SS-31 (Elamipketide): Mitochondria-Targeted Peptide Research Guide

SS-31 (Szeto-Schiller peptide 31), also known by its INN name Elamipketide, is a synthetic tetrapeptide with the sequence D-Arg-Dmt-Lys-Phe-NH₂. It was developed by Hazel Siew-Har Szeto at Cornell University and is distinguished from most research peptides by its unique mechanism: it selectively concentrates in the inner mitochondrial membrane (IMM) independently of mitochondrial membrane potential, where it binds to cardiolipin.

The inclusion of a dimethyltyrosine (Dmt) residue and D-arginine (D-Arg) in its sequence provides both antioxidant activity (via the phenolic hydroxyl of Dmt) and resistance to proteolytic degradation (via the D-amino acid configuration).

Cardiolipin is a unique phospholipid found almost exclusively in the inner mitochondrial membrane, where it plays structural and functional roles essential to mitochondrial physiology:

• Organises and stabilises the electron transport chain (ETC) supercomplex structure
• Essential for the function of Complex I, III, IV, and ATP synthase
• Forms a high-affinity binding site for cytochrome c
• Required for maintenance of cristae morphology

SS-31 binds cardiolipin with high affinity via electrostatic and hydrophobic interactions. This stabilises cardiolipin-cytochrome c interactions, prevents cristae disruption under stress, reduces superoxide generation from the ETC, and inhibits cardiolipin peroxidation — a critical step in apoptotic cytochrome c release. The net effect is preservation of mitochondrial ATP production capacity under conditions of metabolic stress or injury.

The largest body of SS-31 research concerns cardiac protection. Studies in rodent ischaemia-reperfusion (I/R) injury models have demonstrated that SS-31 administered before reperfusion significantly reduces infarct size and preserves left ventricular function. The mechanism involves prevention of mitochondrial permeability transition pore (mPTP) opening during the reperfusion phase — a key driver of reperfusion injury.

Heart failure research using SS-31 has shown improvements in mitochondrial cristae morphology, ATP production, and cardiac mechanical performance in hypertrophic and dilated cardiomyopathy models. A Phase 2 clinical trial (HARP trial) in human heart failure demonstrated improved renal and cardiac function after SS-31 infusion — making it one of the few mitochondria-targeted compounds to have entered human trials.

Age-related mitochondrial dysfunction contributes to sarcopenia (muscle loss) and reduced exercise capacity in older individuals. SS-31 research in aged animal models has documented improvements in skeletal muscle mitochondrial morphology, respiratory function, and contractile performance.

Studies in aged mice and rats have shown SS-31 can partially reverse the accumulation of fragmented, dysfunctional mitochondria in skeletal muscle — findings relevant to research on frailty, sarcopenia, and the biology of musculoskeletal ageing.

RetaLABS SS-31 is supplied as lyophilised powder in 10mg and 50mg vial sizes. Reconstitute with sterile water or bacteriostatic water. Store lyophilised at −20°C and reconstituted solution at 2–8°C for up to 4 weeks. Handle reconstituted solutions with care to avoid oxidation of the Dmt residue.

See the Peptide Reconstitution Guide for full protocol notes. COAs available on request. All products are for laboratory research use only.