What Is SS-31?
SS-31 (Szeto-Schiller Peptide 31), also known by its clinical development name elamipretide, is a synthetic tetrapeptide designed specifically to target the inner mitochondrial membrane. It was developed by Drs. Hazel Szeto and Peter Schiller at Weill Cornell Medical College. Unlike endogenous peptides, SS-31 was rationally designed — its alternating aromatic-cationic amino acid structure was engineered to drive selective mitochondrial accumulation and bind to cardiolipin, the structural phospholipid that organises the electron transport chain.
All products sold by FenaLife are intended strictly for laboratory and academic research purposes. Not for human consumption, injection, or ingestion. These statements have not been evaluated by the FDA.
Molecular Profile
| Property | Value |
|---|---|
| Full name | Szeto-Schiller Peptide 31 / Elamipretide |
| Sequence | D-Arg-2′6′-Dmt-Lys-Phe-NH₂ |
| Length | 4 amino acids (tetrapeptide) |
| Molecular weight | ~640 Da |
| Design | Rational — alternating aromatic-cationic structure |
| Developers | Szeto & Schiller, Weill Cornell Medical College |
| Clinical name | Elamipretide (MTP-131) |
| Half-life (plasma) | ~2–3 hours (rapid tissue uptake) |
| Mitochondrial concentration | ~1000x higher than cytoplasm (driven by membrane potential) |
Mechanism of Action
Mitochondrial Membrane Targeting
SS-31’s alternating aromatic (2′6′-dimethyltyrosine, phenylalanide) and cationic (D-arginine, lysine) residues create a structure that is selectively attracted to the inner mitochondrial membrane by its strong negative charge (membrane potential of −180 mV). SS-31 concentrates approximately 1000-fold in the inner mitochondrial membrane relative to the cytoplasm. This targeting is not receptor-mediated — it is driven by the electrochemical gradient, which means it concentrates preferentially in metabolically active, polarised mitochondria.
Cardiolipin Binding and Protection
Cardiolipin is a unique phospholipid found almost exclusively in the inner mitochondrial membrane. It is essential for organising the ETC supercomplexes (respirasomes) — the physical assemblies of Complexes I, III, and IV that optimise electron transfer and ATP production. Cardiolipin also anchors cytochrome c to the inner membrane, keeping it in position for electron shuttling. Under oxidative stress (ischemia, aging, inflammation), cardiolipin is oxidised by cytochrome c acting as a peroxidase. Oxidised cardiolipin releases cytochrome c into the cytoplasm, triggering apoptosis, and disrupts ETC supercomplex assembly, reducing ATP production and increasing ROS generation.
SS-31 binds directly to cardiolipin, preventing cytochrome c from oxidising it. This preserves ETC supercomplex integrity, maintains ATP production, reduces ROS, and blocks the apoptotic trigger of cytochrome c release.
Downstream Effects
- Preserved ETC Complex I, III, IV activity
- Increased ATP production under stress conditions
- Reduced mitochondrial ROS (reactive oxygen species)
- Inhibition of cytochrome c-mediated apoptosis
- Preserved mitochondrial membrane potential
- Reduced inflammation via mitochondrial ROS-NF-κB axis
Key Research Areas
Cardiac Ischemia-Reperfusion Injury
SS-31’s most extensively studied application is cardiac protection during ischemia-reperfusion (I/R) injury — the damage that occurs when blood flow is restored to ischemic tissue. I/R injury generates massive ROS production and triggers cardiolipin oxidation and cytochrome c release. SS-31 administered prior to or at reperfusion significantly reduces infarct size, preserves cardiac function, and reduces cardiomyocyte apoptosis in rodent and large animal (pig, dog) models. This is the basis for its clinical development in heart failure.
Heart Failure with Preserved Ejection Fraction (HFpEF)
Stealth BioTherapeutics conducted the PROGRESS-HF Phase 2 trial of subcutaneous elamipretide in patients with HFpEF (heart failure with preserved ejection fraction). The trial did not meet its primary endpoint (6-minute walk distance), but secondary endpoints including left ventricular end-systolic volume showed improvement. HFpEF involves mitochondrial dysfunction in cardiomyocytes — the mechanistic rationale for SS-31 remains scientifically sound despite the primary endpoint miss.
Barth Syndrome
Barth syndrome is a rare X-linked genetic disorder caused by mutations in the tafazzin gene, which encodes an enzyme required for cardiolipin remodelling. The disease results in severe cardiomyopathy, skeletal muscle weakness, and neutropenia due to defective cardiolipin. SS-31’s direct cardiolipin-protective mechanism makes it mechanistically rational for this indication. Phase 2 trial data showed functional improvements in Barth syndrome patients receiving elamipretide.
Acute Kidney Injury (AKI)
The kidney is highly metabolically active and particularly vulnerable to mitochondrial dysfunction during ischemia. SS-31 has demonstrated significant renal protection in AKI rodent models, reducing tubular injury markers, preserving GFR, and reducing inflammatory infiltration. Multiple published preclinical studies support this application.
Age-Related Mitochondrial Decline
Mitochondrial dysfunction is a hallmark of aging. Cardiolipin composition changes with age — the proportion of the optimal tetralinoleoyl cardiolipin (L4CL) form declines, impairing ETC supercomplex stability. SS-31 administration in aged rodent models restores mitochondrial function, improves exercise capacity, and partially reverses age-associated metabolic decline. This has made it a subject of longevity biology research.
Eye Disease Research
The retinal pigment epithelium (RPE) is one of the most metabolically demanding tissues in the body. Age-related macular degeneration (AMD) involves RPE mitochondrial dysfunction. SS-31 (as elamipretide) has been studied in Phase 2 trials for dry AMD and Leber’s hereditary optic neuropathy (LHON), conditions with mitochondrial involvement.
Clinical Trial Summary
| Indication | Trial | Phase | Outcome |
|---|---|---|---|
| Heart failure (HFpEF) | PROGRESS-HF | Phase 2 | Primary endpoint not met; secondary endpoints showed LV volume improvement |
| Barth syndrome | TAZPOWER | Phase 2 | Functional improvements; disease-modifying signals |
| Primary mitochondrial myopathy | MMPOWER-3 | Phase 3 | Primary endpoint not met |
| Dry AMD | Phase 2 | Phase 2 | Ongoing / completed |
| LHON | Phase 2 | Phase 2 | Ongoing / completed |
Storage and Handling
| Parameter | Specification |
|---|---|
| Lyophilised storage | −20°C, protect from light |
| Reconstitution solvent | Bacteriostatic water |
| Post-reconstitution storage | 2–8°C, use within 28 days |
| Freeze-thaw (reconstituted) | Avoid |
| Light sensitivity | Protect from light |
Frequently Asked Questions
What does SS-31 stand for?
SS-31 stands for Szeto-Schiller Peptide 31, named after the two researchers who developed it: Dr. Hazel Szeto and Dr. Peter Schiller at Weill Cornell Medical College. The number 31 refers to its designation within their series of mitochondria-targeting peptides. Its clinical name is elamipretide.
Is SS-31 the same as MitoQ?
No. MitoQ is a different mitochondria-targeting antioxidant — a ubiquinone (CoQ10) molecule conjugated to a triphenylphosphonium (TPP) cation for mitochondrial targeting. SS-31 is a peptide that works by binding cardiolipin. They both target mitochondria but through completely different mechanisms and with different molecular targets.
Why did the PROGRESS-HF trial not meet its primary endpoint?
The PROGRESS-HF trial used 6-minute walk distance as its primary endpoint. HFpEF is a heterogeneous syndrome with multiple underlying mechanisms — not all of which are driven by mitochondrial dysfunction. Patient selection for trials in mitochondrial disease research is an active area of investigation. The secondary endpoint improvement in LV volume suggests mechanistic activity, and the mitochondrial rationale for SS-31 in HFpEF remains scientifically intact.
What is the difference between SS-31 and SS-20?
SS-20 (Phe-D-Arg-Phe-Lys-NH₂) is another peptide in the Szeto-Schiller series. Both target cardiolipin and the inner mitochondrial membrane. SS-31 has the more extensive published research record and is the compound that reached clinical trials as elamipretide. SS-20 has primarily preclinical data.
Can SS-31 be studied alongside MOTS-c?
No published combination data exists. Mechanistically they are complementary — SS-31 protects mitochondrial structural integrity (cardiolipin, ETC architecture) while MOTS-c regulates metabolic gene expression via AMPK signalling. For comprehensive mitochondrial biology research, both may be relevant. See the MOTS-c vs SS-31 comparison.
Source SS-31 at FenaLife
FenaLife supplies SS-31 (elamipretide) in the Longevity Research category with Janoshik third-party COA. Free shipping on orders over $100.
See also: MOTS-c vs SS-31 Comparison | Complete MOTS-c Research Guide | Peptide Storage Guide
All products sold by FenaLife are intended strictly for laboratory and academic research purposes. Not for human consumption, injection, or ingestion. These statements have not been evaluated by the FDA.
🔬 Research Compounds Referenced: SS-31 10mg