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title: SS-31 / Elamipretide: A Mitochondria-Targeted Peptide description: "SS-31 (elamipretide) is a synthetic mitochondria-targeted tetrapeptide designed to selectively partition into the inner "

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SS-31 / Elamipretide: A Mitochondria-Targeted Peptide

Quick Facts

Full Name	Elamipretide (USAN); SS-31, MTP-131 (developmental codes)
Class	Synthetic mitochondria-targeted tetrapeptide
Amino Acid Sequence	d-Arg–dmt–Lys–Phe–NH₂ (where dmt = 2',6'-dimethyltyrosine)
Molecular Formula	C₃₆H₅₈N₈O₆
Molecular Weight	~692 Da
Target	Inner mitochondrial membrane cardiolipin
Primary Mechanism	Binds to cardiolipin, stabilizes mitochondrial cristae structure, optimizes electron transport chain supercomplex organization, reduces mitochondrial ROS production
Unique Property	Tetra-peptide that targets mitochondria via aromatic-cationic motif, not cell-penetrating peptides; crosses plasma and mitochondrial membranes without requiring active transport
Route of Administration	Subcutaneous injection (clinical trials); intravenous (preclinical studies)
Regulatory Status	Investigational; Phase II/III clinical trials for mitochondrial disease, heart failure, and ophthalmologic indications
PubChem CID	91668096
CAS Number	2252411-48-8

Executive Summary

SS-31 (elamipretide) is a synthetic mitochondria-targeted tetrapeptide designed to selectively partition into the inner mitochondrial membrane, where it interacts with cardiolipin to stabilize the architecture of mitochondrial cristae and optimize electron transport chain (ETC) supercomplex organization.

Developed initially by Szeto and Schiller, the peptide belongs to the Szeto-Schiller (SS) family of aromatic-cationic peptides, which are distinguished by their ability to penetrate cells and mitochondria without requiring a specific transporter.

Unlike traditional antioxidants that scavenge reactive oxygen species (ROS) after they form, elamipretide addresses the root source of mitochondrial ROS production by improving electron flow efficiency within the respiratory chain.

It is currently under investigation for a broad range of conditions associated with mitochondrial dysfunction, including primary mitochondrial myopathy, heart failure, age-related macular degeneration, and ischemia-reperfusion injury.

Introduction

Mitochondrial dysfunction is a hallmark of numerous pathological states, including cardiovascular disease, neurodegeneration, metabolic disorders, and aging. The central role of mitochondria in ATP production, calcium homeostasis, and apoptosis regulation makes them an important therapeutic target.

In the early 2000s, the Szeto-Schiller group at Weill Cornell Medical College discovered a family of tetrapeptides with the unusual ability to cross both the plasma membrane and mitochondrial membranes through a mechanism dependent on their aromatic-cationic motif rather than classical endocytosis.

The lead compound, SS-31 (later designated elamipretide), emerged from this screen as the most potent and selective mitochondrial protector.

Unlike conventional mitochondrial antioxidants such as MitoQ or MitoTEMPO, which covalently link a lipophilic cation to a conventional antioxidant moiety, elamipretide achieves mitochondrial targeting through its intrinsic physicochemical properties.

Molecular Characteristics

Elamipretide is a tetrapeptide with the sequence d-Arg–dmt–Lys–Phe–NH₂, where dmt denotes 2',6'-dimethyltyrosine. The peptide features alternating aromatic and basic amino acid residues: d-Arg (cationic, guanidinium side chain), dmt (modified aromatic), Lys (cationic), and Phe (aromatic).

This motif-two basic residues separated by one or two aromatic residues-is the signature of the Szeto-Schiller peptide family. The molecule carries a net +2 charge at physiological pH, which facilitates electrostatic interactions with the negatively charged cardiolipin head groups in the inner mitochondrial membrane.

The d-Arg residue at the N-terminus confers resistance to aminopeptidase degradation, while the C-terminal amidation protects against carboxypeptidases. With a molecular weight of approximately 692 Da, elamipretide is sufficiently small for efficient tissue penetration yet large enough for receptor-independent membrane translocation.

Cardiolipin Binding and Mechanism of Action

Cardiolipin is a unique tetra-acyl phospholipid localized almost exclusively in the inner mitochondrial membrane, where it constitutes approximately 20% of total phospholipids.

It plays a critical role in stabilizing the supramolecular architecture of the ETC by anchoring respiratory chain complexes III and IV into supercomplexes (respirasomes), thereby facilitating efficient electron transfer.

Under conditions of oxidative stress, cardiolipin undergoes peroxidation and depletion, leading to supercomplex disassembly, electron leak, and increased mitochondrial ROS production.

Elamipretide binds directly to cardiolipin via electrostatic interactions between the peptide's basic residues and the phosphate groups, reinforced by π-stacking of the aromatic side chains with the unsaturated acyl chains.

This binding restores the tight association between cardiolipin and ETC complexes, reconstituting supercomplex formation and normalizing electron flow.

The outcome is reduced mitochondrial ROS generation (particularly at Complex I and Complex III), improved ADP-stimulated respiration (State III), and stabilization of the mitochondrial membrane potential (ΔΨm).

Biological Research Background

Preclinical Studies

In isolated mitochondria, elamipretide reduces H₂O₂ production by approximately 50–80% and preserves mitochondrial respiration during oxidative challenge.

In animal models of myocardial ischemia-reperfusion injury, elamipretide administered at the onset of reperfusion reduces infarct size by up to 60%, an effect comparable to ischemic preconditioning.

In a mouse model of aging, Siegel and colleagues demonstrated that 8 weeks of elamipretide treatment reversed age-related declines in skeletal muscle mitochondrial respiration, improved grip strength, and increased voluntary running activity without altering mitochondrial content, consistent with improved mitochondrial quality rather than biogenesis.

In a rat model of acute kidney ischemia-reperfusion injury, treatment with elamipretide preserved mitochondrial ultrastructure, reduced tubular cell apoptosis, and attenuated renal functional impairment.

In models of doxorubicin cardiotoxicity, elamipretide prevented mitochondrial membrane depolarization and ATP depletion, reducing cardiomyocyte death by >60%.

Clinical Development

Elamipretide has been evaluated in several clinical trials. A phase II trial in subjects with primary mitochondrial myopathy (MMPOWER-2) demonstrated improvements in the 6-minute walk test and a composite mitochondrial disease rating scale, although the results did not consistently reach statistical significance in the broader cohort.

In chronic heart failure with reduced ejection fraction (HFrEF), elamipretide infusion improved left ventricular systolic function and stroke volume index in a pilot study.

Ophthalmic formulations of elamipretide are under investigation for age-related macular degeneration (AMD) and Leber hereditary optic neuropathy (LHON), capitalizing on the peptide's ability to improve retinal mitochondrial function.

Stealth BioTherapeutics, the developer of elamipretide, has pursued these indications through multiple phase II and III trials.

Current Research Landscape

Elamipretide research continues to expand across multiple therapeutic domains:

• Primary mitochondrial diseases: Phase III trials (MMPOWER-3) are evaluating the long-term safety and efficacy of subcutaneous elamipretide in patients with primary mitochondrial myopathy, with a focus on walking endurance and fatigue.
• Heart failure: The peptide's ability to improve myocardial energetics independently of afterload reduction makes it a unique candidate for heart failure with preserved ejection fraction (HFpEF), where mitochondrial dysfunction is increasingly recognized as a key pathogenic driver.
• Ophthalmology: Subcutaneous and topical formulations are being investigated for AMD and LHON, where retinal cell survival depends critically on mitochondrial function.
• Age-related sarcopenia: Preclinical data demonstrating improvements in skeletal muscle function in aged mice have prompted interest in elamipretide as a potential intervention for sarcopenia and physical frailty.
• Neurological disorders: Mitochondrial dysfunction is implicated in Parkinson's disease, Huntington's disease, and ALS.

The brain bioavailability of elamipretide is limited by the blood-brain barrier, but novel formulations and prodrug strategies are being explored. - Ischemia-reperfusion injury: The robust protective effects observed in preclinical models of cardiac and renal ischemia continue to drive translational research, including studies in organ transplantation and perioperative medicine.

Related Research

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Mitochondrial-derived peptide in metabolic regulation.

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Metabolic Research

Mitochondrial and metabolic peptide research.

Frequently Asked Questions

+ **What makes elamipretide different from conventional antioxidants?**

Conventional antioxidants (e.g., vitamin E, N-acetylcysteine) neutralize ROS after they are already produced. Elamipretide acts upstream by binding to cardiolipin in the inner mitochondrial membrane, stabilizing ETC supercomplex organization, and reducing electron leak. This prevents ROS generation at the source rather than scavenging ROS after formation, making it a mechanistically distinct approach.

+ **How does elamipretide enter cells and mitochondria?**

Elamipretide does not require a specific transporter or receptor for cellular uptake. Its alternating aromatic and basic amino acid motif allows transmembrane passage through a unique mechanism involving electrostatic and hydrophobic interactions with membrane phospholipids. The peptide first partitions into the plasma membrane and then redistributes to the mitochondrial inner membrane, driven by the high cardiolipin content of the latter.

+ **Is elamipretide FDA-approved?**

No. Elamipretide is an investigational compound and has not received FDA approval for any indication. It has been granted Orphan Drug Designation for the treatment of primary mitochondrial myopathy and Leber hereditary optic neuropathy by the FDA.

+ **What is cardiolipin and why is it important?**

Cardiolipin is a unique dimeric phospholipid located almost exclusively in the inner mitochondrial membrane. It is essential for maintaining the structural integrity of mitochondrial cristae and for stabilizing the supercomplexes formed by respiratory chain proteins. Age-related peroxidation and depletion of cardiolipin are linked to mitochondrial dysfunction in diverse diseases, making it a strategic pharmacological target.

+ **Does elamipretide increase mitochondrial biogenesis?**

No. Unlike compounds that activate PGC-1α or AMPK signaling, elamipretide improves the function of existing mitochondria without increasing mitochondrial mass or copy number. Its primary effects are on mitochondrial quality (supercomplex assembly, cristae architecture, respiration efficiency) rather than quantity.

+ **What are the reported side effects of elamipretide?**

In clinical trials, elamipretide has been generally well tolerated. The most common adverse events include injection-site reactions (pain, erythema), headache, nausea, and diarrhea. Serious adverse events have been rare and not consistently attributed to the study drug.

+ **Can elamipretide cross the blood-brain barrier?**

Brain penetration of elamipretide is limited under normal conditions. The peptide has been detected in brain tissue at low concentrations after systemic administration, probably insufficient for therapeutic effects in most CNS indications. Novel formulations, prodrugs, or alternative routes of administration are being explored to enhance CNS bioavailability.

+ **How does elamipretide compare to MitoQ?**

Both compounds target mitochondria but through entirely different mechanisms. MitoQ is a ubiquinone derivative conjugated to a triphenylphosphonium cation that accumulates in mitochondria and acts as a ROS scavenger. Elamipretide is a peptide that binds cardiolipin to stabilize ETC supercomplexes and reduce ROS production at the source. They represent complementary but mechanistically distinct approaches to mitochondrial therapeutics.

About RPL Peptides: RPL Peptides is a supplier of high-purity research peptides with comprehensive analytical documentation including HPLC, LC-MS, and Certificates of Analysis (COA). For researchers requiring certified reference materials for laboratory investigations, visit rplpeptides.com or explore detailed molecular data at the RPL Peptides Data Center.

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):34682-34690. doi:10.1074/jbc.M402999200 - 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):1250-1261. doi:10.1681/ASN.2012121216 - 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):763-771. doi:10.1111/acel.12102 - Klaus S, Ke X, Munch G, et al. Mitochondria-targeted peptide, SS-31 (elamipretide), reduces oxidative stress and inflammation in an experimental model of acute kidney injury. Am J Physiol Renal Physiol. 2018;315(1):F164-F172. doi:10.1152/ajprenal.00580.2017 - Allen ME, Pennington ER, Perry JB, et al. Effects of elamipretide on mitochondrial function and cellular energetics in human cells. J Cell Mol Med. 2020;24(15):8705-8715. doi:10.1111/jcmm.15508 - Shi J, Yu T, Song M, et al. Elamipretide (SS-31) attenuates doxorubicin-induced cardiotoxicity by improving mitochondrial function. J Cell Mol Med. 2022;26(8):2248-2262. doi:10.1111/jcmm.17234 - Eirin A, Ebrahimi B, Zhang X, et al. Mitochondrial protection reverses obesity-induced renal microvascular dysfunction. Kidney Int. 2015;88(5):1060-1072. doi:10.1038/ki.2015.194 - Dai W, Cheung E, Andres A, et al. Mitochondrial-targeted peptide elamipretide improves mitochondrial function in the failing heart. J Am Coll Cardiol. 2014;63(21):2274-2283. doi:10.1016/j.jacc.2013.11.030 - Chatfield KC, Sparagna GC, Chau S, et al. Elamipretide improves mitochondrial function in the failing human heart. JACC Basic Transl Sci. 2019;4(2):147-157. doi:10.1016/j.jacbts.2018.10.003