpoints (walking distance, symptom scale) was met. Only in the open-label extension — without placebo and without blinding — did walking distance improve after 36 weeks by 95.9 m (p = 0.024) and the symptom scale by 2.1 points (p = 0.031); knee-extensor strength and some cardiac parameters also improved. The extension ran for a total of 168 weeks (Thompson et al., 2024): of 10 people, 8 reached the end, the cumulative improvement in walking distance was 96.1 m (p = 0.003), and the biochemical marker of the disease (the ratio of monolysocardiolipin to cardiolipin) improved in parallel with symptoms. On that basis the FDA granted accelerated approval in September 2025 (Shirley, 2026): elamipretide, under the name Forzinity, is meant to improve muscle strength in adults and children with Barth syndrome weighing at least 30 kg — the first medicine aimed at the cause of this disease. Accelerated approval means, however, that the evidence rests on a small group and on open-label data, not on a winning blinded trial.
Other directions — the heart and ageing muscle
Elamipretide was also tested in heart failure. In the PROGRESS-HF trial (Butler et al., 2020) 71 patients with reduced ejection fraction received subcutaneous placebo, 4 mg or 40 mg of the drug for 28 days; left-ventricular end-systolic volume measured by MRI did not differ from placebo (for 40 mg the difference was +2.3 ml; p = 0.28). Most interesting for the topic of ageing is the study by Roshanravan et al. (2021): 39 healthy adults aged 60–85, selected for poorly functioning muscle mitochondria, received a single two-hour infusion of elamipretide or placebo. Immediately after the infusion, the muscle's maximal capacity to produce ATP, measured non-invasively by spectroscopy, was higher than after placebo (for the percentage change p = 0.045), but by day seven the difference had vanished, resting mitochondrial coupling was unchanged and — most importantly — the muscle's fatigue resistance did not improve. In other words: in humans there is a short-lived effect on a biochemical marker, but not on function.
Safety and the limits of the evidence
In clinical trials elamipretide was well tolerated: the most common adverse events were injection-site reactions (Thompson et al., 2024), and in MMPOWER-3 most events were mild or moderate. That does not make the compound “safe for everything” — the data come from patients with rare diseases and from studies lasting weeks or months. The key limits of the evidence: (1) the only clinical success concerns a disease whose defect lies in cardiolipin, exactly the drug's target; (2) in mitochondrial myopathy and in heart failure the blinded trials were negative; (3) in healthy older adults a single infusion changed a marker, not function; (4) the Barth syndrome data come from 8–12 people, mostly from the open-label phase. There are no studies whatsoever in healthy young people or athletes, so “mitochondrial optimisation” with elamipretide is an extrapolation without data. We deliberately give no methods of use and no doses.
The wider context — mitochondria-targeted compounds
SS-31 belongs to the group of compounds targeted at mitochondria. Other strategies in this group are peptides encoded by the mitochondrial genome itself, such as MOTS-c, and precursors of the coenzyme NAD+ (NMN, NR), which — unlike SS-31 — do not act on membrane structure but supply substrate to enzymes. Within this group elamipretide is the only compound that has completed a phase 3 trial and gained approval, which paradoxically makes its negative results the most reliable data in the whole class: we know what it does not do.
Summary
SS-31 (elamipretide) is a four-amino-acid peptide that binds cardiolipin in the inner mitochondrial membrane. In old mice it restores youthful muscle energetics within an hour; in humans a single infusion briefly raises the muscle's capacity to produce ATP but does not change its fatigue resistance. The large phase 3 trial in mitochondrial myopathy returned a null result (−3.2 m in the walk test), and so did the heart-failure trial. The only success — and the FDA approval of September 2025 (Forzinity) — concerns Barth syndrome, an ultra-rare disease of cardiolipin, and rests on open-label extension data from a dozen or so patients. State of the evidence: a well-described mechanism, one approval in a rare disease, negative trials in commoner diseases, and no data at all in healthy people.
Sources
- Karaa A, Bertini E, Carelli V, et al.; MMPOWER-3 Trial Investigators. Efficacy and Safety of Elamipretide in Individuals With Primary Mitochondrial Myopathy: The MMPOWER-3 Randomized Clinical Trial. Neurology. 2023;101(3):e238–e252. PMID: 37268435. DOI: 10.1212/WNL.0000000000207402. pubmed.ncbi.nlm.nih.gov/37268435
- Reid Thompson W, Hornby B, Manuel R, et al. 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. 2021;23(3):471–478. PMID: 33077895. DOI: 10.1038/s41436-020-01006-8. pubmed.ncbi.nlm.nih.gov/33077895
- Thompson WR, Manuel R, Abbruscato A, et al. Long-term efficacy and safety of elamipretide in patients with Barth syndrome: 168-week open-label extension results of TAZPOWER. Genetics in Medicine. 2024;26(7):101138. PMID: 38602181. DOI: 10.1016/j.gim.2024.101138. pubmed.ncbi.nlm.nih.gov/38602181
- Butler J, Khan MS, Anker SD, et al. 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. 2020;26(5):429–437. PMID: 32068002. DOI: 10.1016/j.cardfail.2020.02.001. pubmed.ncbi.nlm.nih.gov/32068002
- Roshanravan B, Liu SZ, Ali AS, et al. In vivo mitochondrial ATP production is improved in older adult skeletal muscle after a single dose of elamipretide in a randomized trial. PLoS One. 2021;16(7):e0253849. PMID: 34264994. DOI: 10.1371/journal.pone.0253849. pubmed.ncbi.nlm.nih.gov/34264994
- Karaa A, Haas R, Goldstein A, Vockley J, Weaver WD, Cohen BH. Randomized dose-escalation trial of elamipretide in adults with primary mitochondrial myopathy. Neurology. 2018;90(14):e1212–e1221. PMID: 29500292. DOI: 10.1212/WNL.0000000000005255. pubmed.ncbi.nlm.nih.gov/29500292
- Shirley M. Elamipretide: First Approval. Drugs. 2026;86(3):377–383. PMID: 41335372. DOI: 10.1007/s40265-025-02269-8. pubmed.ncbi.nlm.nih.gov/41335372
- Birk AV, Liu S, Soong Y, et al. The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipin. Journal of the American Society of Nephrology. 2013;24(8):1250–1261. PMID: 23813215. DOI: 10.1681/ASN.2012121216. pubmed.ncbi.nlm.nih.gov/23813215
- Siegel MP, Kruse SE, Percival JM, et al. Mitochondrial-targeted peptide rapidly improves mitochondrial energetics and skeletal muscle performance in aged mice. Aging Cell. 2013;12(5):763–771. PMID: 23692570. DOI: 10.1111/acel.12102. pubmed.ncbi.nlm.nih.gov/23692570
- Zhao K, Zhao GM, Wu D, et al. Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury. Journal of Biological Chemistry. 2004;279(33):34682–34690. PMID: 15178689. DOI: 10.1074/jbc.M402999200. pubmed.ncbi.nlm.nih.gov/15178689
For in-vitro laboratory research only. It is not a human medicine and is not for treatment.