SS-31

SS-31 (also called elamipretide, Bendavia, or MTP-131) is a synthetic mitochondria-targeted tetrapeptide developed by Stealth BioTherapeutics. The peptide selectively concentrates in the inner mitochondrial membrane, where it binds cardiolipin and is studied for restoring mitochondrial bioenergetics in models of age-related and disease-related decline.

Peppudex card: see the mechanism + evidence-grade summary at [Peppudex / SS-31](https://peppudex.com/peptides/ss-31).

Overview

SS-31 belongs to the Szeto-Schiller (SS) peptide family, named for the Cornell researchers Hazel H. Szeto and Peter W. Schiller who first described the chemistry. The sequence is D-Arg-2′,6′-dimethyl-Tyr-Lys-Phe-NH₂, a four-residue aromatic-cationic motif that crosses the plasma membrane and concentrates 1,000-fold in the inner mitochondrial membrane.

Mechanism

The proposed mechanism is cardiolipin binding. Cardiolipin is a tetra-acyl phospholipid unique to the inner mitochondrial membrane that anchors electron-transport-chain complexes (I-V). With age and oxidative stress, cardiolipin oxidizes and electron leak rises. SS-31 binds cardiolipin and stabilizes the cristae architecture, restoring electron-transport efficiency and reducing reactive-oxygen-species generation.

See: AMPK, Mitochondrial-derived_peptides, Sirtuin_activation.

Evidence

Preclinical data is broad across cardiac, renal, neuromuscular, and ophthalmic models:

• Ischemia-reperfusion · reduced infarct size in rodent heart (Cho et al., 2007)
• Heart failure · improved ejection fraction in canine model (Sabbah et al., 2016)
• Mitochondrial myopathy · improved exercise tolerance in mouse model (Siegel et al., 2013)
• Age-related muscle decline · restored skeletal mitochondrial function (Siegel et al., 2013, PMID 23617560)

Human clinical trials include MMPOWER-3 (Phase 3 in primary mitochondrial myopathy · failed primary endpoint 2020), Barth syndrome (Phase 3 SPIBA-201), and dry age-related macular degeneration (ReCLAIM trials). Results have been mixed; some surrogate endpoints improve while functional endpoints have inconsistently met statistical bars.

Dosing literature

Trials have used subcutaneous 40 mg/day in adults. Pharmacokinetics show rapid absorption and clearance with mitochondrial accumulation lasting 24+ hours after dosing. The wiki does not recommend any human dose; SS-31 is an investigational compound without FDA approval.

Storage

Lyophilized SS-31 is stable at –20 °C for 24 months. After reconstitution with bacteriostatic water, store at 2-8 °C and use within 30 days.

Regulatory status

• United States. Investigational. No FDA-approved indication. Stealth BioTherapeutics has pursued multiple Phase 3 paths.
• World Anti-Doping Agency. Not listed as of the 2024 Prohibited List, though mitochondrial-targeted peptides may fall under S0 (non-approved substances) at WADA discretion.

See also

• NAD-plus · upstream substrate for mitochondrial NADH/sirtuin signaling
• MOTS-c · mitochondrial-derived peptide affecting AMPK
• Reconstitution · vial-prep math
• [Peppudex card · SS-31](https://peppudex.com/peptides/ss-31) · mechanism, evidence grades A-F, FAQs, peer-reviewed sources

References

• Szeto HH. "First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergetics." Br J Pharmacol. 2014;171(8):2029-50. PMID 24117165.
• Siegel MP, et al. "Mitochondrial-targeted peptide rapidly improves mitochondrial energetics and skeletal muscle performance in aged mice." Aging Cell. 2013;12(5):763-71. PMID 23617560.
• Sabbah HN, et al. "Chronic Therapy With Elamipretide (MTP-131), a Novel Mitochondria-Targeting Peptide, Improves Left Ventricular and Mitochondrial Function in Dogs With Advanced Heart Failure." Circ Heart Fail. 2016;9(2):e002206. PMID 26839394.