SS-31 (elamipretide, D-Arg-2’6′-Dmt-Lys-Phe-NH₂) is a cell-permeable tetrapeptide that selectively partitions to the inner mitochondrial membrane (IMM) and binds cardiolipin — the signature phospholipid of the IMM. Cardiolipin is essential for cristae architecture, respiratory chain complex assembly (especially Complex I, III, and IV), and cytochrome c anchoring. Age-related and disease-associated cardiolipin peroxidation disrupts all three functions. SS-31 stabilises cardiolipin against peroxidation, restoring cristae morphology, electron transport efficiency, and ATP production. The Phase 2 SERCA trial demonstrated improved left ventricular function in heart failure patients — the first human evidence for a mitochondria-targeted peptide in cardiac disease.
SS-31 mechanism is unique among all peptides in the QSC catalog — it does not activate a receptor. It works through direct lipid-protein interaction:
Mitochondrial targeting: Alternating aromatic and basic residues → electrostatic attraction to IMM negative membrane potential (−180 mV) → 1000× concentration at IMM vs cytosol
Cardiolipin binding: 2’6′-dimethyltyrosine (Dmt) interacts with cardiolipin headgroup → stabilises cardiolipin against cytochrome c peroxidase activity
Cristae integrity: Cardiolipin stabilisation maintains cristae junction curvature → proper respiratory chain complex (supercomplex) assembly → improved electron transfer efficiency
ROS reduction: Improved ETC efficiency → less electron leak → reduced superoxide production at Complex I/III
Cytochrome c: Prevents cardiolipin-cytochrome c peroxidase complex formation → reduces apoptotic cytochrome c release
Why cardiolipin is the mechanistic target
Cardiolipin is a dimeric phospholipid found almost exclusively in the IMM — it constitutes ~20% of IMM phospholipids. It is required for respiratory supercomplex (respirome) assembly — the physical organisation of Complexes I+III+IV that maximises electron transfer efficiency and minimises ROS production. Oxidised cardiolipin destabilises supercomplexes, reduces ATP production, and increases electron leak. SS-31 is the only compound that directly targets and protects cardiolipin — making it mechanistically irreplaceable for cardiolipin and respiratory supercomplex research.
Key Research Studies & Clinical Data
Key SS-31 research
Study
Model/Population
Key result
Szeto et al. 2014 (JASN)
Aged mouse kidney model
SS-31 restored tubular mitochondrial cristae, reduced ROS, improved renal function
Chatfield et al. 2017 (Sci Trans Med)
Aged mouse exercise tolerance
SS-31 improved mitochondrial respiration and exercise capacity in old mice within 1 hour of injection
SERCA Phase 2 2020
Heart failure with preserved EF (HFpEF) patients, IV infusion
Improved cardiac contractility (LVESV, LVEF) — first human IV mitochondrial peptide trial
SS-31 3 mg/kg IV 10 min before LAD ligation (30 min) + reperfusion (120 min) in rat. Infarct size (TTC), cardiac troponin I, mitochondrial swelling (absorbance), cytochrome c release (WB), caspase-3 activity.
SS-31 1–10 µM in isolated cardiac mitochondria + cytochrome c + H₂O₂. Cardiolipin peroxidation (HPLC-MS), cytochrome c peroxidase activity (fluorometric), cristae disruption (swelling assay).
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Frequently Asked Questions
What is SS-31 (elamipretide)?
SS-31 is a cell-permeable tetrapeptide that selectively binds cardiolipin at the inner mitochondrial membrane. It stabilises cardiolipin against peroxidation, maintaining cristae architecture, respiratory chain complex assembly, and ATP production efficiency. It has Phase 2 human data in heart failure.
What is cardiolipin and why does it matter?
Cardiolipin is a unique dimeric phospholipid found almost exclusively in the inner mitochondrial membrane. It is essential for organising respiratory chain complexes into supercomplexes (I+III+IV) that maximise ATP production efficiency. Cardiolipin oxidation — driven by ageing, ischaemia, and metabolic stress — disrupts supercomplexes, reduces ATP output, and increases reactive oxygen species.
How does SS-31 differ from other antioxidants?
Standard antioxidants (CoQ10, MitoQ) scavenge ROS after they are produced. SS-31 prevents ROS overproduction at the source — by stabilising the respiratory supercomplex assembly that keeps electron transfer efficient and minimises electron leak to oxygen. It also has no antioxidant enzyme or superoxide dismutase activity itself.
What did the Phase 2 SERCA trial show?
The SERCA Phase 2 trial in HFpEF patients showed improved left ventricular end-systolic volume and ejection fraction following IV elamipretide infusion — the first human trial demonstrating cardiovascular benefit from a mitochondria-targeted peptide.
What formats does QSC supply SS-31 in?
QSC supplies SS-31 as 10mg and 50mg lyophilised vials in 10-vial and 20-vial kits, ≥99% purity HPLC verified with Janoshik COA. Ships from domestic QSC warehouses in USA, EU, UK, Canada, and Australia.
Research Use Only: All QSC compounds are sold strictly for laboratory research purposes. Not for human use. Not approved by the FDA or equivalent regulatory bodies for human administration. All purchases confirm research intent and compliance with applicable local regulations.
