Key takeaways
- SS-31, developed as elamipretide, is a synthetic tetrapeptide that concentrates in the inner mitochondrial membrane and binds cardiolipin, the phospholipid that organizes the respiratory chain.
- In cell and animal models it preserved electron-transport efficiency, reduced reactive oxygen species and protected against ischemia–reperfusion injury; in aged mice it improved exercise tolerance.
- Large trials in heart attack, heart failure and mitochondrial myopathy missed their primary endpoints, while a 12-patient Barth syndrome program eventually supported approval.
- FDA granted accelerated approval to elamipretide (Forzinity) for Barth syndrome on September 19, 2025, after a complete response letter earlier that year; a 72-week confirmatory trial began in 2026.
SS-31 is one of very few peptides in the longevity literature to have completed the full arc from bench to regulatory approval, and the story is more instructive than a simple success. The molecule was designed in the late 1990s at Weill Cornell by Hazel Szeto and Peter Schiller, who were looking for opioid analogs and found instead that a class of short, positively charged aromatic peptides accumulated in mitochondria. Over two decades it was tested in kidney ischemia, heart attack, heart failure, mitochondrial myopathy, macular degeneration and an ultra-rare cardiolipin disorder called Barth syndrome. Most of the large trials failed. The smallest one did not, and in September 2025 the U.S. Food and Drug Administration approved elamipretide for that indication. This note explains what SS-31 does at the inner mitochondrial membrane, what the preclinical and clinical record shows, and where the regulatory history stands as of mid-2026. Wednesday does not list SS-31; this is an educational review.
Structure and where it goes
SS-31 is a four-residue peptide with the sequence D-Arg–2′,6′-dimethyltyrosine–Lys–Phe–NH2. The D-arginine and the methylated tyrosine protect it from peptidases, the amide C-terminus removes a negative charge, and the alternating basic and aromatic residues give it a net charge of +3. In 2004 Zhao and colleagues showed that this and related Szeto–Schiller peptides were taken up by cells independently of energy or receptors and concentrated in mitochondria, where they reduced mitochondrial swelling, inhibited oxidative cell death and limited reperfusion injury in isolated hearts.2
Unusually for a mitochondria-targeted compound, SS-31 does not depend on the mitochondrial membrane potential to get in. Lipophilic cations such as MitoQ accumulate in proportion to the potential and are lost when mitochondria depolarize, which is exactly when they are needed most. SS-31 accumulates roughly a thousandfold at the inner membrane regardless of potential, which made it attractive for ischemic tissue.2
Cardiolipin, the target
The mechanism was clarified in 2013. Birk and colleagues showed that SS-31 binds selectively to cardiolipin, a phospholipid with four acyl chains that is found almost exclusively in the inner mitochondrial membrane. Cardiolipin anchors cytochrome c between complexes III and IV, stabilizes the supercomplexes of the electron transport chain and maintains the folded cristae structure that keeps respiration efficient. Under oxidative stress, cytochrome c bound to cardiolipin acquires peroxidase activity and begins oxidizing the lipid, which loosens the respiratory chain, leaks electrons as superoxide and eventually releases cytochrome c to trigger apoptosis.1
SS-31 interrupted this cycle. In the 2013 kidney work, the peptide bound cardiolipin, prevented cytochrome c from converting to a peroxidase, preserved cristae architecture during ischemia and restored ATP production on reperfusion. Renal function in rats recovered faster and tubular cells survived in greater numbers.1 Szeto’s 2014 review named this a “cardiolipin-protective” mechanism, distinguishing it from antioxidant scavenging: the peptide does not neutralize reactive species after they form but reduces their production at the source by keeping the electron transport chain properly assembled.2
SS-31 does not mop up free radicals; it holds the respiratory chain together so that fewer are made.
The preclinical record
Between 2004 and 2019 SS-31 was tested in dozens of rodent and cell models, including cardiac and renal ischemia–reperfusion, pressure-overload heart failure, diabetic kidney disease, skeletal-muscle atrophy, neurodegeneration models and aging. The findings were consistent in direction: preserved mitochondrial respiration, lower hydrogen peroxide emission, reduced tissue injury.2 Two studies are worth singling out for research relevance.
Campbell and colleagues gave SS-31 to 26-month-old mice for eight weeks. Treated animals showed reduced mitochondrial hydrogen peroxide production and restored redox balance in skeletal muscle, along with improved treadmill endurance and greater fatigue resistance, effects not seen in young mice.3
Chatfield and colleagues took the mechanism into human tissue. In cardiac muscle obtained from patients with end-stage heart failure at transplant, ex vivo treatment with elamipretide improved mitochondrial oxygen consumption, restored supercomplex assembly and normalized the cardiolipin profile. Tissue from failing hearts responded; tissue from non-failing donor hearts did not change.4 This is human evidence at the level of mechanism.
Clinical trials: what did not work
Heart attack. EMBRACE STEMI randomized 297 patients undergoing primary angioplasty for anterior ST-elevation myocardial infarction to intravenous elamipretide or placebo before reperfusion. Infarct size measured by creatine kinase-MB release over 72 hours, the primary endpoint, did not differ between arms.5
Heart failure. PROGRESS-HF randomized 71 patients with heart failure and reduced ejection fraction to four weeks of daily subcutaneous elamipretide at two doses or placebo. Left ventricular end-systolic volume, the primary endpoint, did not change significantly, and neither did other structural or functional measures.6
Primary mitochondrial myopathy. This was the indication with the strongest rationale, since patients carry genetic defects in oxidative phosphorylation. Early-phase studies suggested improvements in six-minute walk distance. MMPOWER-3 then randomized 218 patients to 24 weeks of daily elamipretide or placebo. Neither primary endpoint, change in six-minute walk distance or in a fatigue score, was met.7 The compound was well tolerated, with injection-site reactions the main adverse event, but the effect seen in smaller studies did not reproduce.
The dry age-related macular degeneration program produced a phase 2 result that missed its visual-acuity primary endpoint while showing a signal on retinal structure; phase 3 trials are ongoing and no result had been reported as of September 2026.
Reading the evidence
Three adequately powered trials in common cardiovascular and mitochondrial conditions failed on their primary endpoints. A mechanism that works in isolated mitochondria and in aged mice did not translate into measurable clinical benefit in those populations over weeks of treatment. This is the norm in drug development, and it is the context in which the Barth syndrome approval should be read.
Barth syndrome: what did work
Barth syndrome is an X-linked disorder caused by mutations in TAFAZZIN, the enzyme that remodels cardiolipin into its mature form. Affected boys have abnormal cardiolipin, cardiomyopathy, skeletal-muscle weakness, neutropenia and growth delay; the condition is estimated to affect about 150 people in the United States. Because the defect is in cardiolipin itself, a cardiolipin-binding peptide had an unusually direct rationale.
TAZPOWER enrolled 12 participants in a randomized, double-blind, placebo-controlled crossover trial: two 12-week treatment periods separated by a washout, followed by an open-label extension. The primary endpoints, six-minute walk distance and a Barth-specific fatigue scale, were not met in the crossover phase. In the 36-week open-label extension, however, the eight participants who completed it showed improvements in walk distance (about 96 meters), fatigue score, knee extensor strength and left ventricular stroke volume, in a disease whose natural history is decline; the company later reported continued gains through longer follow-up.8 With a dozen patients, a negative blinded phase and a positive open-label phase, the dataset was difficult to interpret, and the regulatory history reflects that.
| Trial | Condition | n | Primary endpoint | Result |
|---|---|---|---|---|
| EMBRACE STEMI5 | Anterior STEMI | 297 | Infarct size (CK-MB AUC) | Not met |
| PROGRESS-HF6 | Heart failure, reduced EF | 71 | LV end-systolic volume | Not met |
| MMPOWER-37 | Primary mitochondrial myopathy | 218 | 6-minute walk; fatigue score | Not met |
| TAZPOWER8 | Barth syndrome | 12 | 6-minute walk; fatigue scale | Not met in crossover; open-label gains in strength and walk distance |
FDA history through 2026
Stealth BioTherapeutics submitted a new drug application for elamipretide in Barth syndrome in January 2024, and FDA accepted it with priority review. On October 10, 2024, the Cardiovascular and Renal Drugs Advisory Committee voted 10 to 6 that the data were sufficient to establish effectiveness, a narrow endorsement that reflected the small sample and the negative blinded phase. The action date was extended to April 29, 2025, and in May 2025 FDA issued a complete response letter. The company stated that the letter cited observations from a manufacturing-facility inspection and requested additional safety data, and that FDA had agreed to a path toward accelerated approval based on knee extensor strength as an intermediate clinical endpoint.9
Stealth resubmitted in August 2025. On September 19, 2025, FDA granted accelerated approval to elamipretide under the brand name Forzinity to improve muscle strength in adult and pediatric patients with Barth syndrome weighing at least 30 kilograms. The approval rests on the knee extensor strength improvement seen in TAZPOWER’s open-label extension, and continued approval is contingent on confirmation of clinical benefit.9 It is the first approved therapy for the disease.
In 2026 the company renamed itself Mighty Therapeutics and, on July 8, announced the first patient dosed in 4TAZPower, a 72-week randomized, double-blind, placebo-controlled confirmatory trial in genetically confirmed Barth syndrome from age five. A pharmacokinetic and safety study in children under 30 kilograms is planned to support a supplemental application in 2027, and development continues in polymerase-gamma-related mitochondrial disease and dry macular degeneration.10
Limits of the record
Forzinity is a prescription drug approved for one ultra-rare indication on the basis of an intermediate endpoint in 12 patients. SS-31 sold as a research chemical is not that drug: it has not passed through the manufacturing, quality and regulatory controls that apply to the approved product, and no evidence supports its use outside laboratory research. The compound’s failures in heart attack, heart failure and mitochondrial myopathy are as much a part of its record as the approval.
Why the compound matters to mitochondrial research
For laboratories, SS-31’s value lies in what it isolates. Because it acts on cardiolipin rather than on a receptor or an enzyme, it lets researchers ask what happens to a cell or tissue when inner-membrane organization is preserved under stress, without confounding effects on other signaling. It has been used in that way to probe the role of mitochondrial redox stress in aging muscle, kidney injury and heart failure.3,4 Its history also offers a calibration point for other mitochondrial compounds in this library, including the endogenous peptides covered in Mitochondrial-Derived Peptides and the coenzyme covered in What Is NAD+? None of those has a clinical record approaching SS-31’s, in either its failures or its one success. For how research compounds differ from approved drugs, see Research Peptides Explained.
Frequently asked questions
What is SS-31?
SS-31 is a synthetic four-amino-acid peptide (D-Arg–dimethyltyrosine–Lys–Phe–NH2) developed by Hazel Szeto and Peter Schiller. It concentrates in the inner mitochondrial membrane and binds cardiolipin, stabilizing the electron transport chain and reducing reactive oxygen species production. Its pharmaceutical name is elamipretide.
Is SS-31 the same as elamipretide?
Chemically, yes; elamipretide is the international nonproprietary name for SS-31, and Forzinity is the approved brand. Practically, research-grade SS-31 is not the approved drug: it is manufactured and sold outside the pharmaceutical quality and regulatory system and is intended only for laboratory use.
Is elamipretide FDA approved?
Yes. On September 19, 2025, FDA granted accelerated approval to elamipretide (Forzinity) to improve muscle strength in patients with Barth syndrome weighing at least 30 kg. Continued approval depends on a confirmatory trial, which began dosing in July 2026. It is not approved for any other condition.
How does SS-31 work in mitochondria?
It binds cardiolipin, the inner-membrane phospholipid that holds cytochrome c and the respiratory complexes in place. By preventing cytochrome c from acquiring peroxidase activity and oxidizing cardiolipin, SS-31 preserves cristae structure and electron-transport efficiency, so fewer electrons leak to form superoxide. It is not a conventional antioxidant scavenger.
Did elamipretide work for mitochondrial myopathy?
No. The 218-patient MMPOWER-3 trial found no significant difference from placebo in six-minute walk distance or fatigue after 24 weeks, despite encouraging smaller studies. The Barth syndrome approval does not extend to primary mitochondrial myopathy.
References & further reading
- Birk AV, Liu S, Soong Y, et al. The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipin. J Am Soc Nephrol. 2013;24(8):1250–1261. doi:10.1681/ASN.2012121216
- Szeto HH. First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergetics. Br J Pharmacol. 2014;171(8):2029–2050. doi:10.1111/bph.12461
- Campbell MD, Duan J, Samuelson AT, et al. Improving mitochondrial function with SS-31 reverses age-related redox stress and improves exercise tolerance in aged mice. Free Radic Biol Med. 2019;134:268–281. doi:10.1016/j.freeradbiomed.2018.12.031
- Chatfield KC, Sparagna GC, Chau S, et al. Elamipretide improves mitochondrial function in the failing human heart. JACC Basic Transl Sci. 2019;4(2):147–157. doi:10.1016/j.jacbts.2018.12.005
- Gibson CM, Giugliano RP, Kloner RA, et al. 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. Eur Heart J. 2016;37(16):1296–1303. doi:10.1093/eurheartj/ehv597
- 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. J Card Fail. 2020;26(5):429–437. doi:10.1016/j.cardfail.2020.02.001
- Karaa A, Bertini E, Carelli V, et al. Efficacy and safety of elamipretide in individuals with primary mitochondrial myopathy: the MMPOWER-3 randomized clinical trial. Neurology. 2023;101(3):e238–e252. doi:10.1212/WNL.0000000000207402
- 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. Genet Med. 2021;23(3):471–478. doi:10.1038/s41436-020-01006-8
- Stealth BioTherapeutics. Stealth BioTherapeutics announces FDA accelerated approval of FORZINITY (elamipretide) injection, the first therapy for progressive and life-limiting ultra-rare genetic disease Barth syndrome. Press release, 19 September 2025. mightytx.com
- Mighty Therapeutics. Mighty Therapeutics announces first patient dosed in phase 4 confirmatory study of elamipretide in Barth syndrome. Press release, 8 July 2026. mightytx.com