OVERVIEW

SS-31 (Elamipretide) is a mitochondria-targeted peptide designed to improve mitochondrial function and ATP production. By stabilizing cardiolipin, a key lipid in mitochondrial membranes, SS-31 helps maintain cellular energy production and metabolic efficiency.

Research suggests SS-31 may:

• Reduce oxidative stress by decreasing reactive oxygen species (ROS).
• Enhance mitochondrial function in high-energy-demanding organs such as the brain, heart, and kidneys.
• Support cellular metabolism and improve tissue recovery.
• Offer therapeutic potential in neurodegenerative diseases, cardiovascular disease, diabetes, and kidney dysfunction.
• Mitigate mitochondrial dysfunction, a root cause of many age-related and chronic diseases.

SS-31 was the first peptide to undergo clinical trials for mitochondrial disorders, earning orphan drug status from the FDA due to its promising role in treating mitochondrial diseases.

RESEARCH

SS-31 and Mitochondrial Disease

Mitochondrial dysfunction is implicated in neurodegenerative, cardiovascular, and metabolic diseases.

• SS-31 stabilizes cardiolipin, preventing the structural breakdown of the electron transport chain (ETC), which is critical for ATP production.
• Rat studies on ischemia-reperfusion injury showed restored ATP levels, reduced necrosis, and improved kidney function.
• Due to its promising therapeutic effects, the FDA granted SS-31 orphan drug status.

SS-31 and Exercise Performance

• Phase II clinical trials showed increased exercise tolerance within 5 days of SS-31 treatment.
• Enhanced mitochondrial respiration and ATP synthesis were observed in muscle cells.
• These findings suggest potential benefits for athletes, aging populations, and individuals with mitochondrial disorders.

SS-31 and Heart Disease

Heart failure is closely linked to mitochondrial dysfunction, which worsens the condition over time.

• Research in human heart tissue demonstrated that SS-31 improves mitochondrial function and oxygen consumption.
• Studies in dogs with heart failure showed enhanced left ventricular function and ATP production after SS-31 administration.
• Clinical trials in heart attack patients (STEMI trials) found that SS-31 reduced cardiomyocyte apoptosis, suggesting potential applications in post-heart attack recovery.

SS-31 and Diabetes

Mitochondrial dysfunction plays a key role in type 2 diabetes and its complications.

• Human studies found that SS-31 reduces oxidative stress and increases SIRT1 levels, a marker of improved insulin sensitivity.
• Diabetic patients experienced reduced inflammation and oxidative stress, supporting SS-31 as a potential treatment for diabetes-related complications.

SS-31 and Inflammation

• SS-31 suppresses inflammatory pathways by inhibiting NF-kappaB and reducing ROS production.
• Studies showed SS-31 decreases FIS1 expression, a protein linked to mitochondrial fragmentation in neurodegenerative diseases.
• In mouse models, SS-31 reduced oxidative stress markers such as CD-36, NADPH oxidase, and MnSOD activation.

SS-31 and Neurodegenerative Diseases

Alzheimer’s and Parkinson’s diseases are associated with mitochondrial dysfunction and oxidative stress.

• SS-31 is currently being investigated for its neuroprotective effects, particularly its ability to enhance mitochondrial stability in neurons.
• Potential therapeutic applications include delaying cognitive decline and reducing neuroinflammation.

STRUCTURE

• Molecular Formula: C₃₂H₄₉N₉O₅
• Molecular Weight: 639.8 g/mol
• Amino Acid Sequence: D-Arg-Tyr(2,6-diMe)-Lys-Phe
• CAS Registry Number: 736992-21-5
• PubChem Identifier: 11764719
• Synonyms: Elamipretide, MTP-131, Bendavia

CITATIONS

1. Szeto, H. H. et al. Mitochondria-targeted peptide accelerates ATP recovery and reduces ischemic kidney injury.J. Am. Soc. Nephrol. (2011).
2. Siegel, M. P. et al. Mitochondrial-targeted peptide rapidly improves mitochondrial energetics and skeletal muscle performance in aged mice. Aging Cell (2013).
3. Birk, A. V. et al. The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipin. J. Am. Soc. Nephrol. (2013).
4. Chatfield, K. C. et al. Elamipretide improves mitochondrial function in the failing human heart. JACC Basic Transl. Sci. (2019).
5. Karaa, A. et al. Randomized dose-escalation trial of elamipretide in adults with primary mitochondrial myopathy. Neurology (2018).
6. Mitochondrial Disease News Elamipretide failed to meet the promise of earlier trial results for primary mitochondrial myopathy. (2020).
7. Neurology Live Could Elamipretide become the first treatment option for primary mitochondrial myopathy?(2020).
8. Sabbah, H. N. et al. Chronic therapy with Elamipretide (MTP-131) improves left ventricular and mitochondrial function in dogs with advanced heart failure. Circ. Heart Fail. (2016).
9. Hortmann, M. et al. The mitochondria-targeting peptide elamipretide diminishes circulating HtrA2 in ST-segment elevation myocardial infarction. Eur. Heart J. Acute Cardiovasc. Care (2019).
10. Escribano-Lopez, I. et al. The mitochondrial antioxidant SS-31 increases SIRT1 levels and ameliorates inflammation, oxidative stress, and leukocyte-endothelium interactions in type 2 diabetes. Sci. Rep. (2018).
11. Mo, Y. et al. SS-31 reduces inflammation and oxidative stress through the inhibition of Fis1 expression in lipopolysaccharide-stimulated microglia. Biochem. Biophys. Res. Commun. (2019).
12. Hou, Y. et al. The antioxidant peptide SS-31 prevents oxidative stress, downregulates CD36, and improves renal function in diabetic nephropathy. Nephrol. Dial. Transplant. (2018).
13. Hou, Y. et al. Mitochondria-targeted peptide SS-31 attenuates renal injury via an antioxidant effect in diabetic nephropathy. Am. J. Physiol.-Ren. Physiol. (2015).