SS-31

SS-31 (elamipretide, MTP-131) is a synthetic tetrapeptide, D-Arg-Dmt-Lys-Phe-NH2 (C32H49N9O5, 639.8 g/mol), in which Dmt denotes dimethyltyrosine. It belongs to the Szeto-Schiller (SS) peptides, an aromatic-cationic class built on alternating aromatic and basic residues. SS-31 is taken up by a variety of cell types and targets the inner mitochondrial membrane, where SS peptides have been reported to concentrate more than 1000-fold and where SS-31 binds cardiolipin, an anionic phospholipid enriched in that membrane.

SS-31 in the research literature

Research on SS-31 has focused on how it interacts with mitochondrial membranes. Early work on SS peptides described scavenging of hydrogen peroxide and peroxynitrite, inhibition of lipid peroxidation, and inhibition of mitochondrial permeability transition and cytochrome c release in cell models. Biophysical studies found that SS-31 partitions into the membrane interfacial region with an affinity tied to surface charge, alters lipid packing without destabilizing bilayers, modulates membrane surface electrostatics and changes calcium distribution at the interface.

A chemical cross-linking mass spectrometry study identified mitochondrial protein interactors of SS-31, all known cardiolipin binders, falling into oxidative phosphorylation and 2-oxoglutarate metabolism groups. In mice challenged with lipopolysaccharide, SS-31 was studied for its effects on hippocampal mitochondrial function, oxidative stress markers and BDNF signaling.