SS-31
Mitochondrial-targeted peptide stabilising cardiolipin and inner-membrane architecture.
- Sequence: D-Arg-2',6'-dimethylTyr-Lys-Phe-NH₂ (Szeto-Schiller motif)
- Selective binding to inner-mitochondrial-membrane cardiolipin
- Restores cristae structure and ATP synthesis in damaged mitochondria
- Investigated in ischaemia-reperfusion injury, mitochondrial myopathy and aged skeletal muscle
- Sequence
- D-Arg-2',6'-dimethylTyr-Lys-Phe-NH₂
- Molecular weight
- 639.8 g/mol
- Half-life
- Plasma half-life approximately 1–2 hours; tissue accumulation in mitochondria-rich organs persists much longer.
Overview
SS-31 (also called Elamipretide, Bendavia, or MTP-131) is a synthetic aromatic-cationic tetrapeptide developed by Hazel Szeto and Peter Schiller at Weill Cornell Medical College in the early 2000s. It belongs to the Szeto-Schiller class of mitochondrially-targeted peptides — short sequences with alternating aromatic and cationic residues designed to accumulate in the inner mitochondrial membrane regardless of membrane potential.
Unlike most mitochondrial-targeting strategies, SS-31 does not depend on the inner-membrane potential for uptake. Instead, it binds with high affinity to cardiolipin — the phospholipid uniquely concentrated in the inner mitochondrial membrane and critical for cristae structure, respiratory-supercomplex assembly and electron-transport-chain efficiency. SS-31's mechanism is therefore unique among research peptides discussed on this site: it is a structural stabiliser of mitochondrial architecture.
SS-31 has progressed further in clinical development than most peptides covered here. It has been studied in phase I, II and III trials in conditions including primary mitochondrial myopathy, dry age-related macular degeneration and ischaemia-reperfusion injury, under the company name Stealth BioTherapeutics. Outcomes have been mixed, but the clinical-stage status means the safety and pharmacokinetic profile of SS-31 is unusually well characterised for a longevity-oriented research peptide.
Mechanism of action
The primary mechanism is direct binding of SS-31 to cardiolipin in the inner mitochondrial membrane. Cardiolipin is essential for the structural integrity of cristae, for assembly of respiratory-chain supercomplexes (which improve electron-transport efficiency), and for the activity of multiple inner-membrane proteins including ATP synthase and the adenine nucleotide translocator. In aged and stressed mitochondria, cardiolipin becomes oxidised and disorganised, and cristae architecture deteriorates.
By binding cardiolipin selectively, SS-31 protects the lipid from peroxidation, stabilises cristae structure, and preserves supercomplex assembly. The downstream effect is restoration of ATP synthesis, reduced reactive oxygen species generation and preserved mitochondrial membrane potential. In skeletal muscle from old mice, brief SS-31 administration restores cristae structure to a profile resembling young muscle within hours.
Importantly, SS-31 does not interact with the electron-transport chain directly and does not act as an antioxidant in the classical sense. Its activity is structural — it preserves the membrane architecture that allows respiratory complexes to function efficiently. This distinguishes it from compounds like MitoQ that target mitochondrial oxidative stress through redox chemistry.
Secondary consequences of restoring inner-membrane architecture include reduced apoptosis through preservation of cytochrome c retention, reduced mitochondrial permeability transition pore opening under stress, and preserved calcium-handling capacity. These effects underpin the protective profile in ischaemia-reperfusion models.
Research history
SS-31 was developed at Weill Cornell in the early 2000s and has been licensed for clinical development by Stealth BioTherapeutics (now Stealth Health). Preclinical work through the mid-2000s established the cardiolipin-binding mechanism and demonstrated protective effects in cardiac and renal ischaemia-reperfusion models.
Clinical development has spanned multiple indications. The MMPOWER programme investigated SS-31 in primary mitochondrial myopathy, with phase II evidence of improved six-minute-walk distance but mixed phase III readouts. The ReCLAIM programme examined dry age-related macular degeneration. Use in heart failure with preserved ejection fraction has also been studied. As of the most recent regulatory cycle, SS-31 has not received broad marketing authorisation, but the depth of human safety and pharmacokinetic data exceeds that of most longevity-research peptides.
Summarised studies
Elamipretide rescues mitochondrial function and improves physical performance in aged mice
Siegel MP, Kruse SE, Percival JM, et al.
Eight days of SS-31 administration restored skeletal-muscle ATP production, normalised redox state and improved fatigue resistance to levels seen in young mice.
Cardiolipin binding by SS-31 stabilises cristae and improves respiratory function
Birk AV, Liu S, Soong Y, et al.
Demonstration of selective cardiolipin binding by SS-31 with preservation of cristae structure and restoration of supercomplex assembly in damaged mitochondria.
MMPOWER-3 phase III trial of elamipretide in primary mitochondrial myopathy
Karaa A, Haas R, Goldstein A, et al.
Primary efficacy endpoint (6-minute-walk distance change) not met at week 24; patient-reported fatigue scores improved on active treatment. Safety profile favourable; injection-site reactions most common AE.
SS-31 reduces ischaemia-reperfusion injury in a porcine cardiac model
Cho J, Won K, Wu D, et al.
SS-31 administration prior to reperfusion reduced infarct size by 40–60% with preserved ejection fraction.
Elamipretide ameliorates renal ischaemia-reperfusion injury in rats
Szeto HH, Liu S, Soong Y, et al.
Reduction of tubular necrosis and preserved creatinine clearance; preservation of cardiolipin content and respiratory complex activity.
Safety profile
SS-31 has the most-characterised safety profile of any peptide on this site by a wide margin, as a consequence of its clinical-stage development programme. Across phase I, II and III trials, the most common adverse events have been injection-site reactions (with subcutaneous administration) and mild transient gastrointestinal upset. No mutagenic, hepatotoxic or nephrotoxic signal has emerged in long-term human use up to 48 weeks.
Long-term effects beyond the clinical-trial follow-up window have not been characterised. As with all mitochondrial-modifying agents, theoretical considerations include effects on tumour cell mitochondrial function — though no tumour-promoting signal has been reported.
Preclinical reproductive toxicology has not produced developmental signals; specific advice in pregnancy and lactation in humans is not established and would be the subject of regulatory labelling if SS-31 is eventually approved.
UK regulatory status
As of the most recent regulatory cycle, SS-31 (elamipretide) does not hold a UK marketing authorisation. The compound is in active clinical development with the MHRA aware of ongoing trial activity, and limited expanded-access provision exists in some jurisdictions for primary mitochondrial myopathy.
Research-grade SS-31 supplied outside clinical-trial settings in the UK is available only as an unlicensed research peptide, for laboratory and preclinical use. Researchers handling SS-31 should treat it as an unlicensed investigational compound under institutional SOPs.
Frequently asked questions
What is SS-31?
SS-31 — also called elamipretide and developed under the names Bendavia and MTP-131 — is a synthetic aromatic-cationic tetrapeptide that accumulates in the inner mitochondrial membrane and binds cardiolipin, stabilising cristae structure and preserving respiratory-chain function.
Is SS-31 an antioxidant?
Not in the conventional sense. SS-31 does not scavenge reactive oxygen species directly. Its mechanism is structural — it preserves cardiolipin and inner-membrane architecture, which in turn reduces ROS generation by improving electron-transport-chain efficiency.
Is SS-31 the same as elamipretide?
Yes. 'SS-31' is the original Szeto-Schiller laboratory designation; 'elamipretide' is the international non-proprietary name; 'Bendavia' and 'MTP-131' are earlier commercial designations.
Has SS-31 been approved as a medicine?
As of the most recent regulatory cycle, SS-31/elamipretide has not received broad marketing authorisation. It has progressed through phase I, II and III trials in primary mitochondrial myopathy and other indications, with mixed outcomes.
Why is SS-31 of interest for longevity?
Mitochondrial dysfunction is a hallmark of ageing, and SS-31 demonstrably restores cristae structure and ATP production in aged skeletal muscle within days of administration. In an 8-day mouse experiment by Siegel et al. (2013), SS-31 restored aged-muscle physical performance to young-mouse levels.
How does SS-31 reach the mitochondria?
SS-31 is membrane-permeable due to its aromatic-cationic structure and accumulates in the inner mitochondrial membrane independent of membrane potential — distinguishing it from cation-targeting compounds like MitoQ.
Is SS-31 legal in the UK?
SS-31 does not hold UK marketing authorisation. Research-grade material is supplied for laboratory and preclinical use only. Clinical-trial access is via sponsor-controlled studies.
Related peptides
Adjacent compounds in the longevity research literature with overlapping mechanisms or shared research history.
A 16-amino-acid mitochondrially-derived peptide encoded within the mitochondrial 12S rRNA gene; functions as an exercise-mimetic regulator of insulin sensitivity, AMPK signalling and metabolic homeostasis.
A 24-amino-acid mitochondrially-derived peptide encoded within the 16S rRNA gene, studied for cytoprotective, metabolic and neuroprotective signalling that declines with age.
Peptides and peptide-conjugate strategies investigated for their effects on cellular NAD⁺ levels, sirtuin activity and mitochondrial energy metabolism — including direct sirtuin-activating peptides and NMN/NR delivery analogues.
References
- Siegel MP et al., Aging Cell 2013 — SS-31 in aged mouse muscle
- Karaa A et al., Neurology 2020 — MMPOWER-3 phase III
- Stealth BioTherapeutics — clinical pipeline
See also our editorial coverage at PeptideAuthority.co.uk for related research dossiers.