Cardiolipin binding
Binding to cardiolipin was characterised with a fluorescent SS-31 analogue, and its effect on cytochrome c peroxidase activity was measured in vitro2. The wider mechanistic programme is summarised in reviews3,7.
Research Peptide · For laboratory research use only
SS-31
Also known as Elamipretide, MTP-131
- Formula
- C32H49N9O5
- CAS
- 736992-21-5
Available as
Overview
SS-31 (elamipretide, also MTP-131) is a synthetic aromatic-cationic tetrapeptide, D-Arg-Dmt-Lys-Phe-NH2, in which Dmt is 2',6'-dimethyltyrosine. It belongs to the Szeto-Schiller (SS) peptides, a series designed to be cell-permeable and to target the inner mitochondrial membrane1,3.
It has been studied in isolated mitochondria, cell culture and rodent models of ischaemia-reperfusion injury and ageing1,2,4,5, and has been the subject of registered clinical trials, including a phase 3 trial in primary mitochondrial myopathy6. A 2025 review summarises its structure, proposed mechanism and development programme7.
Mechanism of action
As described in the research literature
As described in the research literature, SS peptides were reported to concentrate about 1000-fold in the inner mitochondrial membrane, with the dimethyltyrosine residue providing reactive oxygen species scavenging. In isolated mitochondria they inhibited mitochondrial permeability transition, swelling and calcium-induced cytochrome c release, and analogues lacking dimethyltyrosine did not1.
Later work using a polarity-sensitive fluorescent analogue reported that SS-31 binds with high affinity to cardiolipin, an anionic phospholipid of the inner mitochondrial membrane required for cristae formation, and that the SS-31/cardiolipin complex inhibited the cytochrome c peroxidase activity that catalyses cardiolipin peroxidation2. A review by the peptide's originator describes binding through electrostatic and hydrophobic interactions and proposes that it preserves the electron-carrying function of cytochrome c and the organisation of respiratory supercomplexes3.
Research areas
What published studies have examined
Ischaemia-reperfusion models
Early work examined reactive oxygen species, permeability transition and cell death in neuronal N2A cells and isolated mitochondria, and contractile force in an ex vivo heart model of reperfusion-associated myocardial stunning1. A rat renal ischaemia model examined cristae membrane integrity, mitochondrial swelling, ATP recovery on reperfusion, apoptosis and tubular barrier function2.
Ageing models
In aged mice, skeletal muscle mitochondrial energetics were measured in vivo by optical and 31P magnetic resonance spectroscopy, alongside glutathione redox status, mitochondrial H2O2 emission and fatigue resistance4. A study in old mice examined diastolic function, cardiomyocyte proton leak, mitochondrial reactive oxygen species and protein thiol redox state, and compared SS-31 with viral expression of mitochondrial-targeted catalase5.
Registered clinical trials
MMPOWER-3 was a phase 3, randomised, double-blind, placebo-controlled trial in genetically confirmed primary mitochondrial myopathy. Its primary efficacy endpoints were change from baseline to week 24 in 6-minute walk test distance and in total fatigue on the Primary Mitochondrial Myopathy Symptom Assessment (NCT03323749)6. A 2025 review lists other trials, including PROGRESS-HF, TAZPOWER and ReCLAIM7.
Specifications
- Sequence
- D-Arg-Dmt-Lys-Phe-NH2 (Dmt = 2',6'-dimethyl-L-tyrosine)
- Molecular formula
- C32H49N9O5
- Molecular weight
- 639.8 g/mol
- CAS number
- 736992-21-5
- Form
- White to off-white lyophilised powder in a sealed vial (50 mg)
- Storage
- Store lyophilised powder at -20 °C, protected from light and moisture. Once reconstituted, keep refrigerated at 2 to 8 °C and protect from light.
- Solubility and reconstitution
- Reconstitute with bacteriostatic water. Add the diluent slowly down the inside wall of the vial and swirl gently until clear; do not shake.
References
- 1
Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury.
Zhao K, Zhao GM, Wu D, et al. The Journal of Biological Chemistry, 2004.
- 2
The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipin.
Birk AV, Liu S, Soong Y, et al. Journal of the American Society of Nephrology, 2013.
- 3
First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergetics.
Szeto HH British Journal of Pharmacology, 2014.
- 4
Mitochondrial-targeted peptide rapidly improves mitochondrial energetics and skeletal muscle performance in aged mice.
Siegel MP, Kruse SE, Percival JM, et al. Aging Cell, 2013.
- 5
Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice.
Chiao YA, Zhang H, Sweetwyne M, et al. eLife, 2020.
- 6
Efficacy and Safety of Elamipretide in Individuals With Primary Mitochondrial Myopathy: The MMPOWER-3 Randomized Clinical Trial.
Karaa A, Bertini E, Carelli V, et al. Neurology, 2023.
- 7
Elamipretide: A Review of Its Structure, Mechanism of Action, and Therapeutic Potential.
Tung C, Varzideh F, Farroni E, et al. International Journal of Molecular Sciences, 2025.
This page is provided for research and educational reference only. It does not constitute medical advice, dosing guidance, or a recommendation for use. All compounds are strictly for laboratory and in-vitro research purposes.