SS-31 (Elamipretide; INN; also known by development codes MTP-131 and Bendavia) is a synthetic tetrapeptide with the sequence D-Arg-2′6′-Dmt-Lys-Phe-NH₂. It is registered under CAS number 736992-21-5 and has a molecular weight of 639.8 g/mol. SS-31 was designed using the Szeto-Schiller (SS) peptide platform, which incorporates alternating aromatic and basic amino acid residues to create peptides with high mitochondrial targeting efficiency.

The mitochondrial targeting mechanism of SS-31 is based on its interaction with cardiolipin, a unique phospholipid found almost exclusively in the inner mitochondrial membrane (IMM). Cardiolipin contains four acyl chains and two phosphate groups, giving it a net negative charge that attracts the positively charged SS-31 through electrostatic interactions. The aromatic residues in SS-31 (Dmt and Phe) additionally interact with the acyl chains of cardiolipin through hydrophobic interactions. This combination of electrostatic and hydrophobic binding results in SS-31 concentrating in the IMM at concentrations estimated to be 1000-fold higher than in the cytoplasm.

Cardiolipin plays critical structural and functional roles in the IMM. It stabilizes the supercomplexes of the electron transport chain (ETC), facilitates cytochrome c binding to the IMM, and is required for optimal activity of multiple IMM-associated enzymes including ATP synthase. Cardiolipin oxidation — which occurs during oxidative stress and ischemia — disrupts these functions and is associated with mitochondrial dysfunction, cytochrome c release, and apoptosis initiation. SS-31's interaction with cardiolipin is thought to protect it from oxidation, providing a mechanism for the peptide's documented effects on mitochondrial function.

Research applications for SS-31 span multiple disease models. In models of cardiac ischemia-reperfusion injury, SS-31 treatment has been associated with reduced infarct size, preserved mitochondrial membrane potential, and improved cardiac function metrics. In models of aging, SS-31 treatment in aged mice has been associated with improvements in mitochondrial morphology, ATP production, and exercise capacity. In models of metabolic disease including diabetes and obesity, SS-31 has been studied for effects on mitochondrial biogenesis and insulin sensitivity.

For in vitro research, SS-31 is typically used at nanomolar to low micromolar concentrations. Common applications include studies of mitochondrial membrane potential (using JC-1 or TMRM dyes), mitochondrial oxygen consumption rate (using Seahorse XF analyzers), ROS production (using MitoSOX), and cytochrome c release assays. The peptide is supplied as a lyophilized powder and is readily soluble in water.