Mitochondrial
SS-31 (Elamipretide) Guide: Mitochondrial Repair for Energy and Aging
SS-31 is a mitochondria-targeting peptide that repairs the physical structure energy production depends on. It binds to cardiolipin — the lipid holding the inner mitochondrial membrane together — and restores the tight organization that efficient electron flow requires. This is structural repair, not stimulation.
At a Glance
- Tetrapeptide that targets and stabilizes the inner mitochondrial membrane
- Binds cardiolipin — the structural lipid anchoring the electron transport chain
- FDA-approved in 2025 as Forzinity for Barth syndrome (first mitochondria-targeted drug approved in the US)
- Improves ATP production in aging muscle within a single dose
- Typical protocol: 5–10 mg daily loading, then 2–3× per week maintenance
- Works by structural repair, not metabolic stimulation
For mitochondrial context, see our MOTS-c Guide, NAD+ Guide, and Mitochondrial Stack.
What SS-31 Is
SS-31 (also called elamipretide, MTP-131, or Bendavia) is a cell-permeable tetrapeptide with a molecular weight of 639.8 g/mol. At physiological pH, it carries a net charge of 3+ and selectively accumulates in the inner mitochondrial membrane — concentrating approximately 5,000-fold in mitochondria.
Its target is cardiolipin, a lipid unique to the inner mitochondrial membrane. Cardiolipin holds the respiratory chain complexes in position and maintains the tight membrane curvature needed for efficient electron transport. When cardiolipin is damaged or loses binding integrity, electron flow becomes turbulent, byproducts accumulate, and energy output drops — long before the mitochondria themselves fail.
SS-31 restores cardiolipin structure without altering upstream signaling. The result is cleaner electron flow, better membrane charge retention, and more ATP from the same signals.
How Mitochondria Break Down
The inner mitochondrial membrane loosens over time under normal life pressures. Each force is small, but together they erode the structure energy production depends on:
| Stressor | Mechanism |
|---|---|
| Chronic inflammation | Daily immune activity strains membrane lipid anchors |
| Illness/infection | Fever and immune response push mitochondria to maximum output |
| Poor metabolic health | Glucose swings and insulin resistance force harder work on weakened scaffold |
| Alcohol | Even moderate intake generates byproducts challenging membrane stability |
| Sleep disruption | Deep sleep is when membrane repair runs; fragmented sleep leaves restoration incomplete |
| Psychological stress | Stress hormones increase demand while suppressing repair windows |
| Age | Cumulative exposure to all of the above |
The result is familiar: effort feels costlier, recovery takes longer, and energy becomes easier to disrupt — not because fuel is lacking, but because the membrane scaffolding has weakened.
How SS-31 Works
SS-31 binds to cardiolipin on the inner mitochondrial membrane and restores the structural tension that keeps respiratory machinery aligned. Once structure is recovered:
Electron flow becomes cleaner: Respiratory complexes remain in position, reducing turbulence in the chain and minimizing electron leak.
The membrane holds its charge more reliably: A tighter membrane sustains the electrochemical gradient required for continuous ATP production.
Mitochondria experience less internal strain: Cleaner flow produces fewer reactive oxygen species, allowing each mitochondrion to function longer before requiring replacement.
Tissues meet demand with less effort: When machinery moves electrons efficiently, work produces proportionate fatigue rather than exaggerated strain.
These are structural corrections, not forced output. SS-31 does not stimulate the system — it restores the architecture that makes clean energy possible.
SS-31 Benefits
Energy stability
When the membrane is restored, energy becomes more predictable under load. Physical effort produces proportional fatigue instead of delayed crashes. Recovery windows shorten because tissues can power repair programs cleanly rather than working against internal inefficiency.
Daily variability narrows. A poor night's sleep, a missed meal, or a mild illness still registers, but the impact is smaller because the underlying machinery remains stable.
ATP production in aging
Human studies confirm SS-31 reaches its target and improves function in aging tissue. A single IV dose increased skeletal-muscle ATP production in older adults — demonstrating target engagement in the population most affected by mitochondrial decline.
Cardiac function
In failing human heart tissue, SS-31 exposure improved mitochondrial respiration. Clinical trials in Barth syndrome (a genetic disorder of cardiolipin remodeling) showed improvements in cardiac biomarkers and functional capacity over years of treatment — the basis for FDA approval.
NAD+ conservation
SS-31 reduces the cellular "NAD+ burn rate" by fixing structural problems that waste it. When the membrane is stable:
- Electron flow stops leaking, reducing oxidative byproducts
- PARP-driven DNA-repair penalty shrinks (PARP consumes NAD+ when fixing oxidative damage)
- Inflammatory signals that drive CD38 expression quiet down (CD38 degrades NAD+)
Net effect: cells don't just make energy more efficiently — they spend far less NAD+ doing it.
Who SS-31 Benefits
| Profile | Why SS-31 Helps |
|---|---|
| Aging adults | Restores membrane tension that declines with age; stabilizes daily energy |
| GLP-1/retatrutide users | Supports mitochondrial hardware during high oxidative flux from rapid fat loss |
| Low-energy phenotypes | Addresses structural instability underlying chronic fatigue and post-exertional malaise |
| Post-viral recovery | Re-establishes clean energy production after immune activation stresses membranes |
| High physical demand | Athletes, shift workers, sustained cognitive load — reduces mitochondrial strain accumulation |
| Hormonal transition | Peri-menopause, andropause — stabilizes energy under increased inflammatory and sleep disruption |
Across these contexts, the principle is the same: SS-31 is used when life loads the mitochondrial membrane beyond its ability to maintain structure.
Dosing
SS-31 behaves as a structural repair signal rather than continuous therapy. Once membrane sites are saturated, adding more SS-31 doesn't increase the effect.
Reconstitution note: Use bacteriostatic water with sodium chloride (isotonic) to reduce injection site sting and prevent welts.
Standard protocol
| Phase | Dose | Duration | Purpose |
|---|---|---|---|
| Loading | 5–10 mg daily | 5–10 days | Saturate membrane binding sites |
| Maintenance | 5–10 mg | 2–3× per week | Sustain structural integrity |
Timing
Morning or 60–90 minutes before training. The peptide is used intermittently — aligned with stressors rather than fixed schedules.
Administration
Subcutaneous injection. The peptide is well tolerated; transient warmth or brief nausea may occur early and typically resolve quickly. Mild fatigue is expected during loading if baseline mitochondrial damage is significant — this reflects the repair process.
Clinical Research and FDA Approval
Barth syndrome (FDA approved)
SS-31 (as elamipretide/Forzinity) received FDA accelerated approval in September 2025 for Barth syndrome — a genetic disorder defined by defective cardiolipin remodeling. This makes it the first mitochondria-targeted therapeutic approved in the United States.
The TAZPOWER trial showed multi-year improvements in 6-minute walk distance and cardiac biomarkers. A confirmatory post-marketing study is ongoing.
Other conditions (investigational)
| Indication | Trial | Result |
|---|---|---|
| Primary mitochondrial myopathy | MMPOWER-3 | Primary endpoint not met; secondary outcomes showed directional benefit |
| Older adults | ATPmax study | Single IV dose increased skeletal-muscle ATP production |
| Dry AMD | ReCLAIM-2 | Mixed results overall; functional signal in predefined subgroups |
| Failing human heart | Ex vivo study | Improved mitochondrial respiration in human myocardium |
Across studies, the mechanistic signal is consistent: SS-31 reaches its target, stabilizes the membrane, reduces byproduct formation, and improves efficiency. Functional outcomes vary by indication, but structural effects are reproducibly observed.
SS-31 + MOTS-c + NAD+ Stack
Mitochondrial performance depends on three things: structure, signaling, and cofactor availability.
| Component | Role |
|---|---|
| SS-31 | Repairs structure — electrons flow cleanly |
| MOTS-c | Activates adaptive signaling — more mitochondria, better fuel choice |
| NAD+ | Supplies cofactor — the redox currency mitochondria run on |
Together: better engines (SS-31) + more engines (MOTS-c) + fuel for both (NAD+). The result is a mitochondrial system that runs younger than its chronological age.
This combination is known as the Mitochondrial Integration & Transformation Triad (MITT). See: Mitochondrial Stack
Side Effects and Safety
Common:
- Transient warmth or flushing (early doses)
- Brief nausea (typically resolves quickly)
- Mild fatigue during loading phase (reflects repair process)
Rare:
- No serious adverse events dominant in published trials
The Barth syndrome trials — which included extended treatment over years — showed acceptable tolerability. The FDA approval reflects a positive benefit-risk assessment in a population with severe mitochondrial dysfunction.
Regulatory Status
FDA approved: Elamipretide (trade name Forzinity) received accelerated approval in 2025 for Barth syndrome. This is the first mitochondria-targeted drug approved in the US. A confirmatory post-marketing study is required under the accelerated-approval framework.
Other indications: For all non-Barth uses, elamipretide remains investigational. Access occurs through expanded-access programs and investigator-led protocols.
Why limited approvals: The constraint is economic — developing a specialized mitochondrial therapeutic across diverse chronic conditions is costly. The Barth syndrome approval reflects a focused strategy on a well-defined genetic population.
FAQ
What does SS-31 do?
SS-31 binds to cardiolipin on the inner mitochondrial membrane and restores structural integrity. This allows cleaner electron flow, more efficient ATP production, and reduced oxidative byproducts. It's structural repair, not stimulation.
How long does SS-31 take to work?
Effects begin rapidly — target engagement is measurable within hours. A loading phase of 5–10 days saturates membrane binding sites. Sustained benefits require intermittent maintenance dosing.
Is SS-31 FDA approved?
Yes, for Barth syndrome under the trade name Forzinity (September 2025). For all other uses, it remains investigational.
Can SS-31 help with aging?
Published data shows SS-31 improves ATP production in aging muscle and reduces markers of mitochondrial inefficiency. It's used intermittently — short repair phases spaced through the year — to restore alignment and maintain steadier daily output.
How is SS-31 different from MOTS-c?
SS-31 repairs mitochondrial structure (the hardware). MOTS-c activates adaptive signaling to build more mitochondria and improve fuel selection (the software). They're complementary — most effective when combined with NAD+ support.
What's the best dosing protocol for SS-31?
Start with a loading phase of 5–10mg daily for 5–10 days to saturate cardiolipin binding sites. Then maintain with 5–10mg 2–3 times per week. Morning dosing or 60–90 minutes before training works best. Unlike MOTS-c, SS-31 is structural repair—once binding sites are occupied, more doesn't help. Higher doses don't produce proportionally better effects.
How do I reconstitute and store SS-31?
Reconstitute with isotonic bacteriostatic water (containing 0.9% sodium chloride) to minimize injection site reactions. Plain BAC water works but may cause more sting. Store lyophilized powder refrigerated or frozen; once reconstituted, keep at 2–8°C and use within 4–6 weeks. Protect from light and temperature fluctuations.
Can I combine SS-31 with NAD+?
Yes, and they're synergistic. SS-31 repairs membrane structure so electrons flow cleanly, which reduces the NAD+ burn rate (less oxidative damage means less NAD+ spent on repair). Adding NAD+ support (IV or IM, not just oral) ensures the cofactor is available when the membrane can finally use it efficiently. This is the basis of the MOTS-c + SS-31 + NAD+ mitochondrial stack.
What side effects does SS-31 have?
Most people experience mild transient effects: brief warmth or flushing, occasional nausea that resolves quickly, and fatigue during the loading phase (especially if baseline mitochondrial function is poor). Serious adverse events are rare in published data. The long-term Barth syndrome trials showed acceptable tolerability over years of treatment.
How long should I run SS-31?
SS-31 works as a repair signal, not continuous therapy. Most practitioners recommend loading phases (5–10 days) followed by intermittent maintenance (2–3× weekly for 4–8 weeks), then breaks. Some use periodic "tune-up" cycles a few times per year rather than continuous dosing. The goal is restoring structure, not permanent saturation.
Where can I get SS-31?
For Barth syndrome, elamipretide (Forzinity) is now FDA-approved and available through specialty pharmacies. For other uses, it remains investigational and is available through research peptide suppliers, select compounding pharmacies, or expanded-access programs through clinicians. Quality varies significantly among research suppliers—look for third-party testing and certificates of analysis.
Related Topics
- MOTS-c Guide — exercise mimetic for metabolic adaptation
- NAD+ Guide — essential cofactor for mitochondrial function
- Mitochondrial Stack — SS-31 + MOTS-c + NAD+ combined
- Tesamorelin Guide — GH-axis support for energy and recomposition
- GLP-1 Comparison — metabolic interventions (SS-31 supports during rapid fat loss)
References
- Thompson WR, Hornby B, Manuel R, et al. A phase 2/3 randomized clinical trial of elamipretide in Barth syndrome. Genet Med 2021. https://www.nature.com/articles/s41436-020-01006-8
- Thompson WR, Manuel R, Batzner A, et al. TAZPOWER: 168-Week Open-Label Extension. Genet Med 2024. https://pubmed.ncbi.nlm.nih.gov/38602181/
- Karaa A, Haas R, Goldstein A, et al. MMPOWER-3: Primary Mitochondrial Myopathy. Neurology 2023. https://pubmed.ncbi.nlm.nih.gov/37268435/
- Siegel MP, Kruse SE, Percival JM, et al. In vivo mitochondrial ATP production is improved in older adult skeletal muscle after a single dose of elamipretide. PLoS ONE 2021. https://pmc.ncbi.nlm.nih.gov/articles/PMC8282018/
- Sabbah HN, Gupta RC, Kohli S, et al. Elamipretide improves mitochondrial function in the failing human heart. JACC Basic Transl Sci 2019. https://www.jacc.org/doi/10.1016/j.jacbts.2018.12.005
- Szeto HH, Liu S. Cardiolipin-targeted peptides rejuvenate mitochondrial function, remodel mitochondria, and promote tissue regeneration. Int J Mol Sci 2025. https://pmc.ncbi.nlm.nih.gov/articles/PMC11816484/
This content is for educational purposes only. Elamipretide (Forzinity) is FDA-approved for Barth syndrome. For all other uses, it remains investigational and is available through research suppliers, compounding pharmacies, or expanded-access programs. Work with a qualified healthcare provider before starting any peptide protocol.