SS-31
Also known as: Elamipretide, MTP-131, Bendavia, Szeto-Schiller 31
A cardiolipin-binding tetrapeptide that concentrates in the inner mitochondrial membrane, studied for its effects on mitochondrial bioenergetics.
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Molecular Data
- Class
- Aromatic-cationic tetrapeptide / Mitochondria-targeted cardiolipin-binding compound
- Molecular Weight
- 639.80 Da
- Molecular Formula
- C₃₂H₄₉N₉O₅
- Half-Life
- Short in plasma (hours); tissue mitochondrial residence is considerably longer
- Sequence / Structure
- D-Arg-Dmt-Lys-Phe-NH₂ (Dmt = 2′,6′-dimethyltyrosine; C-terminal amide)
Mechanism of Action
SS-31 belongs to the Szeto-Schiller family of aromatic-cationic tetrapeptides. Its alternating aromatic and basic residues give it a net positive charge at physiological pH while remaining cell-permeable, and it accumulates in the inner mitochondrial membrane without depending on the membrane potential — the feature that distinguishes it from earlier mitochondria-targeted compounds such as the triphenylphosphonium conjugates.
- Cardiolipin binding: SS-31 associates selectively with cardiolipin, the signature anionic phospholipid of the inner mitochondrial membrane required for cristae curvature and for assembly of the respiratory supercomplexes.
- Protection of cytochrome c: By binding cardiolipin, SS-31 suppresses the peroxidase activity that cytochrome c acquires when it forms a cardiolipin complex. That peroxidase activity drives cardiolipin peroxidation and is an early step in mitochondrial injury during ischemia.
- Cristae preservation and ATP recovery: In ischemia models, pretreatment preserved cristae architecture, prevented mitochondrial swelling, and allowed prompt ATP recovery on reperfusion.
- Reduced mitochondrial ROS: Downstream of cardiolipin protection, electron leak from the respiratory chain falls, lowering mitochondrial reactive oxygen species production in stressed cells.
SS-31 is not an enzyme inhibitor or receptor ligand in the usual sense — its target is a membrane lipid, which is why it is described in the literature as a cardiolipin-protective compound rather than a conventional antioxidant.
Research History
SS-31 emerged from work by Hazel Szeto and Peter Schiller, who were originally designing opioid-receptor peptide analogues and found that certain aromatic-cationic sequences partitioned into mitochondria. The tetrapeptide numbered 31 in that series became the lead compound.
The mechanistic case was consolidated by Birk and colleagues in 2013, who showed the compound binds cardiolipin directly and protects cristae during renal ischemia — reframing earlier "antioxidant" descriptions around a specific lipid target.
Under the development name elamipretide, the compound was taken into human trials by Stealth BioTherapeutics across mitochondrial myopathy, heart failure, Barth syndrome, and ophthalmic indications. The MMPOWER programme in primary mitochondrial myopathy is the most thoroughly reported: an early dose-escalation trial reported an increase in six-minute walk distance, while the larger MMPOWER-3 trial did not meet its primary endpoint. As of this writing, elamipretide has not been approved by the FDA for any indication, and the compound remains investigational.
Notable Studies
Birk AV, Liu S, Soong Y, Mills W, Singh P, Warren JD, Seshan SV, Pardee JD, Szeto HH. · Journal of the American Society of Nephrology
Established the cardiolipin-binding mechanism. SS-31 inhibited cytochrome c peroxidase activity, preserved cristae membranes during renal ischemia in rats, and allowed rapid ATP recovery on reperfusion, which in turn restored the actin cytoskeleton and tubular barrier function.
Karaa A, Haas R, Goldstein A, Vockley J, Weaver WD, Cohen BH. · Neurology
Phase 1/2 randomised, double-blind, placebo-controlled trial in 36 participants with genetically confirmed primary mitochondrial myopathy, using intravenous elamipretide in a dose-escalating sequence with six-minute walk distance as the primary efficacy measure.
Karaa A, Bertini E, Carelli V, et al. · Neurology
The largest controlled trial of the compound to date. Included here because it did not meet its primary endpoint — the negative result is part of the evidence picture and is the reason elamipretide remains investigational.
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