Subject: SS-31: The Mitochondrial Peptide With Way More Uses Than People Realize
From: Derek from Research Radar <[email-masked]>
To: [email-masked]
Date: Wed, 6 May 2026 18:59:21 +0000
List-Id: <derekpruski.substack.com>

View this post on the web at https://derekpruski.substack.com/p/ss-31-the-mitochondrial-peptide-with

Research and educational purposes only. Nothing in this piece is medical advice. If you’re considering anything personally, that’s a conversation for a qualified clinician.
Most of the SS-31 conversation in the peptide world stops at one sentence: “it repairs mitochondria.” And that’s true — but it massively undersells what this peptide actually does and where it’s been studied.
When you start digging through the literature, SS-31 has clinical trial data in places you probably wouldn’t expect. Kidney disease. Macular degeneration. Heart failure. Barth syndrome. Glaucoma. Hearing loss. Diabetic complications. Some of the most interesting research isn’t about energy or aging in a generic sense — it’s about specific organ systems that people don’t usually associate with mitochondrial peptides.
This piece walks through what SS-31 is, hits the mitochondrial mechanism quickly so we have a foundation, and then spends most of the time on the applications nobody talks about.
What SS-31 Actually Is (The Quick Version)
SS-31 — also called elamipretide, MTP-131, and Bendavia in different research contexts — is a synthetic tetrapeptide. Four amino acids, no more. It was discovered by Dr. Hazel Szeto at Weill Cornell Medical College, hence the “SS” naming.
What makes it unique:
SS-31 doesn’t just float around the cell. It selectively concentrates inside the inner mitochondrial membrane at concentrations 1,000 to 5,000 times higher than the surrounding tissue.
That kind of targeting precision is rare for any compound, let alone a peptide.
Once it gets there, it binds to a phospholipid called cardiolipin — the structural backbone of the inner mitochondrial membrane. Cardiolipin is what holds the cristae (the folded inner structure of the mitochondria) in place, and it’s required for the electron transport chain to assemble properly. When cardiolipin gets damaged or oxidized, mitochondria literally fall apart from the inside.
SS-31 protects cardiolipin from peroxidation and stabilizes the membrane structure. Net result: mitochondria stop leaking, ATP production goes back up, ROS drops, and cells stop dying from energy failure.
That’s the headline mechanism. Now the stuff people don’t talk about enough.
The Kidney Story
This is one of the most underrated areas of SS-31 research, and it makes total sense once you understand the kidney’s biology.
Why kidneys are mitochondria-dependent. The kidney is one of the most metabolically demanding organs in the body. Specifically, the proximal tubules — the part of the nephron responsible for reabsorbing nutrients, electrolytes, and water back into the bloodstream — are packed with mitochondria. They have to be, because reabsorption is an active transport process that requires enormous amounts of ATP. When mitochondria fail in the kidney, the kidney fails.
What the research shows. SS-31 has been studied across nearly every category of kidney disease in research models — acute kidney injury, ischemia-reperfusion injury (the damage that happens when blood flow returns to a tissue after being cut off), diabetic nephropathy, polycystic kidney disease, atherosclerotic renal artery stenosis, and aging-related kidney decline.
The atherosclerotic renal artery stenosis trial. This one is worth pulling out specifically. In a Phase 2a clinical trial, patients undergoing stent revascularization for atherosclerotic renal artery stenosis received SS-31 infusions. The peptide was well tolerated with no serious adverse events. More importantly, the research showed measurable improvements in renal blood flow and oxygenation in the affected kidneys. This is real human data in a serious, late-stage kidney condition.
The mechanism in kidneys. SS-31 reduces tubular cell apoptosis (cells dying from energy failure), reduces fibrosis (scarring that progressively destroys kidney function), and preserves mitochondrial structure in the proximal tubules. In aging research, it’s been shown to reverse some age-related decline in kidney function in animal models.
For anyone interested in longevity from a “preserve organ function” angle, the kidneys are usually one of the first places to start failing in older populations. SS-31 might be one of the most direct mitochondrial tools available for that exact problem.
The Eye Story
This is the one almost nobody knows about, and it might be the most clinically advanced application of SS-31 in humans.
Why eyes are mitochondrial. The retina — specifically the photoreceptors and the retinal pigment epithelium (RPE) — has one of the highest mitochondrial densities of any tissue in the body. Vision is metabolically expensive. Every time a photon hits a photoreceptor, mitochondria have to fire to convert that signal into something the brain can read. As mitochondria age, the photoreceptors start dying, and you get age-related macular degeneration (AMD).
The ReCLAIM trials
SS-31 has been studied in a series of clinical trials for dry AMD with noncentral geographic atrophy — the early-to-intermediate form of the leading cause of irreversible blindness in people over 50. These trials are called ReCLAIM and ReCLAIM-2, and they’ve been running through Phase 1 and Phase 2.
Patients received subcutaneous SS-31 at 40 mg daily for 24 to 48 weeks. The trials demonstrated:
Good safety and tolerability
Positive effects on visual function, particularly under low-luminance conditions (one of the first things to go in early AMD)
Preservation of ellipsoid zone integrity (a marker of photoreceptor health on retinal imaging)
Currently in Phase 3
As of 2025, Stealth BioTherapeutics has Phase 3 trials running — ReNEW and ReGAIN — with 360 patients each, evaluating SS-31 specifically for dry AMD. This is genuinely advanced clinical development for a peptide.
Beyond AMD
Preclinical research has also shown effects on glaucoma (where retinal ganglion cells die from mitochondrial dysfunction in the optic nerve), diabetic retinopathy, and dry eye disease. The eye is mitochondria-dense, and SS-31 keeps showing up wherever mitochondria are the bottleneck.
If you have family history of macular degeneration or you’re already noticing low-light vision changes, this is an area of the literature worth understanding deeply.
The Heart Story (Beyond Generic “Cardioprotection”)
I’m including this because most people who hear “SS-31 helps the heart” assume it’s just generic cardioprotection. The actual research is more specific and more interesting.
Barth syndrome
This is a rare X-linked genetic disease where boys are born with a defect in the TAZ gene, which makes the enzyme responsible for properly maturing cardiolipin. Without functional cardiolipin, their mitochondria — especially in the heart — can’t form proper cristae structure. They develop severe cardiomyopathy and skeletal muscle weakness, often in infancy.
SS-31 was tested in Barth syndrome patients in the TAZPOWER trial and its open-label extension. Long-term treatment (48 weeks) showed significant improvements in:
6-minute walk test performance
Cardiac stroke volume
Barth Syndrome Symptom Assessment scores
SS-31 received orphan drug designation for Barth syndrome and is now FDA-approved as Forzinity — making it one of the very few peptides to make it through to actual approval.
HFpEF (heart failure with preserved ejection fraction)
This is the heart failure type that’s notoriously difficult to treat. SS-31 has been studied here too, with mixed results — improvements in mitochondrial bioenergetics measured at the molecular level, but the functional cardiac improvements haven’t always translated. The PROGRESS-HF trial is ongoing.
The honest take: SS-31 has the strongest cardiac evidence in genetic cardiolipin deficiency (Barth) and demonstrable mitochondrial heart disease. The general “I want to protect my heart” use case has weaker evidence than the specific “my mitochondria are failing in my heart muscle” use case. Important distinction.
The Neuroprotection Angle
The brain is mitochondria-heavy, and SS-31 crosses the blood-brain barrier — though brain concentrations are lower than what you see in kidney, heart, and skeletal muscle.
Alzheimer’s disease (preclinical). In AD mouse models, SS-31 has been shown to reduce amyloid-beta accumulation, protect synaptic function, reduce neuroinflammation, and preserve cognitive performance. The mechanism is what you’d expect — neurons in AD brains have failing mitochondria, and SS-31 stabilizes them before the cells die.
Parkinson’s disease (preclinical). Dopaminergic neurons are extremely mitochondria-dependent. SS-31 protected dopaminergic neurons in MPTP-induced PD models in mice and reduced motor deficits.
Stroke and TBI. After a stroke or traumatic brain injury, the brain accumulates oxidative stress that causes secondary damage. SS-31 has shown protection against this secondary injury phase in animal models.
Anesthesia-induced cognitive decline. There’s a specific area of research on post-operative cognitive dysfunction in older patients exposed to anesthesia like isoflurane. SS-31 prevented the cognitive deficits in aged mice and preserved hippocampal mitochondrial function. Niche, but interesting if you know anyone facing major surgery in older age.
Important caveat: almost all CNS data is preclinical. There’s no completed Phase 2 or Phase 3 SS-31 trial in Alzheimer’s or Parkinson’s specifically, and the brain concentrations achieved with subcutaneous dosing are lower than other tissues. Use this section as a “promising direction” rather than “established outcome.”
The Less-Discussed Applications
A quick rundown of areas where SS-31 has preclinical research that almost never gets talked about:
Hearing loss. SS-31 has been studied for noise-induced and age-related hearing loss. Hair cells in the cochlea are mitochondria-rich and die from oxidative damage. SS-31 protected them in animal models of noise exposure.
Diabetic complications. Beyond diabetic nephropathy and retinopathy mentioned above, SS-31 has been studied in diabetic cardiomyopathy and peripheral nerve damage. The common thread: high glucose damages mitochondria across multiple tissues, and SS-31 protects them.
Osteoarthritis. Cartilage cells (chondrocytes) have failing mitochondria in OA, and SS-31 has shown chondroprotective effects in animal models.
Skin aging. Some early research on SS-31 and skin elasticity, photoaging protection, and wound healing — though most of this is in vitro or in animal models, not human trials.
Skeletal muscle aging (sarcopenia). In aged mice, SS-31 restored ATP production in skeletal muscle within roughly an hour of administration, improved exercise tolerance, and increased muscle mass over longer treatment periods. The MOTS-c-style use case overlaps here, but SS-31 works on a different mechanism (membrane stabilization vs. metabolic signaling).
Sepsis and ischemia-reperfusion injury. In critical care research models, SS-31 has shown protection against multi-organ failure driven by mitochondrial collapse.
The Honest Take on SS-31
A few things that don’t get said enough.
It’s one of the only peptides with serious human clinical trial data. Most peptides we talk about have preclinical research and anecdotal protocols. SS-31 has Phase 2 and Phase 3 trials across multiple indications, FDA approval in Barth syndrome (as Forzinity), and a pharmaceutical company (Stealth BioTherapeutics) running a full development pipeline behind it.
Not every trial has been a win. The MMPOWER-3 trial in primary mitochondrial myopathy missed its primary endpoint of 6-minute walk test improvement, though patients reported less fatigue. Some HFpEF and HFrEF trials have shown molecular improvements without translating to functional cardiac changes. The compound isn’t a cure-all, and the literature reflects that honestly.
It works best where mitochondria are the bottleneck. SS-31 is a precision tool, not a generic “feel better” peptide. In conditions where mitochondrial dysfunction is genuinely the upstream driver — Barth syndrome, certain kidney injuries, dry AMD, mitochondrial disease — the effects are real. In conditions where mitochondria are downstream of bigger problems, SS-31 can support but won’t reverse the underlying issue.
It pairs with — not replaces — other mitochondrial tools. Urolithin A drives mitophagy (clearing damaged mitochondria). MOTS-c drives metabolic signaling and AMPK activation. SS-31 stabilizes the structural membrane of existing mitochondria. These are three different mechanisms operating on three different layers of the same system. They’re complementary, not competitive.
What the Research Dosing Looks Like
Across the major clinical trials, the standard research dose has been 40 mg subcutaneously once daily. That’s the dose used in the Barth syndrome trials, the dry AMD ReCLAIM and ReCLAIM-2 trials, and the heart failure trials.
Treatment duration in the literature ranges from 4 weeks (cardiac trials) to 48 weeks or longer (Barth syndrome, AMD). Effects on mitochondrial function in tissues like skeletal muscle have been observed within hours, but structural and functional benefits in conditions like AMD, Barth, and kidney disease typically take months of continuous dosing.
Half-life is short — about 2 to 4 hours in plasma — but tissue accumulation is what matters because of the cardiolipin binding affinity. Oral bioavailability is poor; subcutaneous is the standard research route.
Final Thoughts
SS-31 is one of the few peptides where the breadth of the research actually matches the hype around it. The mitochondrial repair story is real, but the more interesting story is the specific organ systems where it’s been studied at depth — kidneys, eyes, hearts with genetic mitochondrial disease.
If aging is a story about energy failure cascading through one tissue at a time, SS-31 is a tool that addresses the structural integrity of the energy production system itself. Not the inputs (NAD+, CoQ10), not the cleanup (mitophagy via UA), but the actual physical membrane where ATP gets made.
That’s a different layer of the cellular machinery than most other longevity tools. And that’s why it deserves to be understood for more than just “it helps mitochondria.”
This is for research and educational purposes only. Nothing in this piece is medical advice, and this isn’t a recommendation to use SS-31 personally. If you’re interested in the topic for any non-research reason, that’s a conversation for a qualified medical professional who knows your situation.
If this was useful, share it with someone who’s been chasing the longevity rabbit hole and only knows SS-31 as “the mitochondria one” — and let me know in the comments what underrated compound you’d like me to break down next.
— Derek
References
Foundational mechanism
Szeto HH. First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergetics. Br J Pharmacol. 2014;171(8):2029-2050.
Zhao W, Xu Z, Cao J, et al. Mitochondrial protein interaction landscape of SS-31. Proc Natl Acad Sci USA. 2020;117(36):22247-22255.
Kidney disease comprehensive review
Wang Z, Chen Z, Li B, et al. SS-31, a Mitochondria-Targeting Peptide, Ameliorates Kidney Disease. Oxidative Medicine and Cellular Longevity. 2022. Full text [ https://substack.com/redirect/1fe740c9-560b-44d2-a2bb-0adb620fe3e4?j=eyJ1IjoiNGl3b2U2In0.sVDxRtmZ85v8kfdamY0krRXGMy3p768BWtuZifRB-Zs ]
Atherosclerotic renal artery stenosis trial
Saad A, et al. Phase 2a Clinical Trial of Mitochondrial Protection (Elamipretide) During Stent Revascularization in Patients With Atherosclerotic Renal Artery Stenosis. Circ Cardiovasc Interv. 2017;10(9):e005487.
Dry AMD Phase 1 trial (ReCLAIM)
Mettu PS, Allingham MJ, Cousins SW. Phase 1 Clinical Trial of Elamipretide in Dry Age-Related Macular Degeneration and Noncentral Geographic Atrophy: ReCLAIM NCGA Study. Ophthalmol Sci. 2022;2(1):100086. Full text [ https://substack.com/redirect/35da6e17-5c61-4644-8fcd-253165dbdf5f?j=eyJ1IjoiNGl3b2U2In0.sVDxRtmZ85v8kfdamY0krRXGMy3p768BWtuZifRB-Zs ]
Dry AMD Phase 2 trial (ReCLAIM-2)
ReCLAIM-2: A Randomized Phase II Clinical Trial Evaluating Elamipretide in Age-related Macular Degeneration, Geographic Atrophy Growth, Visual Function, and Ellipsoid Zone Preservation. Ophthalmology Science. 2024. Full text [ https://substack.com/redirect/e00344cb-3f97-4bad-b525-a0e6ae973f1f?j=eyJ1IjoiNGl3b2U2In0.sVDxRtmZ85v8kfdamY0krRXGMy3p768BWtuZifRB-Zs ]
Barth syndrome trial (TAZPOWER)
Reid Thompson W, et al. A phase 2/3 randomized clinical trial followed by an open-label extension to evaluate the effectiveness of elamipretide in Barth syndrome. Genet Med. 2021;23(3):471-478.
Comprehensive 2025 review
Elamipretide: A Review of Its Structure, Mechanism of Action, and Therapeutic Potential. Int J Mol Sci. 2025;26(3):944. Full text [ https://substack.com/redirect/af9fa280-8b39-4b6c-b481-0b5be1767f23?j=eyJ1IjoiNGl3b2U2In0.sVDxRtmZ85v8kfdamY0krRXGMy3p768BWtuZifRB-Zs ]
Neuroprotection review
Neuroprotective Effects of a Small Mitochondrially-Targeted Tetrapeptide Elamipretide in Neurodegeneration. Front Integr Neurosci. 2021;15:747901. Full text [ https://substack.com/redirect/b5dbd811-3f64-4b52-9c6c-c088c0c3f253?j=eyJ1IjoiNGl3b2U2In0.sVDxRtmZ85v8kfdamY0krRXGMy3p768BWtuZifRB-Zs ]
Aging skeletal muscle
Campbell MD, Marcinek DJ, et al. Improving mitochondrial function with SS-31 reverses age-related redox stress and improves exercise tolerance in aged mice. Free Radic Biol Med. 2019.
Alzheimer’s disease (preclinical)
Reddy PH, Manczak M, Kandimalla R. Mitochondria-targeted small molecule SS31: a potential candidate for the treatment of Alzheimer’s disease. Hum Mol Genet. 2017;26(8):1483-1496.
Independent assessment
Alzheimer’s Drug Discovery Foundation Cognitive Vitality Report — SS-31 [ https://substack.com/redirect/6a12e434-a54a-4ab4-945b-963a3be38b6d?j=eyJ1IjoiNGl3b2U2In0.sVDxRtmZ85v8kfdamY0krRXGMy3p768BWtuZifRB-Zs ]

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