SS-31
FDA-approved mitochondria-targeted tetrapeptide (Elamipretide); stabilizes cardiolipin in the inner mitochondrial membrane to restore electron transport chain efficiency, ATP production, and prevent oxidative damage. Approved for Barth syndrome (2023).
Quick Facts
| Property | Value |
|---|---|
| Also Known As | Elamipretide, MTP-131, Bendavia, RX-31 |
| Category | Mitochondrial / Anti-Aging / Cardiac |
| Sequence | D-Arg-Dmt-Lys-Phe-NH2 (4 amino acids; contains non-natural dimethyltyrosine) |
| Molecular Weight | 639.80 g/mol |
| Molecular Formula | C32H49N7O5 |
| PubChem CID | 90488836 |
| Administration | SubQ / IV |
| Typical Dose Range | 40 mg/day SubQ (FDA-approved); 1-5 mg/day (functional medicine) |
| Half-Life | 1.28-4 hours (plasma); persists in mitochondria much longer |
| Storage | Lyophilized -20C; reconstituted 2-8C |
| FDA Status | FDA-Approved (Elamipretide, Barth syndrome, September 2023) |
| WADA Status | Not listed |
Mechanism of Action
SS-31 (elamipretide) is the first drug that directly targets and repairs mitochondrial function from within the organelle. Its +3 net charge at physiological pH drives rapid, energy-independent concentration within mitochondria at 5,000-fold over extracellular levels, where it selectively binds cardiolipin — the signature phospholipid of the inner mitochondrial membrane that is essential for organizing electron transport chain (ETC) supercomplexes. PMID 39940712
By stabilizing cardiolipin-protein interactions, SS-31 restores ETC supercomplex organization, maximizing ATP yield while minimizing reactive oxygen species (ROS) leak from Complexes I and III. It also inhibits cytochrome c peroxidase activity, preventing the conversion of cytochrome c from an electron carrier to a pro-apoptotic trigger, thereby blocking the mitochondrial death cascade. The dimethyltyrosine (Dmt) residue provides direct ROS scavenging of hydrogen peroxide, hydroxyl radicals, and peroxynitrite. PMID 35037146
SS-31 inhibits mitochondrial permeability transition pore (mPTP) opening, protecting against ischemia-reperfusion injury. It also activates SIRT1/PGC-1alpha signaling to promote mitochondrial biogenesis. Importantly, SS-31 crosses the blood-brain barrier (brain/plasma AUC ratio = 1.694), enabling neuroprotective applications. It is NOT hepatically metabolized and undergoes 100% renal elimination. PMID 31747905
In the EMBRACE heart failure RCT, elamipretide improved left ventricular end-systolic volume in heart failure patients with reduced ejection fraction, confirming translational relevance of the mitochondrial mechanism. PMID 29217757
Long-term TAZPOWER data in Barth syndrome patients demonstrated sustained cardiac function improvement and functional capacity over 168 weeks of treatment. PMID 38602181
Key Research Areas
- Barth Syndrome (FDA-approved): Cardiolipin remodeling defect; elamipretide restores ETC function. PMID 33001359, PMID 38602181
- Heart Failure: EMBRACE RCT demonstrated improvement in LV end-systolic volume. PMID 29217757
- Aging and Sarcopenia: Improves cardiac and skeletal muscle function during aging; restores ADP sensitivity in aged mitochondria. PMID 40080911, PMID 37462785
- Neuroprotection: Improves mitochondrial dysfunction, synaptic and memory impairment in neuroinflammatory models; crosses BBB. PMID 31747905
- Comprehensive Mechanism Review: Structure-activity relationships and therapeutic potential across diseases. PMID 39940712
Evidence Level Summary
| Evidence Type | Count | Notes |
|---|---|---|
| Human RCTs | 1 | EMBRACE heart failure trial |
| Human observational | 1 | TAZPOWER long-term Barth syndrome |
| Animal in vivo | 2 | LPS neuroinflammation model, aged muscle/heart |
| In vitro | 0 | — |
| Systematic reviews | 0 | — |
| Narrative reviews | 4 | Mechanism reviews, Barth syndrome, mitochondrial targeting |
Clinical Applications
- Anti-Aging — Mitochondrial restoration, SIRT1 activation
- Sarcopenia — Skeletal muscle mitochondrial function in aging
- Neuroprotection — BBB-crossing, synaptic protection
- Mitochondrial Health — ETC supercomplex stabilization
- Wound Healing — Cellular energy for tissue repair
Protocols Using This Peptide
Ageless Peps Products
- AP-SS31-Vial — SS-31 Vial, $84
Dosing Reference
Research Dosing Ranges (from literature)
| Route | Dose Range | Frequency | Duration | Source |
|---|---|---|---|---|
| SubQ | 40 mg | Once daily | Ongoing (Barth syndrome) | FDA label |
| SubQ | 20 mg | Once daily | eGFR <30 adjustment | FDA label |
| SubQ | 1-5 mg | Once daily | 30-60 days on / 30-60 days off | Functional medicine |
Cycling
Functional medicine: 30-60 days on, 30-60 days off. Energy effects typically noticed within 1-2 weeks; cognitive effects 2-4 weeks. FDA-approved use is continuous. No tolerance or dependency reported.
Contraindications & Safety
- Contraindications: Prior anaphylaxis to elamipretide (absolute); neonates if multi-dose formulation contains benzyl alcohol
- Common side effects: Injection site reactions (up to 80% in clinical trials — most common); generally mild and transient
- Drug interactions: No significant systemic drug interactions due to 100% renal elimination without hepatic metabolism
- Pregnancy/nursing: Insufficient data; avoid
- Special populations: Renal dose adjustment: 20 mg if eGFR <30; no systemic organ toxicity demonstrated in clinical trials
Synergistic Combinations
- MOTS-C + SS-31 — Dual mitochondrial support (MDP + cardiolipin stabilizer)
- NAD+ + SS-31 — Comprehensive cellular energy restoration (NAD+ biosynthesis + ETC efficiency)
- VIP + LL-37 + SS-31 — Immune + mitochondrial support stack
- Epitalon + SS-31 — Anti-aging: telomere + mitochondrial protection
Related Research
| PMID | Title | Year | Study Type |
|---|---|---|---|
| 33001359 | Barth syndrome cardiomyopathy: targeting the mitochondria with elamipretide | 2020 | Review |
| 39940712 | Elamipretide: A Review of Its Structure, Mechanism of Action | 2025 | Review |
| 40080911 | Elamipretide Improves Cardiac and Skeletal Muscle Function During Aging | 2025 | Animal in vivo |
| 31747905 | SS-31 improves mitochondrial dysfunction, synaptic and memory impairment | 2019 | Animal in vivo |
| 35037146 | Targeting mitochondrial dysfunction with elamipretide | 2022 | Review |
| 29217757 | Elamipretide Heart Failure RCT (EMBRACE) | 2018 | RCT (Level II) |
| 37462785 | SS-31 Improves ADP Sensitivity in Aged Mitochondria | 2023 | Animal in vivo |
| 38602181 | TAZPOWER Long-Term Elamipretide in Barth Syndrome | 2024 | Observational (Level II) |
References
- PMID 33001359 — Barth syndrome review
- PMID 39940712 — Structure/mechanism review
- PMID 40080911 — Aging muscle/heart
- PMID 31747905 — Neuroinflammation model
- PMID 35037146 — Mitochondrial targeting review
- PMID 29217757 — EMBRACE HF RCT
- PMID 37462785 — ADP sensitivity aging
- PMID 38602181 — TAZPOWER long-term
Related
#peptide #mitochondrial #anti-aging #subq