SS-31 (Elamipretide): Mitochondrial Peptide

Every cell in your body depends on mitochondria to produce energy. When these organelles fail — because of genetic disease, aging, or injury — the consequences ripple outward: muscles weaken, hearts struggle to pump, neurons degenerate, and vision fades. For decades, scientists had no way to directly fix a broken mitochondrion. They could target the symptoms, but not the source.

SS-31 changed that equation. Discovered by accident in a pharmacology lab at Weill Cornell Medicine, this four-amino-acid peptide passes through cell membranes and concentrates in the inner mitochondrial membrane, where it binds a lipid called cardiolipin. That interaction stabilizes the machinery that produces ATP — the molecule cells use as fuel — while reducing the harmful byproducts of energy production.

After 20 years of research, more than 150 peer-reviewed publications, and multiple clinical trials, SS-31 reached a milestone in September 2025: the FDA granted accelerated approval to elamipretide (the pharmaceutical name for SS-31) under the brand name Forzinity. It became the first mitochondria-targeted therapy ever approved. The indication was narrow — improving muscle strength in Barth syndrome — but the drug's broader potential in eye disease, mitochondrial myopathy, and aging continues to drive active Phase 3 programs.

Quick Facts
What Is SS-31 (Elamipretide)?
Development History
How SS-31 Works: Mechanisms of Action
Clinical Research
Preclinical Research
Administration and Dosing
Safety Profile and Side Effects
Legal and Regulatory Status
Limitations and Setbacks
Frequently Asked Questions
The Bottom Line

Quick Facts

Property	Details
Full name	Elamipretide (formerly SS-31, MTP-131, Bendavia)
Brand name	Forzinity
Type	Synthetic tetrapeptide
Sequence	D-Arg-Dmt-Lys-Phe-NH₂ (Dmt = 2',6'-dimethyltyrosine)
Molecular weight	~640 Da
Developer	Hazel Szeto, M.D., Ph.D. (Weill Cornell Medicine); commercialized by Stealth BioTherapeutics
Primary mechanism	Binds cardiolipin on the inner mitochondrial membrane; stabilizes electron transport chain and cristae structure
Other reported effects	Reduces reactive oxygen species (ROS), improves ATP synthesis, protects mitochondrial membrane potential
FDA status	Accelerated approval (September 2025) for Barth syndrome; investigational for all other indications
Active clinical programs	Dry age-related macular degeneration (Phase 3), primary mitochondrial disease from nuclear DNA mutations (Phase 3)

What Is SS-31 (Elamipretide)?

SS-31 is a synthetic tetrapeptide — a chain of just four amino acids — designed to penetrate cells and accumulate inside mitochondria. Its sequence contains two positively charged residues (D-arginine and lysine) and two aromatic residues (dimethyltyrosine and phenylalanine). The positive charges attract it to the negatively charged inner mitochondrial membrane, while the aromatic rings make it lipophilic enough to cross cell membranes without a special delivery system.

Once inside the cell, SS-31 concentrates in mitochondria at levels roughly 1,000-fold higher than in the surrounding cytoplasm. It embeds in the inner membrane and binds directly to cardiolipin — a phospholipid found almost exclusively in mitochondria that the electron transport chain requires to function properly.

The peptide is water-soluble, easy to synthesize, and stable enough for subcutaneous injection. Unlike some mitochondria-targeted compounds (such as MitoQ and SkQ1), SS-31 does not depend on mitochondrial membrane potential for uptake, meaning it can still reach damaged mitochondria that have partially lost their charge gradient. It also has virtually no opioid receptor activity — an intentional design choice, since the original peptide series included mu-opioid receptor agonists.

Development History

SS-31's story begins with a mistake — the good kind.

In the early 2000s, pharmacologist Hazel Szeto and peptide chemist Peter Schiller at the Montreal Clinical Research Institute were designing synthetic opioid peptides to study pain signaling. One compound behaved strangely: despite being water-soluble and highly polar, it showed potent central nervous system activity after subcutaneous injection in rodents.

"I had one compound that did not behave like I thought it would," Szeto later recalled. "It bothered me, so rather than tossing it aside, I started looking into it."

She found that the peptide was entering cells and concentrating inside mitochondria. The pair developed a family of compounds — the Szeto-Schiller (SS) peptides — and through roughly 30 iterations eliminated the opioid activity while retaining mitochondrial targeting. SS-31 reduced opioid receptor affinity by 2,000-fold compared to the original lead compound.

In 2006, Szeto founded Stealth Peptides (later Stealth BioTherapeutics) to bring the compound to clinical development. Over the next decade, elamipretide accumulated FDA designations: Orphan Drug (2018), Fast Track, and Rare Pediatric Disease (2020) for Barth syndrome.

The path to approval was rough. Stealth submitted its first NDA for Barth syndrome in August 2021; the FDA refused to file it. A second submission in January 2024 gained priority review, but the FDA issued a complete response letter in May 2025 — essentially a rejection — while suggesting accelerated approval based on muscle strength as an intermediate endpoint. Stealth resubmitted in July 2025 and received accelerated approval on September 19, 2025. Forzinity became the first FDA-approved mitochondria-targeted drug and the first compound discovered at Weill Cornell Medicine to reach market.

How SS-31 Works: Mechanisms of Action

The Cardiolipin Connection

The central target of SS-31 is cardiolipin, an unusual phospholipid with two phosphate head groups and four fatty acid tails. Cardiolipin makes up about 20% of the inner mitochondrial membrane's lipid content and is found almost nowhere else in the cell. It stabilizes the curved folds (cristae) of the inner membrane, anchors electron transport chain complexes, and helps organize them into supercomplexes — tightly packed clusters that improve electron transfer efficiency.

When cardiolipin is damaged — by oxidation, by mutations (as in Barth syndrome), or by aging — cristae flatten, supercomplexes fall apart, and the electron transport chain leaks electrons that react with oxygen to form reactive oxygen species (ROS). ROS then damage more cardiolipin, creating a vicious cycle. SS-31 binds electrostatically to cardiolipin's phosphate groups, stabilizing cristae curvature and supercomplex organization.

Beyond Antioxidant Activity

Early research described SS-31 as a mitochondrial antioxidant. But the past decade has shown that direct radical scavenging is probably not its main mechanism. Instead, SS-31 reduces ROS at the source by improving electron transport chain efficiency. It also prevents cytochrome c — normally an electron shuttle — from switching into a destructive peroxidase form when cardiolipin is oxidized.

A 2020 PNAS study mapped SS-31's protein interaction partners. All were known cardiolipin-binding proteins involved in ATP production or 2-oxoglutarate metabolism. This supports the model that SS-31 works through the lipid membrane rather than any single protein target — which explains why it shows effects across so many disease models.

Clinical Research

Barth Syndrome: The Path to Approval

Barth syndrome is an X-linked genetic disorder caused by tafazzin gene mutations that produce structurally abnormal cardiolipin. The disease leads to muscle weakness, cardiomyopathy, immune deficiency, and exercise intolerance. About 150 people in the US have the condition.

The TAZPOWER trial randomized 12 patients to elamipretide 40 mg daily or placebo. The double-blind phase did not reach statistical significance on its primary endpoints (6-minute walk test and fatigue scores). But the 168-week open-label extension showed sustained improvements in knee extensor muscle strength (median increase of 63 newtons), walk distance, cardiac function, and fatigue in the 8 patients who completed it. The FDA's accelerated approval was based on muscle strength as an intermediate endpoint.

Heart Failure: PROGRESS-HF and EMBRACE-STEMI

PROGRESS-HF randomized 71 patients with heart failure with reduced ejection fraction to placebo, 4 mg, or 40 mg elamipretide daily for 28 days. The primary endpoint (change in left ventricular end-systolic volume by cardiac MRI) was not met at either dose. The EMBRACE-STEMI trial of IV elamipretide in acute heart attack patients also failed its primary endpoint of reduced infarct size, though it showed a transient reduction in new heart failure within 24 hours. One likely explanation for both failures is treatment duration — animal studies showing cardiac improvement used 8-12 weeks, not 28 days.

The retina is packed with mitochondria, and mitochondrial dysfunction in photoreceptors contributes to geographic atrophy — the irreversible vision loss in dry AMD. The ReCLAIM Phase 1 studies showed improved visual acuity (especially in low-light conditions) after 24 weeks of daily elamipretide in patients with intermediate AMD.

The ReCLAIM-2 Phase 2 trial (176 patients, 48 weeks) missed its primary visual acuity and geographic atrophy endpoints. But elamipretide reduced progressive loss of the ellipsoid zone (EZ) — the mitochondria-rich photoreceptor layer — by 43-47% versus placebo. This finding led the FDA to accept EZ preservation as the primary endpoint for Phase 3.

Two Phase 3 trials are underway: ReNEW (360 patients, 96 weeks) reached 50% enrollment by March 2025, with data expected in 2026. A second trial, ReGAIN, is planned alongside it.

Primary Mitochondrial Myopathy: MMPOWER Trials

The MMPOWER-3 Phase 3 trial (218 patients, 24 weeks) failed its primary endpoints in a genetically diverse population. But a post hoc analysis found that patients with nuclear DNA mutations (especially those affecting the mitochondrial replisome) responded well (25.2 meters improvement vs. 2.0 for placebo), while patients with primary mitochondrial DNA mutations did not. The explanation: elamipretide stabilizes normal electron transport chain proteins in a compromised membrane, but it cannot repair structurally broken proteins encoded by mutant mtDNA.

This led to the NuPOWER trial (NCT05162768), a Phase 3 study targeting nuclear DNA mutation patients. Approximately 130 subjects are enrolled and results are pending.

Preclinical Research

Aging

In a 2020 eLife study, 8 weeks of SS-31 substantially reversed diastolic dysfunction in 24-month-old mice (roughly 70 in human years). The treatment normalized proton leak, reduced ROS, and reversed oxidative modifications on cardiac proteins including titin. In skeletal muscle, the same treatment reversed age-related decline in ATP production and improved treadmill endurance. A long-term study (10 months of treatment starting at 18 months of age) showed improved physical performance in males and improved cognitive performance in females.

A consistent finding: SS-31 only helps dysfunctional tissue. Young mice showed no improvement. A 2025 study confirmed the peptide improves function without changing epigenetic or transcriptomic markers of aging.

Kidney Disease and Neurodegeneration

In diabetic nephropathy models, SS-31 protected kidney cell mitochondria and reduced fibrosis. In renal ischemia-reperfusion models, it accelerated ATP recovery. In Alzheimer's and Parkinson's disease mouse models, SS-31 protected neurons from mitochondrial dysfunction and oxidative damage, though brain concentrations remain low compared to plasma.

Administration and Dosing

Forzinity is administered as a subcutaneous injection — 40 mg once daily for Barth syndrome patients weighing at least 30 kg. It is supplied as 280 mg/3.5 mL solution (80 mg/mL) in single-use vials. The NuPOWER trial uses a higher dose (60 mg daily), suggesting dose optimization is ongoing.

In clinical trials, elamipretide has also been given intravenously at 0.01 to 0.25 mg/kg/h over 2-4 hours. For severe renal impairment (eGFR below 30 mL/min), the dose is halved. Injection site rotation is recommended.

Safety Profile and Side Effects

Across multiple trials involving hundreds of patients, elamipretide has shown a favorable safety profile. Injection site reactions are the most common side effect — pain, redness, swelling, itching, and bruising. In ReCLAIM-2, 60% of elamipretide patients experienced them versus 27% on placebo. The mechanism: elamipretide activates MRGPRX2 receptors on skin mast cells. A Phase 1 study found that topical mometasone before injection reduces reactions without affecting absorption.

Other reported side effects (mild to moderate): headache, dizziness, abdominal pain, and flatulence. No treatment-related serious adverse events led to discontinuation in the 168-week TAZPOWER extension. No deaths in any trial have been attributed to the drug.

Legal and Regulatory Status

Elamipretide received FDA accelerated approval on September 19, 2025, under the brand name Forzinity — for Barth syndrome only. It is not a DEA-scheduled controlled substance. The drug holds Orphan Drug, Fast Track, Rare Pediatric Disease, and Priority Review designations. In the EU, it has Orphan Drug Designation but is not yet approved.

Products marketed as "SS-31" for "research use only" are not pharmaceutical-grade and are not legal for human use. Forzinity became commercially available through AnovoRx Specialty Pharmacy in December 2025.

Limitations and Setbacks

An honest accounting of elamipretide's development record:

Failed primary endpoints are the pattern. PROGRESS-HF failed in heart failure. EMBRACE-STEMI failed in heart attack. MMPOWER-3 failed in mitochondrial myopathy. ReCLAIM-2 failed its visual acuity endpoint. The Barth syndrome NDA was rejected twice before approval came via a secondary endpoint.

Small patient populations limit statistical power. TAZPOWER had 12 patients. Barth syndrome affects about 150 Americans. With samples this small, the line between signal and noise gets blurry.

The right-patient problem. Elamipretide works best when electron transport chain proteins are intact but their membrane environment is compromised. When the ETC proteins themselves are broken (primary mtDNA mutations), membrane stabilization doesn't help. This makes patient selection a genuine challenge.

The translation gap. Preclinical aging data in mice is remarkable but untested in humans. There are no clinical trials of elamipretide for "aging" as an indication, and the FDA does not currently recognize aging as a disease.

Frequently Asked Questions

Is SS-31 the same thing as elamipretide?

Yes. SS-31 was the laboratory name (the 31st Szeto-Schiller peptide). It was renamed MTP-131 and then elamipretide for clinical development. The brand name is Forzinity.

Can SS-31 reverse aging?

In mice, SS-31 has reversed age-related declines in heart function, muscle endurance, and mitochondrial efficiency. But no human trials have tested it for aging, and the drug does not change epigenetic markers of biological age — it improves function without rewinding molecular clocks.

How does SS-31 compare to Humanin and MOTS-c?

They work differently. Humanin and MOTS-c are mitochondrial-derived peptides — encoded by mitochondrial DNA and released as signaling molecules. SS-31 is a synthetic peptide that physically targets the inner mitochondrial membrane. Think of Humanin and MOTS-c as messengers and SS-31 as a structural repair agent.

Is SS-31 available as a "research peptide"?

Some vendors sell products labeled SS-31 for "research use only." These are not pharmaceutical-grade, not FDA-approved, and their purity is unverified. The approved formulation (Forzinity) is available only by prescription for Barth syndrome.

Does SS-31 have opioid effects?

No. Its mu-opioid receptor affinity is roughly 2,000-fold lower than the original Szeto-Schiller lead compound. At therapeutic doses, it has no meaningful opioid activity.

What else is Stealth BioTherapeutics developing?

Beyond ongoing elamipretide trials, Stealth is developing bevemipretide (SBT-272) — a second-generation cardiolipin-targeting compound formulated as a topical eye drop for dry AMD and a subcutaneous injection for neurological conditions. Earlier-stage compounds include SBT-255 (cardiac/muscular myopathies) and the SBT-580 series.

The Bottom Line

SS-31 is the first drug ever approved that directly targets mitochondrial membranes. That matters — not because of what it treats today (a rare disease affecting about 150 Americans), but because of what it proves: you can design a small molecule to reach a specific organelle and restore its core machinery.

The clinical record is mixed. Most of elamipretide's major trials failed their primary endpoints. The drug works best in a specific biological context — compromised membrane environment with intact electron transport chain proteins — which makes broad application difficult. But the preclinical aging data is hard to ignore, and the ongoing Phase 3 trials in AMD and mitochondrial myopathy could expand the drug's reach.

For readers exploring mitochondrial health and longevity science, SS-31 fits alongside other peptides like Humanin, MOTS-c, Epitalon, and GHK-Cu. Our guides on peptides for mitochondrial health, best peptides for anti-aging and longevity, and best peptides for cardiovascular health cover the broader picture.

The science of mitochondrial medicine is still young. SS-31 is its first graduate.

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