SS-31
SS-31 is a synthetic aromatic-cationic tetrapeptide, D-Arg-Dmt-Lys-Phe-NH2, in which Dmt is 2',6'-dimethyltyrosine; its alternating basic and aromatic residues are the structural motif shared by the Szeto-Schiller peptide series. The peptide is cell-permeable and concentrates roughly 1,000-fold in the inner mitochondrial membrane, where it partitions into the lipid interfacial region rather than the aqueous matrix. Developed clinically as elamipretide and earlier called MTP-131 or Bendavia, it has been tested in phase 2 and phase 3 trials in primary mitochondrial myopathy, Barth syndrome, heart failure, reperfusion injury and retinal degeneration. On 19 September 2025 the US FDA granted it accelerated approval for Barth syndrome, the first therapy aimed at that disorder's mitochondrial cause, with a confirmatory trial required as a condition; every other application remains investigational.
Information on this page is provided for laboratory research reference. The compound is not a drug, supplement, or medical product, and is not for human or veterinary use, ingestion, or consumption.
No reviewed report has been published for this product family yet. The molecular values opposite are public reference data, not results measured on a CRX sample.
Browse published reports →- Arg
- D-Arginine
- Dmt
- 2′,6′-Dimethyltyrosine — Dimethylated tyrosine; the aromatic anchor of the SS-31 alternating motif.
SS-31 binds cardiolipin, the dimeric anionic phospholipid restricted to the inner mitochondrial membrane, with high affinity, and this interaction is the best-established element of its pharmacology. Biophysical work on model and mitochondrial membranes shows the peptide partitions into the interfacial region with an affinity and binding density set by surface charge, leaves lamellar bilayers intact even at saturating concentrations, but alters lipid packing and shifts membrane surface electrostatics, which in turn redistributes divalent cations such as calcium at the interface. The SS-31/cardiolipin complex also suppresses the peroxidase activity of the cytochrome c/cardiolipin complex by shielding its haem iron, limiting the cardiolipin peroxidation that dismantles cristae during ischaemia. The original framing was radical scavenging by the dimethyltyrosine residue, supported by the observation that analogues lacking that residue failed to inhibit mitochondrial ROS generation or swelling; whether scavenging, electrostatic tuning of the bilayer, or cristae stabilisation is the dominant effect in a living animal is not settled. A proposed downstream consequence is stabilisation of respiratory-chain supercomplexes: in tafazzin-knockdown mice SS-31 improved respiratory capacity and supercomplex organisation without changing the abnormal monolysocardiolipin/cardiolipin ratio, which argues the peptide acts on respiratory-chain function rather than on cardiolipin composition itself.1,2,4,5,6
Primary binding partner. A polarity-sensitive fluorescent analogue of SS-31 showed high-affinity binding to cardiolipin, the anionic phospholipid required for cristae formation; binding density scales with membrane surface charge.2,4
Inhibited. The SS-31/cardiolipin complex protects the haem iron of cytochrome c, blocking the peroxidase activity that catalyses cardiolipin peroxidation and cristae damage during ischaemia.4
Modulated. SS-31 binding changes the surface charge of model and mitochondrial membranes and alters the interfacial distribution of calcium; analogues that shift surface charge differently show different potency, supporting electrostatic tuning as a mechanistic component.2,5
Proposed stabilisation. In tafazzin-knockdown mouse heart mitochondria, SS-31 promoted supercomplex organisation and raised respiratory rates without correcting the underlying cardiolipin abnormality.6
Mitochondrial function
In MMPOWER-3, a 24-week phase 3 randomised, double-blind trial in 218 adults with genetically confirmed primary mitochondrial myopathy, elamipretide missed both primary endpoints: six-minute walk distance differed from placebo by -3.2 m (95% CI -18.7 to 12.3; p = 0.69) and total fatigue score on the Primary Mitochondrial Myopathy Symptom Assessment by -0.07 (95% CI -0.10 to 0.26; p = 0.37).7
In MMPOWER-2, a randomised, double-blind, placebo-controlled crossover trial in 30 adults with genetically confirmed primary mitochondrial myopathy, participants walked 398.3 +/- 134.16 m during the elamipretide period versus 378.5 +/- 125.10 m during placebo, a 19.8 m difference that was not significant (95% CI -2.8 to 42.5; p = 0.0833); patient-reported total fatigue favoured elamipretide (p = 0.0006).8
In TAZPOWER, a 28-week randomised, double-blind, placebo-controlled crossover trial in 12 patients with Barth syndrome, elamipretide separated from placebo on neither primary endpoint, with no significant improvement in six-minute walk distance or in the Barth Syndrome Symptom Assessment score.9
In the 168-week open-label extension of TAZPOWER, the 10 patients with Barth syndrome who continued elamipretide walked a cumulative 96.1 m farther on the six-minute walk test than at open-label baseline (p = 0.003 at week 168, 8 of 10 reaching that visit), with improved left ventricular volumes and monolysocardiolipin/cardiolipin ratios. The extension had no concurrent control group; the FDA granted accelerated approval contingent on a confirmatory trial.3,10
In a randomised, double-blind, placebo-controlled trial in 39 healthy adults aged 60 to 85 with poorly functioning skeletal-muscle mitochondria, a single two-hour elamipretide infusion raised maximal in vivo ATP production relative to placebo immediately after infusion by fractional change (%delta-ATPmax p = 0.045) though not by absolute change (delta-ATPmax p = 0.055). No difference remained at day 7; resting coupling and fatigue resistance were unchanged.11
In PROGRESS-HF, a 28-day phase 2 randomised, placebo-controlled trial in 71 patients with heart failure with reduced ejection fraction (mean 31% +/- 7%), neither the 4 mg nor the 40 mg elamipretide arm changed left ventricular end-systolic volume on cardiac MRI versus placebo (40 mg: difference of means 2.3 mL, 95% CI -1.9 to 6.5, p = 0.28; 4 mg: -0.3 mL, 95% CI -4.6 to 4.0, p = 0.90).12
Tissue repair
In ReCLAIM-2, a 48-week phase 2 randomised, double-masked trial in 176 patients with dry age-related macular degeneration and non-central geographic atrophy, neither primary endpoint was met; elamipretide showed 43% less progression in complete ellipsoid zone attenuation (nominal p = 0.0034) and 47% less partial attenuation (nominal p = 0.0040) than placebo, and more patients gained at least 10 letters of low-luminance visual acuity (14.6% versus 2.1%; nominal p = 0.0404).13
In EMBRACE STEMI, a multicentre phase 2a randomised, double-blind trial in patients undergoing primary percutaneous coronary intervention for a first anterior ST-elevation myocardial infarction, intravenous MTP-131 did not reduce infarct size as 72-hour creatine kinase-MB area under the curve (5,570 +/- 486 versus 5,785 +/- 426 ng.h/mL with placebo, not significant) and did not improve prespecified MRI, angiographic, electrocardiographic or clinical outcomes.14
In obese ZSF1 rats modelling heart failure with preserved ejection fraction, which had 6.8% lower skeletal-muscle cardiolipin than lean controls (p = 0.007), 12 weeks of elamipretide raised contractile force by 8.2% in soleus (p = 0.041) and 10.9% in extensor digitorum longus (p = 0.016) versus saline-treated HFpEF rats, reduced titin hyperphosphorylation (soleus -35.4%, p < 0.001) and prevented fibre atrophy (soleus +49%, p = 0.001).15
Longevity & cellular ageing
In 27-month-old mice, a single 3 mg/kg intraperitoneal injection of SS-31 returned resting and maximal in vivo skeletal-muscle ATP production, oxidative-phosphorylation coupling (P/O) and cellular energy state (PCr/ATP) within one hour to the levels measured in 5-month-old mice, with no effect in the young animals; eight days of treatment increased whole-animal endurance relative to saline-injected controls.16
In old mice, eight weeks of SS-31 substantially reversed age-related diastolic dysfunction, normalised the raised mitochondrial proton leak in cardiomyocytes and shifted cardiac protein thiols to a more reduced state relative to untreated old mice; SS-31 added no further benefit in old mice already expressing mitochondria-targeted catalase, implicating mitochondrial oxidative stress as the shared mechanism.17
In mice randomised at 24 months to eight weeks of SS-31 or saline and examined at 26 months, treatment reduced glomerulosclerosis and glomerular senescence markers (p16, senescence-associated beta-galactosidase), lowered the podocyte injury marker desmin, improved cytoskeletal integrity (synaptopodin) and raised glomerular endothelial cell density relative to saline controls.18
What investigators recorded alongside the results above, at the rates their papers state.
Any adverse event (predominantly injection-site reactions: erythema, pruritus, pain, swelling, induration, bruising, haemorrhage, urticaria, nodules and masses)7
98.2% (107/109) with elamipretide versus 76.1% (83/109) with placebo; injection-site reactions were the only category exceeding 10% frequency in the elamipretide group, and most events were mild or moderate in intensity
Serious adverse events7
4.6% (5/109) with elamipretide versus 2.8% (3/109) with placebo, none deemed treatment-related; no participant had an adverse event with an outcome of death or hospitalisation
Adverse events leading to treatment discontinuation7
7.3% (8/109) with elamipretide versus 1.8% (2/109) with placebo
Any adverse event (most commonly injection-site pruritus, pain, bruising and erythema)13
86% of the elamipretide group versus 71% of the placebo group over 48 weeks
Injection-site reactions under prolonged continuous dosing10
the most common adverse event across 168 weeks of daily subcutaneous dosing in the 10 patients who entered the extension, which was uncontrolled; elamipretide was reported as well tolerated over this period
Absence of repeat-dose safety data in people without a mitochondrial disease diagnosis11,19
not established. The only randomised trial in participants without such a diagnosis gave a single two-hour infusion to 39 adults aged 60-85 and followed them for 7 days, so nothing has been published on the consequences of prolonged exposure outside the patient populations enrolled in the disease trials; the class review likewise notes that human trials have been short-term
- 1.Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury. · J Biol Chem · 2004 · PMID 15178689
- 2.The mitochondria-targeted peptide SS-31 binds lipid bilayers and modulates surface electrostatics as a key component of its mechanism of action. · J Biol Chem · 2020 · PMID 32273339
- 3.Elamipretide: The first cardiolipin-directed mitochondrial therapeutic for Barth syndrome approved under accelerated approval. · Drug Discov Ther · 2026 · PMID 41260682
- 4.The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipin. · J Am Soc Nephrol · 2013 · PMID 23813215
- 5.Structure-activity relationships of mitochondria-targeted tetrapeptide pharmacological compounds. · Elife · 2022 · PMID 35913044
- 6.Beneficial effects of SS-31 peptide on cardiac mitochondrial dysfunction in tafazzin knockdown mice. · Sci Rep · 2022 · PMID 36400945
- 7.Efficacy and Safety of Elamipretide in Individuals With Primary Mitochondrial Myopathy: The MMPOWER-3 Randomized Clinical Trial. · Neurology · 2023 · PMID 37268435
- 8.A randomized crossover trial of elamipretide in adults with primary mitochondrial myopathy. · J Cachexia Sarcopenia Muscle · 2020 · PMID 32096613
- 9.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 · PMID 33077895
- 10.Long-term efficacy and safety of elamipretide in patients with Barth syndrome: 168-week open-label extension results of TAZPOWER. · Genet Med · 2024 · PMID 38602181
- 11.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 · PMID 34264994
- 12.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 · PMID 32068002
- 13.ReCLAIM-2: A Randomized Phase II Clinical Trial Evaluating Elamipretide in Age-related Macular Degeneration, Geographic Atrophy Growth, Visual Function, and Ellipsoid Zone Preservation. · Ophthalmol Sci · 2025 · PMID 39605874
- 14.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 · PMID 26586786
- 15.Targeting Mitochondrial Dysfunction With Elamipretide (SS-31) Improves Skeletal Muscle Performance in a HFpEF Rat Model. · Circ Heart Fail · 2026 · PMID 42290373
- 16.Mitochondrial-targeted peptide rapidly improves mitochondrial energetics and skeletal muscle performance in aged mice. · Aging Cell · 2013 · PMID 23692570
- 17.Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice. · Elife · 2020 · PMID 32648542
- 18.The mitochondrial-targeted peptide, SS-31, improves glomerular architecture in mice of advanced age. · Kidney Int · 2017 · PMID 28063595
- 19.Effect of mitochondrial-targeted antioxidants on glycaemic control, cardiovascular health, and oxidative stress in humans: A systematic review and meta-analysis of randomized controlled trials. · Diabetes Obes Metab · 2022 · PMID 35165982
- 20.SS-31 and NMN: Two paths to improve metabolism and function in aged hearts. · Aging Cell · 2020 · PMID 32779818
- 21.Synergistic Protective Effects of Mitochondrial Division Inhibitor 1 and Mitochondria-Targeted Small Peptide SS31 in Alzheimer's Disease. · J Alzheimers Dis · 2018 · PMID 29400667