SS-31 vs Glutathione
SS-31, marketed under the names elamipretide and MTP-131, is a synthetic tetrapeptide that binds cardiolipin in the inner mitochondrial membrane and stabilises cristae architecture; in September 2025 it received FDA accelerated approval for Barth syndrome. Glutathione is the endogenous tripeptide that serves as the principal intracellular thiol antioxidant and redox buffer, studied in humans as an oral, liposomal, topical and intravenous preparation and through precursor strategies such as glycine plus N-acetylcysteine. No published study has administered both to the same subjects. The relationship in the literature runs in one direction instead: glutathione redox status is one of the standard readouts used to demonstrate that SS-31 has done something. Repeated animal and cell studies gave SS-31 and then measured the ratio of reduced to oxidised glutathione, glutathione content or S-glutathionylation as evidence of restored redox balance. That is a real and repeated connection, but it is not a comparison of two treatments.
No study has compared them directly.
Everything below is drawn from separate studies that used different models, endpoints and species. That is a real limit on what can be concluded, not a formality.
No published study has administered glutathione and SS-31 as parallel treatments and compared them, so any ranking between the two is indirect. What exists instead is a substantial body of work in which SS-31 was the intervention and glutathione was the measurement. In aged mice, a single SS-31 injection and an eight-week course both shifted skeletal muscle glutathione redox status towards the reduced state, the longer course also reversing cysteine S-glutathionylation across the muscle proteome. In diet-induced metabolic syndrome in pigs, elamipretide improved the myocardial ratio of reduced to oxidised glutathione alongside NADPH generation. In leukocytes taken from patients with type 2 diabetes, ex vivo SS-31 raised glutathione content. In porcine oocytes, SS-31 in the maturation medium raised glutathione content and lowered reactive oxygen species. The closest approach to a comparison is a 2026 mouse study of ozone-induced airway injury in which SS-31 and N-acetylcysteine, a glutathione precursor rather than glutathione itself, were given separately and produced comparable effects on airway hyperresponsiveness, mucus and the glutathione ratio. Two reviews list glutathione esters and the Szeto-Schiller peptides side by side as distinct mitochondrial antioxidant strategies without testing either.
The 11 publications that cover both
- 01Animal in vivo2026
Mechanisms of Anti-Oxidants, N-Acetylcysteine and Elamipretide (SS-31), on Ozone-Induced Airway Hyperresponsiveness and Mucus Hypersecretion.
Xie M, et al. · Lung · wild-type C57BL/6J mice given intraperitoneal N-acetylcysteine or SS-31 before a single ozone exposure, with BEAS-2B human bronchial epithelial cells pretreated in parallel in vitro
N-acetylcysteine, a glutathione precursor, and SS-31 comparably attenuated ozone-induced airway hyperresponsiveness, reduced bronchoalveolar lavage inflammatory cell influx and decreased mucus production and MUC5B expression. Both improved redox balance, lowering reactive oxygen species and malondialdehyde, raising superoxide dismutase activity and improving the ratio of reduced to oxidised glutathione, and both suppressed PI3K/AKT and NLRP3/caspase-1/GSDMD signalling. Glutathione itself was not administered in either arm.
- 02Animal in vivo2013
Mitochondrial-targeted peptide rapidly improves mitochondrial energetics and skeletal muscle performance in aged mice.
Siegel MP, et al. · Aging Cell · young and old mice given a single intraperitoneal injection of SS-31 or saline, with in vivo optical and phosphorus-31 magnetic resonance spectroscopy one hour later and a separate eight-day treatment arm
Age-related declines in resting and maximal mitochondrial ATP production, in coupling of oxidative phosphorylation and in cell energy state were reversed within an hour of a single SS-31 treatment, with no observable effect in young muscle. The change was accompanied by a more reduced glutathione redox status and lower mitochondrial hydrogen peroxide emission. Aged muscle was more fatigue resistant one hour after treatment, and eight days of treatment increased whole-animal endurance capacity.
- 03Animal in vivo2019
Improving mitochondrial function with SS-31 reverses age-related redox stress and improves exercise tolerance in aged mice.
Campbell MD, et al. · Free Radical Biology and Medicine · young and aged female C57BL/6Nia mice treated with SS-31 for eight weeks; in vivo phosphorus-31 and optical spectroscopy, permeabilised fibre respirometry and thiol redox proteomics
SS-31 reversed the age-related decline in maximum mitochondrial ATP production and in coupling of oxidative phosphorylation, without an increase in mitochondrial protein expression or in permeabilised-fibre respiration. Glutathione redox status in aged skeletal muscle became more reduced after treatment, and thiol redox proteomics showed a broad reversal of cysteine S-glutathionylation across the muscle proteome. Treated aged mice had greater gastrocnemius mass, more fatigue-resistant muscle and increased treadmill endurance.
- 04Animal in vivo2018
Mitochondrial targeted peptides preserve mitochondrial organization and decrease reversible myocardial changes in early swine metabolic syndrome.
Yuan F, et al. · Cardiovascular Research · domestic pigs after sixteen weeks of diet-induced metabolic syndrome, treated with subcutaneous elamipretide for the final four weeks, against lean controls; six animals per group
Metabolic syndrome disorganised myocardial mitochondria, reduced tetralinoleoyl cardiolipin, disrupted the ATP to ADP balance and lowered both the NADPH to NADP ratio and the ratio of reduced to oxidised glutathione, before overt cardiac dysfunction appeared. Elamipretide improved mitochondrial organisation and the cardiolipin species profile, restored the ATP to ADP ratio and cytochrome c oxidase activity, decreased hydrogen peroxide production and improved generation of NADPH and glutathione, attenuating oxidative stress and apoptosis.
- 05Animal in vivo2012
Mitochondrial permeability transition in the diabetic heart: contributions of thiol redox state and mitochondrial calcium to augmented reperfusion injury.
Sloan RC, et al. · Journal of Molecular and Cellular Cardiology · hearts and isolated mitochondria from control and streptozotocin-induced diabetic rats, with ex vivo ischaemia-reperfusion experiments and agents given at the onset of reperfusion
Myocardial glutathione was more oxidised in diabetic hearts than in controls, which translated into increased oxidation of the adenine nucleotide translocase, and diabetic mitochondria were more sensitive to permeability transition pore opening. Diabetic animals treated with the mitochondria-targeted peptide MTP-131 showed improved resistance to pore opening, and MTP-131 given at reperfusion reduced infarct size in both control and diabetic hearts, as did a pore blocker and a calcium uniporter blocker.
- 06Animal in vivo2013
Redox-dependent increases in glutathione reductase and exercise preconditioning: role of NADPH oxidase and mitochondria.
Frasier CR, et al. · Cardiovascular Research · rats exercised for ten consecutive days, with isolated hearts exposed to ischaemia and reperfusion; subsets exercised after treatment with NADPH oxidase inhibitors or with the mitochondrial reagents mitoTEMPO or Bendavia
Exercise protected against infarction and arrhythmia, preserved coronary flow and increased glutathione reductase activity in a redox-dependent manner without changing enzyme protein levels, and a glutathione reductase inhibitor abolished the benefit. The cardioprotective effect was lost when animals exercised after NADPH oxidase inhibition but not after treatment with the mitochondrial reagents, one of which was Bendavia, the trade name of the SS-31 peptide, used here to lower mitochondrial reactive oxygen species.
- 07Animal in vivo2019
SS31 Ameliorates Sepsis-Induced Heart Injury by Inhibiting Oxidative Stress and Inflammation.
Liu Y, et al. · Inflammation · thirty-five C57BL/6 mice in four groups (sham, lipopolysaccharide, SS31, SS31 plus lipopolysaccharide), with parallel H9C2 cardiomyocyte experiments
SS31 restored myocardial morphology and reduced messenger RNA levels of IL-6, IL-1beta and TNF-alpha in vitro and in vivo, and ameliorated the myocardial energy deficit that followed sepsis. It normalised the activity of malondialdehyde, glutathione peroxidase and superoxide dismutase in both settings and maintained mitochondrial membrane potential. The cardioprotective effect was reported to be partly linked to NF-kappaB signalling.
- 08In vitro2018
The mitochondrial antioxidant SS-31 increases SIRT1 levels and ameliorates inflammation, oxidative stress and leukocyte-endothelium interactions in type 2 diabetes.
Escribano-Lopez I, et al. · Scientific Reports · leukocytes from 51 patients with type 2 diabetes and 57 controls, treated or not with SS-31 ex vivo; mitochondrial reactive oxygen species, membrane potential, glutathione content, SIRT1, NF-kappaB p65 and TNF-alpha measured
Mitochondrial reactive oxygen species production was increased in leukocytes from patients with type 2 diabetes and was restored by SS-31 treatment. SS-31 also increased mitochondrial membrane potential, glutathione content and SIRT1 levels, raised leukocyte rolling velocity and reduced rolling flux and adhesion. NF-kappaB p65 and TNF-alpha, both elevated in the diabetic samples, were reduced. Glutathione was an outcome measure here rather than a treatment.
- 09In vitro2025
Mitochondrial-Targeted Protective Potential of Elamipretide for the In Vitro Production of Porcine Embryos.
Nguyen ST, et al. · Animals (Basel) · porcine oocytes matured in medium supplemented with SS-31 across a concentration series against untreated and solvent controls, followed by in vitro fertilisation and embryo culture
Oocytes matured in SS-31-supplemented medium showed higher maturation and blastocyst formation rates than untreated controls, along with significantly lower reactive oxygen species, higher glutathione content, improved mitochondrial membrane potential and less DNA fragmentation after maturation. Glutathione was assayed as a marker of antioxidant capacity; it was not one of the supplements tested.
- 10Review2014
Mitochondria-targeted agents: Future perspectives of mitochondrial pharmaceutics in cardiovascular diseases.
Ajith TA, Jayakumar TG · World Journal of Cardiology · narrative review of mitochondria-targeted molecules studied experimentally and clinically in cardiovascular disease
The review grouped choline esters of glutathione and N-acetyl-L-cysteine with superoxide dismutase mimetics, triphenylphosphonium-ligated antioxidants and the Szeto-Schiller peptides SS-02 and SS-31 as separate strategies for delivering antioxidant capacity to mitochondria in heart failure. The authors described many of the results in the field as inconclusive and did not compare the glutathione esters against the peptides in any experiment.
- 11Review2021
Mitochondrial Dysfunction and Oxidative Stress Caused by Cryopreservation in Reproductive Cells.
Gualtieri R, et al. · Antioxidants (Basel) · narrative review of mitochondrial damage and oxidative stress during cryopreservation of gametes and gonadal tissue across species, including antioxidant supplementation strategies
The review described elamipretide, also known as SS-31, as a cardiolipin-binding tetrapeptide and cited work in which it protected cryopreserved human sperm on motility, viability, acrosomal function, membrane and chromatin integrity and mitochondrial membrane potential. Separately it described supplementation with the glutathione donor glutathione ethyl ester as improving cryotolerance of mouse oocytes and reducing oxidative stress in bovine oocytes. The two were presented as alternative supplementation approaches and were not compared.
Side by side.
| SS-31 | Glutathione | |
|---|---|---|
| Evidence maturity | Approved drug | Early clinical |
| Studies cited here | 16 | 15 |
| Published 2023 or later | 11 | 9 |
| Newest paper | 2026 | 2026 |
| Sequence and origin | A synthetic aromatic-cationic tetrapeptide, also designated elamipretide and MTP-131, engineered to concentrate in the inner mitochondrial membrane. It has no endogenous counterpart. | An endogenous tripeptide of glutamate, cysteine and glycine, synthesised in every cell and present at millimolar concentrations intracellularly, where it functions as the principal thiol antioxidant and redox buffer. |
| Mechanism as described in the literature | Binds cardiolipin in the inner mitochondrial membrane, stabilising cristae architecture and improving electron transport efficiency and ATP synthesis, with reduced mitochondrial reactive oxygen species emission as a downstream consequence. | Acts as the reducing substrate for glutathione peroxidases and glutaredoxins, buffers the cellular thiol redox environment and participates in detoxification and protein S-glutathionylation. Systemic supply depends on cysteine availability, which is why precursor strategies are studied. |
| Size of the evidence base | Sixteen verified studies in this library, of which eleven are human clinical trials, four are animal in vivo and one is a review. | Fifteen verified studies, of which ten are human clinical, two are systematic reviews and three are narrative reviews. The human work splits into pharmacokinetics, dermatological pigmentation trials and precursor-repletion studies. |
| Best-characterised finding | Sustained functional gains in Barth syndrome across a phase 2/3 trial and its long open-label extension, and rapid restoration of mitochondrial ATP production in aged skeletal muscle in rodents and in one randomised single-dose human study. | Repeated oral dosing raises whole-blood, erythrocyte and lymphocyte glutathione pools in healthy adults, with return to baseline after washout, and systemic exposure varies substantially with formulation. |
| Human data | Randomised controlled trials in Barth syndrome, primary mitochondrial myopathy, heart failure with reduced ejection fraction and Leber hereditary optic neuropathy. Results are mixed: the phase 3 MMPOWER-3 trial missed its primary endpoints, as did the phase 2 heart failure and optic neuropathy trials. | Small trials, generally under sixty participants and four weeks to six months long, covering oral bioavailability, skin pigmentation, Parkinson's disease and precursor repletion with glycine plus N-acetylcysteine. Direct administration in Parkinson's disease has not outperformed placebo. |
| Regulatory status | Granted FDA accelerated approval on 19 September 2025 as FORZINITY, to improve muscle strength in adult and paediatric Barth syndrome patients above a stated weight, on a muscle-strength surrogate endpoint. Continued approval is contingent on confirmatory trials. | Available as a dietary supplement in oral and liposomal forms. Intravenous glutathione is not an approved treatment for skin lightening, anti-ageing or general wellness in any major jurisdiction. |
| Safety signals reported | Long-term safety outside the small Barth syndrome cohorts is limited, and the approval rests on a very small cohort with clinical benefit not yet confirmed. | Reported harms include anaphylaxis, hepatotoxicity, and cardiomyopathy in one participant of an intranasal trial. No long-term safety data exist for repeated parenteral administration. |
| Basis of most marketing claims | Extrapolation from a rare-disease approval and from rodent ageing studies to exercise capacity, longevity and body composition in healthy people, for which no controlled trial exists. | Extrapolation from intracellular antioxidant biochemistry and short pigmentation trials to infusion-based wellness use, where controlled efficacy data are essentially limited to a single placebo-controlled dermatology study. |
And what it does not.
These two are not competitors in the literature; one is largely the instrument by which the other is judged. Across rodent ageing, swine metabolic syndrome, diabetic myocardium, human diabetic leukocytes and porcine oocytes, SS-31 was administered and glutathione status was measured to show that mitochondrial redox balance had shifted. That is a consistent and repeated finding, and it says nothing about whether taking glutathione produces the same result. No study has given both, and the closest approach substituted N-acetylcysteine, a precursor, which performed comparably to SS-31 on airway endpoints in mice. Separately, the two records are very different in shape. SS-31 has randomised trials and an accelerated approval in one rare mitochondrial disease, with its largest trial in mitochondrial myopathy missing its endpoints. Glutathione has small, heterogeneous human trials, disputed oral bioavailability, effects on blood pools that revert after washout, and documented harms from parenteral use. Neither has controlled human evidence for longevity, exercise capacity or body composition.
Common questions.
- Has any study given both SS-31 and glutathione to the same subjects?
No. Searches of PubMed and Europe PMC returned no experiment in which glutathione and SS-31 were both administered, as parallel arms or in combination. The nearest published comparison is a 2026 mouse study of ozone-induced airway injury in which SS-31 and N-acetylcysteine were given in separate arms; N-acetylcysteine is a glutathione precursor rather than glutathione itself. Two reviews list glutathione esters and the Szeto-Schiller peptides side by side as alternative strategies, without testing either.
- Why does glutathione keep appearing in SS-31 studies if it was not administered?
Because the ratio of reduced to oxidised glutathione is a standard index of cellular redox state, so investigators use it to demonstrate that a mitochondrial intervention has changed something measurable. In aged mouse muscle, swine myocardium, human diabetic leukocytes and porcine oocytes, SS-31 treatment was followed by a more reduced glutathione status or higher glutathione content. The peptide was the treatment in every case; glutathione was the outcome variable used to interpret it.
- Does raising glutathione produce the same effects as SS-31?
The published record does not answer that. The two act at different points: SS-31 binds cardiolipin and stabilises cristae architecture, with lower reactive oxygen species emission as a consequence, while glutathione supplies reducing equivalents to peroxidases throughout the cell. A mouse airway study found that N-acetylcysteine and SS-31 produced comparable protection against ozone injury, which is suggestive for one model and one insult, but no study has compared them on mitochondrial energetics or on any clinical endpoint.
- Which of the two has the stronger regulatory position?
SS-31, and only narrowly. Elamipretide received FDA accelerated approval in September 2025 for Barth syndrome, based on improvement in knee extensor muscle strength in a very small cohort, with continued approval contingent on confirmatory trials. Glutathione is sold as a dietary supplement; intravenous glutathione is not approved for skin lightening, anti-ageing or general wellness anywhere, and controlled efficacy data for infusion are essentially limited to a single placebo-controlled dermatology study.
- Do the aged-mouse results support use for exercise capacity in people?
Not on their own. Aged mice given SS-31 recovered mitochondrial ATP production, showed more reduced glutathione redox status and reversed protein S-glutathionylation, and were more fatigue resistant with greater treadmill endurance. Those are rodent findings. One randomised human study reported improved in vivo mitochondrial ATP production in older adult skeletal muscle after a single dose, but no controlled trial has tested elamipretide for exercise capacity, athletic performance or body composition in healthy people.
For research purposes only. Not for human consumption, diagnosis, treatment, or prevention of any condition. Nothing on this page is medical advice, and no comparison here should be read as a recommendation of either compound.