Ss 31 Elamipretide Research
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SS-31 (Elamipretide): Mitochondrial Membrane Research
SS-31, also known as Elamipretide or MTP-131, is a synthetic tetrapeptide studied in laboratory settings for its role in mitochondrial membrane biology, cardiolipin interactions, and oxidative stress research. It belongs to the Szeto-Schiller (SS) peptide class, a family of mitochondria-targeted peptides designed to concentrate in the inner mitochondrial membrane.
SS-31 (Elamipretide): Mitochondrial Inner Membrane Targeting
Chemical and Molecular Data
| Property | Value |
|---|---|
| Molecular formula | C32H52N12O6 |
| Molecular weight | 664.84 g/mol |
| CAS number | 736992-21-5 |
| Sequence | D-Arg-Dmt-Lys-Phe-NH2 |
| Amino acid count | 4 |
| Non-natural residues | D-Arg (pos. 1), Dmt (2,6-dimethyltyrosine, pos. 2) |
| Peptide class | Szeto-Schiller (SS) peptide |
| Purity | greater than or equal to 98% as verified by HPLC |
| Form | Lyophilised powder |
| Storage | -20 degrees C, protected from light and moisture |
| Reconstitution | Sterile water recommended |
SS-31 (Elamipretide): Mitochondrial Inner Membrane Targeting
Structural Design and Mitochondrial Targeting
SS-31 is designed with an alternating aromatic-cationic motif. The alternating pattern of aromatic (Dmt, Phe) and cationic (D-Arg, Lys) residues gives the peptide amphipathic properties critical for its interaction with the inner mitochondrial membrane.
Critically, SS-31 concentrates in the inner mitochondrial membrane independently of membrane potential, unlike many other mitochondrial-targeting molecules (such as triphenylphosphonium-conjugated compounds). This makes SS-31 useful for studying mitochondrial function in compromised or depolarised mitochondria — conditions found in ischaemia-reperfusion injury, heart failure, and ageing research models.
Cardiolipin Biology Research
The primary mechanistic focus in SS-31 research is its interaction with cardiolipin — a unique phospholipid found almost exclusively in the inner mitochondrial membrane. Cardiolipin is essential for the organisation and function of the electron transport chain, particularly cytochrome c anchoring and Complex I, III, and IV activity.
Laboratory research has examined SS-31's effects on cardiolipin organisation and oxidation. Under oxidative stress conditions, cardiolipin can become peroxidised and release cytochrome c from the inner membrane, initiating apoptosis. SS-31 has been studied for its ability to interact with cardiolipin and protect it from peroxidation in cell and mitochondria isolation models.
Electron Transport Chain Research
Research has examined SS-31's effects on electron transport chain efficiency and reactive oxygen species (ROS) production. Studies in isolated mitochondria and cell culture models have investigated changes in oxygen consumption rate, ATP production, and ROS output following SS-31 treatment. This connects SS-31 research to broader mitochondrial biology studies relevant to MOTS-c and NAD+ research.
SS Peptide Family Comparison
| Peptide | Sequence | Net charge | Cardiolipin affinity | Primary research |
|---|---|---|---|---|
| SS-02 | Dmt-D-Arg-Phe-Lys-NH2 | +3 | High | Mitochondrial targeting |
| SS-20 | Phe-D-Arg-Phe-Lys-NH2 | +3 | Moderate | Antioxidant research |
| SS-31 (Elamipretide) | D-Arg-Dmt-Lys-Phe-NH2 | +3 | Very high | Cardiolipin / OXPHOS |
Cardiolipin Biology: Why It Matters
Cardiolipin is unique among mammalian phospholipids: it has four acyl chains (making it a dimeric phospholipid), is found almost exclusively in the inner mitochondrial membrane, and is essential for the organisation and stability of the electron transport chain supercomplexes.
Key cardiolipin research areas relevant to SS-31 studies include:
- ETC supercomplex assembly. Cardiolipin acts as a molecular glue holding respiratory chain complexes (CI, CIII, CIV) together into supercomplexes (also called respirasomes). These assemblies increase OXPHOS efficiency and reduce electron leak that generates ROS. SS-31's interaction with cardiolipin has been studied in the context of supercomplex stability.
- Cytochrome c binding. In healthy mitochondria, cytochrome c is anchored to the inner membrane by cardiolipin interaction. When cardiolipin is peroxidised by ROS, cytochrome c dissociates and is released to the cytoplasm, initiating the intrinsic apoptosis cascade. SS-31 research has examined whether cardiolipin binding can prevent this peroxidation-induced release.
- ATP synthase. Cardiolipin is required for the proper folding and dimerisation of ATP synthase (Complex V), and SS-31's effects on ATP production have been studied in this context.
Frequently Asked Questions
Why does SS-31 concentrate in the inner mitochondrial membrane without a membrane potential?
Most mitochondrially targeted compounds (such as triphenylphosphonium or MitoQ) rely on the large negative mitochondrial membrane potential (approximately -180 mV) to drive their accumulation in the mitochondrial matrix. SS-31 does not require membrane potential for inner membrane targeting — instead, it is driven by electrostatic and hydrophobic interactions with cardiolipin itself. This means SS-31 can concentrate at its target site even in depolarised mitochondria (as occur in ischaemia and in pathological states), making it a distinctive research tool for studying mitochondrial biology under stress conditions.
Published Research References
For laboratory and analytical research purposes only. Not for human or veterinary use. No dosage or administration guidance is provided or implied.
Related research compounds: MOTS-c | NAD+ | SLU-PP-332
Cardiolipin Peroxidation and Cytochrome c Release
One of the most mechanistically important aspects of SS-31 research concerns the relationship between cardiolipin peroxidation and the initiation of the intrinsic apoptosis pathway. In healthy mitochondria, cytochrome c is anchored to the inner mitochondrial membrane through a specific and high-affinity interaction with cardiolipin. Cytochrome c functions both as an electron carrier between Complex III and Complex IV, and as a signalling protein when released to the cytoplasm.
When cardiolipin is peroxidised by reactive oxygen species (particularly hydroxyl radicals generated from the Fenton reaction when free iron interacts with H2O2), the peroxidised cardiolipin loses its high-affinity cytochrome c binding capacity. Cytochrome c dissociates from the inner membrane and accumulates in the intermembrane space. When the outer mitochondrial membrane subsequently permeabilises (through BAX/BAK pore formation), cytochrome c is released to the cytoplasm, forming the apoptosome with Apaf-1 and pro-caspase-9, initiating the caspase cascade.
SS-31 research examines whether its interaction with cardiolipin can prevent cardiolipin peroxidation and cytochrome c release. Published studies using isolated mitochondria subjected to oxidative stress have measured cytochrome c content (by ELISA or Western blot) in mitochondrial fractions following SS-31 treatment versus vehicle, with lipid peroxidation (TBARS, 4-HNE) as a parallel endpoint.
ATP Synthase Dimerisation and Cristae Structure
A less-examined but mechanistically important role of cardiolipin is its requirement for ATP synthase dimerisation. ATP synthase monomers dimerize in the inner mitochondrial membrane through specific protein-protein interactions at their Fo domains, and this dimerisation drives the curvature of the inner membrane at cristae ridges — creating the characteristic folded membrane architecture of the mitochondrial interior.
Disruption of cardiolipin by peroxidation or depletion impairs ATP synthase dimerisation, flattening cristae structure and reducing OXPHOS efficiency. Research examining SS-31 in the context of cristae morphology uses transmission electron microscopy (TEM) to quantify cristae density and structure in isolated mitochondria or intact cells under oxidative stress conditions.
Frequently Asked Questions
Why does SS-31 concentrate in the inner mitochondrial membrane without membrane potential?
Most mitochondrially targeted research compounds (triphenylphosphonium conjugates, MitoQ) require the large negative mitochondrial membrane potential (approximately -180 mV) for electrophoretic accumulation in the matrix. SS-31 does not use this mechanism — it concentrates in the inner membrane through direct electrostatic and hydrophobic interaction with cardiolipin, independently of membrane potential. This makes SS-31 uniquely valuable for studying mitochondria under pathological conditions where membrane potential is collapsed — as occurs in ischaemia, severe oxidative stress, and in dying cells — where potential-dependent compounds would not accumulate.
How is cardiolipin content measured in SS-31 research experiments?
Standard approaches include: NAO (10-nonyl acridine orange) fluorescence staining, which selectively binds cardiolipin and can be measured by flow cytometry or confocal microscopy; mass spectrometry-based lipidomics measuring specific cardiolipin species; and ELISA or dot-blot using anti-cardiolipin antibodies (though antibody-based methods have specificity limitations). For peroxidised cardiolipin specifically, mass spectrometry detection of cardiolipin peroxidation products provides the most specific measurement.
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