Skip to main content

SS-31

Fixing the Body's Energy & Metabolic Machinery

Overview

Energy has a structure. We rarely talk about it that way, but the body produces energy through physical machinery—tightly organized membranes and protein complexes that convert fuel into usable power. When that machinery is young, energy is clean and predictable.

As it loosens with age, inflammation, stress, or illness, the same routines begin to feel heavier. Sleep becomes less restorative, recovery slows, and daily energy becomes more sensitive to disruptions such as dietary changes, infections, or prolonged exertion. Effort produces more strain and less usable output.

SS-31 is compelling because it targets this structural layer directly. It binds to cardiolipin—the lipid that holds the inner mitochondrial membrane together—and restores the tightness that efficient energy production depends on. When that structure is repaired, electron flow becomes cleaner, fewer byproducts accumulate, and the system generates more usable energy from the same signals.

This is not stimulation. It is structural repair. The difference matters. SS-31 does not push the system harder—it restores the hardware so normal physiology works the way it used to.

Mechanism of Action

SS-31 binds to cardiolipin at the inner mitochondrial membrane and restores the structural tension required for efficient electron transfer. Once this alignment is recovered:

  • Electron leak falls: Respiratory complexes remain in closer proximity, reducing byproducts and improving ATP yield.
  • Membrane potential stabilizes: A tighter membrane holds the electrochemical gradient more consistently, supporting sustained output in high-demand tissues.
  • Mitochondrial turnover improves: Lower oxidative strain reduces pressure on repair pathways, allowing mitochondria to function longer before replacement.
  • Tissue efficiency rises: With cleaner electron flow, cells meet metabolic demand with less strain, which is why effort feels smoother instead of heavier.

These are structural shifts—not signaling shifts—and they explain why the effects of SS-31 are subtle but meaningful: the machinery works better, so the system works better.

The Breakdown of Mitochondria

The mitochondrial membrane does not fail all at once. It loosens gradually as life applies pressure to it. The forces that erode its structure are the same forces most people encounter for decades—small enough to ignore in the moment, cumulative enough to matter over time.

Major contributors include:

  • Chronic inflammation: Immune activity from stress, injury, allergies, or low-grade infection increases oxidative pressure on the membrane
  • Illness and infection: Fevers and acute immune responses create metabolic load that leaves lasting marks on cardiolipin structure
  • Alcohol: Even moderate intake increases mitochondrial workload and generates byproducts that weaken membrane architecture over repeated exposures
  • Poor metabolic health: Insulin resistance, glucose swings, and impaired fat oxidation all force mitochondria to run harder on a weakened scaffold
  • Environmental stressors: Pollution, heat, and toxins increase the energetic cost of maintaining homeostasis
  • Sleep disruption: Deep sleep is when mitochondrial repair programs run; shorter or fragmented sleep leaves restoration incomplete
  • Prolonged psychological stress: Stress hormones increase mitochondrial demand and suppress nightly repair cycles

These forces compound slowly. The result is the familiar energetic phenotype of aging: less restorative sleep, slower recovery, effort that feels costlier than it should, and energy that becomes more sensitive to illness, disruption, or changes in routine.

SS-31 targets the structural layer where these pressures accumulate. It restores the membrane tension that aging and metabolic stress gradually erode.

System Behavior

When the mitochondrial membrane is restored, the system behaves more predictably under load. Energy no longer swings sharply with minor stressors. Physical effort produces proportionate fatigue instead of delayed crashes. Mental stamina holds longer before dropping off. Recovery windows shorten because tissues can generate ATP cleanly rather than working against structural resistance.

Daily variability narrows. A poor night of sleep, a missed meal, or mild illness still registers, but the impact is smaller because the underlying machinery does not destabilize as easily. The system regains margin: more output for the same input, fewer penalties for routine disruptions.

Effort becomes smoother not because the system is stimulated, but because the machinery is no longer leaking energy as it works.

Who Benefits

People notice SS-31 when their energy has become harder to stabilize—slower recovery, disproportionate fatigue after mild exertion, or a sense that daily routines cost more than they should. These patterns reflect structural mitochondrial drift.

Aging adults.
Membrane tension declines with age, making energy less predictable and recovery slower. SS-31 is used intermittently—short repair phases spaced through the year—to restore alignment and maintain steadier daily output.

GLP-1 and tri-agonist users.
Rapid fat oxidation increases mitochondrial workload. SS-31 supports the hardware during high oxidative flux.

Low-energy phenotypes.
Chronic fatigue, post-exertional malaise, and energy fragility often stem from unstable mitochondrial structure. SS-31 is used during periods when these symptoms intensify, then tapered once stability returns.

Post-viral or post-illness recovery.
Immune activation and inflammation stress mitochondrial membranes. SS-31 is used through the recovery window to re-establish clean energy production.

High physical demand individuals.
Athletes, shift workers, and people under sustained cognitive or physical load accumulate mitochondrial strain faster. SS-31 is used around heavy training blocks or intense work cycles.

Injury recovery and rehabilitation.
Healing requires sustained ATP production. SS-31 supports mitochondrial efficiency in recovering tissues.

Hormonal transition (peri-menopause, andropause).
Inflammation, sleep disruption, and metabolic instability increase sharply during transition phases. SS-31 helps stabilize energy by reinforcing membrane structure under increased strain.

Across these contexts, the principle is the same: SS-31 is used when life loads the mitochondrial membrane beyond its ability to maintain structure.

NAD⁺ & MOTS-c Synergies

NAD⁺ Conservation Through Structural Repair

SS-31 reduces the cellular demand for NAD⁺ by lowering the processes that consume it most aggressively. Cleaner electron transfer produces fewer oxidative byproducts, which reduces PARP activation and the NAD⁺ cost of DNA repair. Stabilizing the membrane also quiets the inflammatory signaling that drives CD38 expression, slowing NAD⁺ degradation. The result is a system that not only produces energy more efficiently but spends less NAD⁺ in the process.

MOTS-c Synergy

Mitochondrial performance depends on structure, signaling, and cofactor supply. SS-31 restores the membrane structure that efficient electron transfer requires. MOTS-c activates the adaptive program that increases mitochondrial number and improves fuel handling. Combined, the system gains both more engines (MOTS-c) and better-engineered engines (SS-31), producing cleaner, more stable energy under load.

The Mitochondrial Stack

NAD⁺ provides the redox currency mitochondria need to operate. MOTS-c expands oxidative capacity and improves fuel selection. SS-31 restores the structural layer that determines how efficiently that capacity can be used. Together, they address the three constraints that govern energy stability: how well mitochondria are built, how well they adapt, and whether they have the resources to execute.

These interventions repair the hardware, improve the adaptive software, and supply the cofactor reserve that mitochondrial performance depends on.

Clinical Research & Human Studies

Human trials have focused on diseases where mitochondrial structure is most impaired. In Barth syndrome, a genetic disorder defined by defective cardiolipin remodeling, SS-31 (elamipretide) showed improvements in functional capacity and cardiac performance over months to years of treatment. These findings contributed to its 2025 accelerated approval as Forzinity—the first mitochondria-targeted therapeutic authorized in the United States.

In primary mitochondrial myopathy, SS-31 did not meet the primary endpoint in the MMPOWER-3 trial but showed consistent directional benefits across secondary measures, including patient-reported fatigue and functional parameters. Studies in older adults demonstrated acute increases in skeletal-muscle ATP production following a single IV dose, confirming target engagement in aging tissue.

Ophthalmology programs explored SS-31 in dry AMD and LHON, reflecting the peptide's relevance to tissues with high energetic demand. Results were mixed overall but suggested benefit in specific subgroups. Expanded-access reports across rare mitochondrial diseases, including CPEO-plus, MPAN, and severe pediatric presentations, describe symptomatic improvement or stabilization when conventional options were limited.

Across studies, the mechanistic signal has been consistent: SS-31 reaches its mitochondrial target, stabilizes the membrane, reduces byproduct formation, and improves efficiency in tissues under energetic strain. Functional outcomes vary by indication, but the structural effects are reproducibly observed.

Dosing

SS-31 behaves as a structural repair signal rather than a continuous therapy. Typical practice uses:

  • Loading: 5–10 mg daily for 5–10 days
  • Maintenance: 5–10 mg, 2–3× per week
  • Timing: Morning or 60–90 minutes before training
  • Cycle: Intermittent use, aligned with stressors rather than fixed schedules

SS-31 binds cardiolipin with high affinity, so membrane saturation—not blood levels—determines effect. This is why SS-31 is used intermittently rather than continuously.

Tolerability is high. Transient warmth, brief nausea, or mild fatigue may occur early and typically resolve quickly.

Discovery

SS-31 emerged from work on cardiolipin—the structural lipid that anchors the respiratory chain and preserves the tight curvature of the inner mitochondrial membrane. Researchers observed that when cardiolipin is damaged or loses its binding integrity, electron transfer becomes inefficient and mitochondrial output collapses long before the organelle itself fails. Restoring cardiolipin structure became a mechanistic target for conditions marked by fragile energy: cardiomyopathies, mitochondrial myopathies, and age-related decline.

The peptide was designed to localize directly to the inner membrane and stabilize cardiolipin without altering upstream signaling. Early work demonstrated that SS-31 could restore cristae structure, reduce electron leak, and improve coupling efficiency between oxygen consumption and ATP production. These findings guided its progression into human studies.

Regulatory Status

Elamipretide (SS-31) achieved FDA accelerated approval in 2025 under the trade name Forzinity for Barth syndrome, the first mitochondria-targeted therapeutic approved in the United States. A confirmatory post-marketing study is ongoing as part of the accelerated-approval framework. The compound also holds orphan-drug and rare pediatric disease designations.

For all non-Barth indications, elamipretide remains investigational. This reflects economic constraints around developing a specialized mitochondrial therapeutic across diverse chronic conditions, not a safety limitation. Access for other mitochondrial diseases occurs through expanded-access programs and investigator-led protocols.

References

Human Studies

  • Barth Syndrome – TAZPOWER Phase 2/3 + Extension (Genet Med, 2021–2024)
    Multi-year improvements in 6-minute walk distance and cardiac biomarkers; basis for accelerated approval.

  • Primary Mitochondrial Myopathy – MMPOWER-3 (Neurology, 2023)
    Primary endpoint not met; secondary outcomes showed directional benefit in fatigue and patient-reported function.

  • Older Adults – ATPmax Study (PLoS ONE, 2021)
    A single IV dose increased in vivo skeletal-muscle ATP production, confirming target engagement in aging muscle.

  • Dry AMD – ReCLAIM-2 (Ophthalmology Science, 2024)
    Mixed results overall with functional signal in predefined subgroups.

  • Failing Human Heart Tissue – JACC Basic Transl Sci (2019)
    Ex vivo human myocardium exposed to SS-31 showed improved mitochondrial respiration, supporting translational relevance.