Product description
What is SS-31?
SS-31 (also known as Elamipretide, MTP-131 or Bendavia) is a synthetic tetrapeptide with the sequence D-Arg-2′,6′-dimethyl-Tyr-Lys-Phe-NH₂, developed as a first-in-class targeted therapy mitochondria. The peptide was designed by Professor Hazel Szeto's team to selectively accumulate in the inner mitochondrial membrane and protect the cells' bioenergetic functions.
Structurally, SS-31 is characterized by an alternating pattern of aromatic and cationic amino acids, which gives it unique properties - the ability to penetrate cell membranes and high selectivity towards mitochondria. The molecule contains a modified tyrosine (2′,6′-dimethyltyrosine, Dmt), which prevents oxidation and stabilizes the peptide structure. The positive charges of arginine and lysine residues are partially shielded by π electrons in the aromatic rings of phenylalanine and Dmt, which enables high cellular permeability despite the presence of charged amino acids.
The molecular weight of SS-31 is approximately 640 Da and the molecular formula is C₃₂H₄₉N₉O₅. The amphophilic nature of the peptide - with hydrophobic (Phe, Dmt) and hydrophilic (D-Arg, Lys) regions - allows it to interact with both the lipid bilayer and the aqueous environment inside cells.
SS-31 was developed in response to the growing understanding of the role of mitochondrial dysfunction in a broad spectrum of diseases, including cardiovascular diseases, neurodegenerative diseases, metabolic syndromes and aging. The peptide is undergoing advanced clinical trials and received FDA approval in September 2025 for the treatment of Barth syndrome.
Mechanism of action
Cardiolipin binding - The key mechanism of action of SS-31 is the selective binding of cardiolipin, a unique phospholipid located almost exclusively in the inner mitochondrial membrane. The electrostatic attraction between the positively charged amino acid residues of the peptide and the negatively charged cardiolipin facilitates the accumulation of SS-31 in the mitochondria. This bond stabilizes cardiolipin, preventing its oxidation and maintaining the mitochondrial membrane potential.
Stabilization of the structure of mitochondrial crests - Cardiolipin is necessary for the proper structure of mitochondrial crists, which constitute a platform for the respiratory chain complexes. SS-31, by stabilizing cardiolipin, maintains the integrity of the cristae, which directly translates into the effectiveness of oxidative phosphorylation and ATP production.
Reduction of Reactive Oxygen Species Production - By optimizing the function of the electron transport chain, SS-31 reduces electron "leakage" that leads to the formation of reactive oxygen species (ROS). Reducing oxidative stress protects against damage to proteins, lipids and mitochondrial DNA.
Improving mitochondrial bioenergetics - Studies have shown that SS-31 increases the respiratory control ratio (RCR) and the rate of ADP phosphorylation, improving the efficiency of mitochondrial energy conversion. In aging cardiomyocytes, the peptide normalizes proton leakage and restores normal parameters of mitochondrial respiration.
Mitochondrial protein interactions - Chemical cross-linking-mass spectrometry studies have identified 12 proteins that interact with SS-31, all of which are known cardiolipin ligands. They belong to two functional groups: proteins involved in ATP production by oxidative phosphorylation and proteins involved in 2-oxoglutarate metabolism and signaling.
Directions of scientific research
SS-31 is the subject of intensive preclinical and clinical research in the context of diseases associated with mitochondrial dysfunction.
Barth syndrome
In September 2025, the FDA approved elamipretide (SS-31) as the first therapy for Barth syndrome, a rare mitochondrial disease caused by a mutation in the TAFAZZIN gene, leading to impaired cardiolipin metabolism. In a Phase II/III clinical trial, 48-week exposure to the peptide resulted in a significant improvement in performance in the 6-minute walk test (mean improvement of 96.1 meters), improvement in cardiac stroke volume, normalization of cardiolipin levels and reduction in fatigue.
Heart failure
PROGRESS-HF and other clinical trials have shown that SS-31 can improve mitochondrial function in the failing human heart. In studies in aging mice, 8 weeks of SS-31 treatment significantly reversed cardiac diastolic dysfunction, a hallmark of cardiac aging in both mice and humans. The peptide normalized proton leakage and reduced ROS production in cardiomyocytes.
Aging of skeletal muscle and the heart
A 2025 study (Mitchell et al.) showed that 2 months of elamipretide treatment improved cardiac and skeletal muscle function during aging without detectable changes in epigenetic or transcriptomic tissue age. In aged mice, the peptide improved myocardial contractility and reversed diastolic dysfunction.
Ischemia-reperfusion injury
Preclinical studies have demonstrated the protective and regenerative effects of SS-31 in models of renal, cardiac and brain ischemia-reperfusion injury. The peptide reduces mitochondrial damage during reperfusion, when restoring blood flow may paradoxically increase oxidative stress.
Neurodegenerative diseases and aging
As mitochondrial dysfunction underlies many neurodegenerative diseases (Alzheimer's, Parkinson's) and the general aging process, SS-31 is being investigated for potential neuroprotective and geroprotective applications.
Scientific context
SS-31 belongs to the class of "Szeto-Schiller peptides" (SS peptides) - compounds designed to selectively target mitochondria. The peptide represents a new therapeutic approach by directly repairing mitochondrial function, unlike traditional antioxidants that act non-specifically.
Compared to other mitochondrial interventions, SS-31 offers a unique combination of features:
- Selectivity - accumulates specifically in mitochondria, without affecting other cellular compartments
- Mechanism - works by stabilizing the membrane structure without being a classic free radical scavenger
- Bioavailability - despite its peptide nature, it has good tissue penetration
The history of the approval of SS-31 for Barth syndrome represents a breakthrough in mitochondrial medicine and paves the way for the study of the peptide in other conditions related to mitochondrial dysfunction. Clinical trials for TAZPOWER (mitochondrial myopathies), MMPOWER-3 (primary mitochondrial myopathy) and ReCLAIM (dry macular degeneration) are ongoing.
Research safety profile
General Tolerance - In clinical trials, SS-31 demonstrated a good safety profile even at relatively high doses. The peptide was well tolerated in long-term (up to 52 weeks) studies in patients with Barth syndrome.
Adverse effects - The most frequently observed symptoms included: hypersensitivity reactions (rash, hives), edema-related symptoms (arthralgia, pain in extremity), peripheral edema, muscle pain (myalgia), injection site reactions.
Immunogenicity — IgG antibodies to elamipretide and cross-reactivity with endogenous GHRH were detected in some patients. However, the presence of antibodies did not significantly affect the reduction of visceral fat tissue or the IGF-1 response.
Theoretical Concerns - Due to the mechanism of action at the mitochondrial level, long-term cardiovascular safety requires further evaluation. Caution is advised in critically ill patients.
Regulatory Status - In September 2025, the FDA approved elamipretide (Stealth BioTherapeutics) for the treatment of Barth syndrome, making it the first mitochondrial therapy approved in the US. Clinical trials continue for other indications.
Bibliography - latest scientific research
- Tung C et al. Elamipretide: A Review of Its Structure, Mechanism of Action, and Therapeutic Potential. Int J Mol Sci. 2025;26(3):944. PubMed
- Mitchell W et al. The Mitochondria-Targeted Peptide Therapeutic Elamipretide Improves Cardiac and Skeletal Muscle Function During Aging Without Detectable Changes in Tissue Epigenetic or Transcriptomic Age. Aging Cell. 2025;24(6):e70026. PubMed
- Signorile A et al. SS-31 treatment ameliorates cardiac mitochondrial morphology and defective mitophagy in a murine model of Barth syndrome. Sci Rep 2024;14(1):13808. PubMed
- Reid Thompson W et al. A phase 2/3 randomized clinical trial followed by an open-label extension to evaluate the effectiveness of elamipretide in Barth syndrome. Genet Med. 2021;23(3):471-478. PubMed
- Chavez JD et al. Mitochondrial protein interaction landscape of SS-31. Proc Natl Acad Sci USA. 2020;117(26):15363-15373. PubMed
- Dai DF et al. Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice. Elife. 2020;9:e55513. PubMed
- Campbell MD 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. PubMed
- Szeto HH. First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergetics. Br J Pharmacol. 2014;171(8):2029-2050. PubMed
- Birk AV 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. PubMed
- Russo S et al. Beneficial effects of SS-31 peptide on cardiac mitochondrial dysfunction in Tafazzin knockdown mice. Sci Rep 2022;12(1):19847. PubMed
