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 the first mitochondria-targeted therapy of its kind. The peptide was designed by Professor Hazel Szeto's team to selectively accumulate in the inner mitochondrial membrane and protect cellular bioenergetic function.
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 for mitochondria. The molecule contains a modified tyrosine (2′,6′-dimethyltyrosine, Dmt), which prevents oxidation and stabilizes the peptide structure. The positive charges of the arginine and lysine residues are partially shielded by π electrons in the aromatic rings of phenylalanine and Dmt, enabling high cellular permeability despite the presence of charged amino acids.
The molecular weight of SS-31 is approximately 640 Da, and its molecular formula is C₃₂H₄₉N₉O₅. The amphiphilic 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 a growing understanding of the role of mitochondrial dysfunction in a broad spectrum of diseases, including cardiovascular disorders, neurodegenerative diseases, metabolic syndromes, and the aging process. The peptide is undergoing advanced clinical research and, as of September 2025, received FDA approval for the treatment of Barth syndrome.
Mechanism of action
Cardiolipin binding - The key mechanism of action of SS-31 is selective binding to cardiolipin, a unique phospholipid located almost exclusively in the inner mitochondrial membrane. Electrostatic attraction between the peptide's positively charged amino acid residues and negatively charged cardiolipin facilitates accumulation of SS-31 in mitochondria. This binding stabilizes cardiolipin, preventing its oxidation and maintaining the mitochondrial membrane potential.
Stabilization of mitochondrial cristae structure - Cardiolipin is essential for the proper structure of mitochondrial cristae, which serve as the platform for respiratory chain complexes. By stabilizing cardiolipin, SS-31 preserves cristae integrity, which directly translates into the efficiency of oxidative phosphorylation and ATP production.
Reduction of reactive oxygen species generation - By optimizing electron transport chain function, SS-31 reduces electron “leak” that leads to the formation of reactive oxygen species (ROS). Lower oxidative stress protects against damage to proteins, lipids, and mitochondrial DNA.
Improvement of mitochondrial bioenergetics - Studies have shown that SS-31 increases the respiratory control ratio (RCR) and the rate of ADP phosphorylation, improving the efficiency of energy conversion in mitochondria. In aging cardiomyocytes, the peptide normalizes proton leak and restores proper mitochondrial respiration parameters.
Interactions with mitochondrial proteins - Chemical cross-linking studies with mass spectrometry identified 12 proteins that interact with SS-31, all of them known cardiolipin ligands. They fall into two functional groups: proteins involved in ATP production through oxidative phosphorylation and proteins participating in 2-oxoglutarate metabolism and signaling.
Scientific research directions
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 disturbed cardiolipin metabolism. In a phase II/III clinical trial, 48 weeks of peptide exposure resulted in a significant improvement in 6-minute walk test performance (mean improvement 96,1 meters), improved stroke volume, normalization of cardiolipin levels, and reduced fatigue.
Heart failure
Clinical studies PROGRESS-HF and others have shown that SS-31 may improve mitochondrial function in the failing human heart. In studies on aging mice, 8 weeks of SS-31 treatment significantly reversed cardiac diastolic dysfunction - a hallmark of heart aging in both mice and humans. The peptide normalized proton leak and reduced ROS production in cardiomyocytes.
Skeletal muscle and heart aging
A 2025 study (Mitchell et al.) showed that 2 months of elamipretide treatment improves heart and skeletal muscle function during aging without detectable changes in the epigenetic or transcriptomic age of tissues. In old mice, the peptide improved myocardial contractility and reversed diastolic dysfunction.
Ischemia-reperfusion injury
Preclinical studies have demonstrated protective and regenerative effects of SS-31 in models of ischemia-reperfusion injury of the kidney, heart, and brain. The peptide reduces mitochondrial damage during reperfusion, when the restoration of blood flow can paradoxically intensify oxidative stress.
Neurodegenerative diseases and aging
Because mitochondrial dysfunction underlies many neurodegenerative diseases (Alzheimer's disease, Parkinson's disease) and the general aging process, SS-31 is being studied for potential neuroprotective and geroprotective applications.
Scientific context
SS-31 belongs to the class of “Szeto-Schiller peptides” (SS peptides) - compounds designed for selective mitochondrial targeting. The peptide represents a novel therapeutic approach based on direct repair of mitochondrial function, as opposed to traditional antioxidants that act nonspecifically.
Compared with other mitochondrial interventions, SS-31 offers a unique combination of features:
- Selectivity - accumulates specifically in mitochondria without affecting other cellular compartments
- Mechanism - acts by stabilizing membrane structure rather than as a classic free-radical scavenger
- Bioavailability - despite its peptide nature, shows good tissue penetration
The approval history of SS-31 for Barth syndrome marks a breakthrough in mitochondrial medicine and opens the way to studying the peptide in other conditions associated with mitochondrial dysfunction. Clinical studies TAZPOWER (mitochondrial myopathies), MMPOWER-3 (primary mitochondrial myopathy), and ReCLAIM (dry age-related macular degeneration) are ongoing.
Safety profile in studies
Overall tolerability - In clinical studies, SS-31 showed a good safety profile even at relatively high doses. The peptide was well tolerated in long-term studies (up to 52 weeks) in patients with Barth syndrome.
Adverse effects - The most commonly observed symptoms included hypersensitivity reactions (rash, hives), symptoms related to edema (joint pain, limb pain), peripheral edema, muscle pain (myalgia), and injection-site reactions.
Immunogenicity - In some patients, IgG antibodies against elamipretide and cross-reactivity with endogenous GHRH were detected. However, the presence of antibodies did not significantly affect reduction of visceral fat tissue or the IGF-1 response.
Theoretical concerns - Due to its mechanism of action at the mitochondrial level, long-term cardiovascular safety requires further evaluation. Caution is recommended 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 approved mitochondrial therapy in the US. Clinical studies 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
