SS-31 is a synthetic tetrapeptide also known in the published literature as elamipretide, MTP-131, and by the development code name Bendavia. It belongs to a small family of compounds called Szeto-Schiller peptides, named for Hazel Szeto and Peter Schiller, who first described this approach to targeting mitochondria. Unlike many research peptides that act through a cell-surface receptor, SS-31 is studied for a biophysical property: it concentrates selectively in the inner mitochondrial membrane because of its affinity for cardiolipin, a phospholipid found almost exclusively at that location. This article covers the molecule's structure, its proposed membrane-level mechanism, and what cell and animal studies have measured. For a broader comparison across mitochondria-related research peptides, see mitochondrial research compounds: NAD+, MOTS-c and SS-31 compared; this piece does not repeat that comparison and instead focuses on SS-31 itself.
| Attribute | Detail |
|---|---|
| Names | SS-31, elamipretide, MTP-131, Bendavia |
| Class | Synthetic aromatic-cationic tetrapeptide, Szeto-Schiller peptide family |
| Sequence | D-Arg-2',6'-Dmt-Lys-Phe-NH2 |
| Proposed binding target | Cardiolipin, a phospholipid concentrated in the inner mitochondrial membrane |
| What studies examine | Mitochondrial membrane potential, reactive oxygen species output, electron transport chain function, ATP synthesis, mitochondrial swelling |
| Model systems used | Isolated mitochondria, cultured cells under oxidative or ischemic stress, rodent and canine models, human clinical trials as an investigational drug |
| Form supplied | Lyophilized powder, research use only |
What is the chemical structure of SS-31?
SS-31 is written as D-Arg-2',6'-Dmt-Lys-Phe-NH2, a tetrapeptide of just four residues. The sequence alternates between a basic, positively charged residue and an aromatic residue: arginine (cationic), 2',6'-dimethyltyrosine or Dmt (aromatic), lysine (cationic), and phenylalanine (aromatic), with an amidated C-terminus. This alternating aromatic-cationic motif is the defining structural feature of the whole Szeto-Schiller peptide series, not unique to SS-31 alone. The arginine is in the D-configuration rather than the natural L-form, which makes the peptide more resistant to breakdown by cellular proteases. Dmt is a modified tyrosine with two extra methyl groups on its aromatic ring; researchers have reported that this modification gives the residue redox-active properties that can scavenge certain reactive oxygen species in biochemical assays, distinguishing SS-31 from a simple structural analog (Zhao et al., 2004; Szeto, 2006).
Why does SS-31 concentrate in the inner mitochondrial membrane?
Most of a cell's membranes carry a net negative surface charge, but the inner mitochondrial membrane is unusual in how much of that charge comes from cardiolipin, a phospholipid with four acyl chains that is largely absent from the plasma membrane and other organelle membranes. Published work proposes that SS-31's cationic residues form an electrostatic interaction with the negatively charged phosphate groups on cardiolipin, while its aromatic residues, Dmt and phenylalanine, insert into the adjacent hydrophobic acyl-chain region of the same lipid. Because this binding combination is comparatively specific to cardiolipin, researchers have reported mitochondrial accumulation of the peptide far above the surrounding cytosolic concentration in cell-based work, offered as the explanation for why a four-residue peptide can act at the inner membrane without a dedicated transport protein (Birk et al., 2013; Szeto and Birk, 2014).
What is cardiolipin, and why does it matter for mitochondrial function?
Cardiolipin is concentrated at the cristae, the folded inner-membrane structures where most of the electron transport chain complexes and ATP synthase are organized. Several ETC complexes and the ADP/ATP carrier associate with cardiolipin directly, and laboratory work has linked changes in cardiolipin content or oxidation state to impaired electron transport chain assembly and function. Because cardiolipin is especially vulnerable to oxidative damage during metabolic or ischemic stress, researchers studying SS-31 have proposed that stabilizing cardiolipin at the cristae membrane is the mechanistic link between the peptide binding the lipid and the downstream changes in mitochondrial readouts reported in these studies (Birk et al., 2013).
What have cell-based studies measured?
Early characterization work exposed isolated mitochondria and cultured cells to oxidative or ischemic stress and measured mitochondrial membrane potential, cytochrome c release, mitochondrial swelling, and cell death markers, reporting that SS-31 and related aromatic-cationic peptides limited these changes relative to untreated controls (Zhao et al., 2004). Later work using cell and tissue models of acute kidney injury measured mitochondrial bioenergetics directly, including electron transport chain activity and ATP production, reporting that SS-31 exposure was associated with better-preserved respiratory function in cardiolipin-containing membranes compared with controls (Birk et al., 2013). Across this literature, reactive oxygen species output, often measured as superoxide or hydrogen peroxide generation from isolated mitochondria, is one of the most commonly reported endpoints alongside membrane potential.
What have animal studies measured?
In aged mice, a single research group measured in vivo mitochondrial energetics in skeletal muscle using phosphorus magnetic resonance spectroscopy, along with ex vivo muscle fatigue resistance and mitochondrial respiration, reporting higher energetic measures in treated animals relative to their own untreated baseline (Siegel et al., 2013). In a canine model of chronic heart failure, researchers measured mitochondrial structure and cardiac function parameters, a line of animal work later cited to help justify moving the same molecule, under the name elamipretide, into human clinical investigation (Daubert et al., 2017). Across this literature, the recurring endpoints are mitochondrial membrane potential, ATP content, electron transport chain enzyme activity, and oxidative damage to mitochondrial lipids and proteins.
Has elamipretide been studied in human clinical trials?
Yes. Under the name elamipretide, this same tetrapeptide has advanced into human clinical trials conducted as an investigational drug, meaning it has not received marketing approval and remains under study. Published trial reports include a randomized, placebo-controlled study in people with chronic heart failure that measured safety and pharmacodynamic endpoints (Daubert et al., 2017), and a randomized trial using a step-up exposure design in adults with primary mitochondrial myopathy that measured tolerability and exercise-related outcomes (Karaa et al., 2018). This article describes those trials as part of the published record; it is not a guide for use in any subject, and Homegrown Peptides does not supply SS-31 for any purpose other than laboratory research.
How does SS-31 compare to other mitochondria-targeted research peptides?
SS-31 is one of several compounds studied in the broader category of mitochondria-related research peptides, alongside the coenzyme precursor NAD+ and the mitochondrial-derived peptide MOTS-c; a side-by-side overview of how these three differ in origin and proposed mechanism is covered in mitochondrial research compounds: NAD+, MOTS-c and SS-31 compared. Because SS-31 works at the membrane-lipid level rather than through enzymatic cofactor supply, researchers generally consider it mechanistically distinct from NAD+-raising compounds even when both appear in the same oxidative-stress research program; background on the coenzyme side of that comparison is in what is NAD+.
Handling notes
SS-31 is supplied as a lyophilized powder for research use. Like other short synthetic peptides, it should be stored and reconstituted per the certificate of analysis using standard bench technique; this is bench math for preparing a solution for an assay, not guidance for use in any subject. See peptide half-life explained for why cold storage and prompt use after reconstitution matter for an experimental timeline. Confirm identity and purity from the lot-specific certificate of analysis before use in an assay. Lot-specific specs are posted on our SS-31 lot page.
Frequently asked questions
Is SS-31 the same thing as elamipretide?
Yes. SS-31 is the original research designation for this tetrapeptide; elamipretide and MTP-131 are names used for the same molecule as it moved into pharmaceutical development and clinical investigation.
Does SS-31 act on a cell-surface receptor?
No. The published mechanism centers on a direct interaction between the peptide and cardiolipin, a phospholipid in the inner mitochondrial membrane, rather than binding to a receptor on the cell surface.
What is Dmt, and why is it in the sequence?
Dmt, or 2',6'-dimethyltyrosine, is a modified aromatic amino acid used in place of standard tyrosine or phenylalanine at one position. Researchers have reported that its modified ring structure contributes redox-active, reactive-oxygen-species-scavenging properties measured in cell-free and cell-based assays.
What model systems have studied SS-31?
Published work includes isolated mitochondria, cultured cells exposed to oxidative or ischemic stress, aged mice, a canine heart failure model, and, under the name elamipretide, human clinical trials conducted as an investigational drug.
Has SS-31 been studied in humans?
Under the name elamipretide, yes, in registered clinical trials described as investigational drug studies. This article summarizes the published cell, animal, and clinical-trial literature; it is not medical guidance and does not describe use in any subject.
How is SS-31 supplied for laboratory use?
As a lyophilized powder intended for research use only, sold by lot with an accompanying certificate of analysis.
References
- Zhao K, Zhao GM, Wu D, et al. Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury. J Biol Chem. 2004;279(33):34682-90. PubMed 15178689.
- Szeto HH. Mitochondria-targeted peptide antioxidants: novel neuroprotective agents. AAPS J. 2006;8(3):E521-31. PubMed 17025271.
- Birk AV, Liu S, Soong Y, et al. The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipin. J Am Soc Nephrol. 2013;24(8):1250-61. PubMed 23813215.
- Siegel MP, Kruse SE, Percival JM, et al. Mitochondrial-targeted peptide rapidly improves mitochondrial energetics and skeletal muscle performance in aged mice. Aging Cell. 2013;12(5):763-71. PubMed 23692570.
- Szeto HH, Birk AV. Serendipity and the discovery of novel compounds that restore mitochondrial plasticity. Clin Pharmacol Ther. 2014;96(6):672-83. PubMed 25188726.
- Daubert MA, Yow E, Dunn G, et al. Novel mitochondria-targeting peptide in heart failure treatment: a randomized, placebo-controlled trial of elamipretide. Circ Heart Fail. 2017;10(12):e004389. PubMed 29217757.
- Karaa A, Haas R, Goldstein A, et al. Randomized dose-escalation trial of elamipretide in adults with primary mitochondrial myopathy. Neurology. 2018;90(14):e1212-e1221. PubMed 29500292.
Research use only. Homegrown Peptides products are for laboratory research and are not for human or animal use. Nothing in this article is medical advice.
