SS-31 (10mg)

SS-31 Research

Elamipretide (SS-31) is a mitochondrion-targeted peptide with broad research areas focusing on improving mitochondrial function and addressing various health conditions related to mitochondrial dysfunction.

SS-31 composed of alternating aromatic and basic amino acid residues that give it a unique ability to penetrate cell membranes and specifically target the inner mitochondrial membrane.

The peptide works by interacting with cardiolipin, a phospholipid found exclusively in the inner mitochondrial membrane that plays a crucial role in maintaining proper mitochondrial function.

Under conditions of oxidative stress, cardiolipin can become oxidized, leading to disruption of the electron transport chain, increased production of reactive oxygen species, and ultimately mitochondrial dysfunction. SS-31 helps to protect cardiolipin from oxidation and restore normal mitochondrial function.

SS-31 and Mitochondrial Dysfunction

Elamipretide primarily interacts with cardiolipin, a phospholipid in the inner mitochondrial membrane, which is crucial for mitochondrial function¹. This interaction helps stabilize mitochondrial membranes, improve ATP production, and reduce oxidative stress by modulating surface electrostatics and lipid packing².

SS-31 has also been shown to inhibit the Nrf2-mediated NLRP3 inflammasome in macrophages, which is significant in reducing inflammation and oxidative stress³.

Neuroprotection and Cognitive Function

Elamipretide has been shown to mitigate the effects of neuroinflammation and oxidative stress, which are significant contributors to cognitive decline. In models of lipopolysaccharide (LPS)-induced neuroinflammation, elamipretide reduced inflammatory cytokines and oxidative stress markers, leading to improved functional connectivity in the hippocampus and related brain regions⁴.

It also attenuated isoflurane-induced cognitive deficits in developing rats by protecting against oxidative stress and mitochondrial damage⁵.

Elamipretide has demonstrated efficacy in improving learning and memory impairments across various models, including those induced by chronic sleep deprivation, traumatic brain injury, and perioperative neurocognitive disorders (PND). It enhances synaptic integrity and reverses synaptic signaling protein deficits, which are critical for cognitive function⁶.

In aged mice, elamipretide improved neurovascular coupling and cognitive functions such as spatial working memory and motor skills by reducing mitochondrial oxidative stress and enhancing cerebromicrovascular function. It also showed potential in treating age-related vascular cognitive impairment by protecting against cerebromicrovascular dysfunction⁷.

Aging and Exercise Tolerance

SS-31 treatment significantly increases treadmill endurance in aged mice, suggesting improved exercise tolerance. This improvement is attributed to enhanced mitochondrial function and redox homeostasis⁸.

The gastrocnemius muscle in SS-31 treated aged mice shows greater fatigue resistance and increased mass compared to untreated aged controls, contributing to better exercise performance⁹.

Cardiac Health

Elamipretide has been effective in reversing diastolic dysfunction, a common feature of cardiac aging. It normalizes increased proton leak and reduces mitochondrial reactive oxygen species (ROS), which are critical in improving heart function in aged mice¹⁰.

The treatment with SS-31 also affects phosphorylation of cardiac proteins, such as cMyBP-C, which is linked to improved cardiac function. However, some phosphorylation changes, like those in cMyBP-C S307, are not influenced by elamipretide¹¹.

Pulmonary and Musculoskeletal Health

Elamipretide has shown promise in the treatment of idiopathic pulmonary fibrosis (IPF), a severe lung disease characterized by progressive fibrosis. In a study using a bleomycin-induced mouse model, SS-31 treatment significantly reduced pulmonary fibrosis and inflammation.

This was achieved by inhibiting the Nrf2-mediated NLRP3 inflammasome in macrophages, leading to decreased levels of inflammatory cytokines such as IL-1β and IL-18. These findings suggest that SS-31 could be a potential therapeutic agent for IPF by targeting mitochondrial oxidative stress in macrophages¹².

SS-31 has also been investigated for its effects on tendinopathy, a condition associated with mitochondrial dysfunction. In a murine model of supraspinatus tendinopathy, SS-31 treatment improved mitochondrial function and promoted tendon healing.

This was evidenced by increased mitochondrial number and improved cristae morphology, as well as enhanced superoxide dismutase activity and gene expression related to mitochondrial function. These results suggest that SS-31 could be an effective treatment for promoting tendon healing, especially when combined with mechanical interventions¹³.

References

1. Chavez, J., Tang, X., Campbell, M., Reyes, G., Kramer, P., Stuppard, R., Keller, A., Zhang, H., Rabinovitch, P., Marcinek, D., & Bruce, J. (2019). Mitochondrial protein interaction landscape of SS-31. Proceedings of the National Academy of Sciences, 117, 15363 – 15373. https://doi.org/10.1101/739128.
2. Mitchell, W., Ng, E. A., Tamucci, J. D., Boyd, K. J., Sathappa, M., Coscia, A., Pan, M., Han, X., Eddy, N. A., May, E. R., Szeto, H. H., & Alder, N. N. (2020). The mitochondria-targeted peptide SS-31 binds lipid bilayers and modulates surface electrostatics as a key component of its mechanism of action. The Journal of biological chemistry, 295(21), 7452–7469. https://doi.org/10.1074/jbc.RA119.012094
3. Nie, Y., Li, J., Zhai, X., Wang, Z., Wang, J., Wu, Y., Zhao, P., & Yan, G. (2023). Elamipretide(SS-31) Attenuates Idiopathic Pulmonary Fibrosis by Inhibiting the Nrf2-Dependent NLRP3 Inflammasome in Macrophages. Antioxidants, 12. https://doi.org/10.3390/antiox12122022.
4. Zhao, W., Xu, Z., Cao, J., Fu, Q., Wu, Y., Zhang, X., Long, Y., Zhang, X., Yang, Y., Li, Y., & Mi, W. (2019). Elamipretide (SS-31) improves mitochondrial dysfunction, synaptic and memory impairment induced by lipopolysaccharide in mice. Journal of Neuroinflammation, 16. https://doi.org/10.1186/s12974-019-1627-9.
5. Wu, J., Hao, S., Sun, X., Zhang, H., Li, H., Zhao, H., Ji, M., Yang, J., & Li, K. (2017). Elamipretide (SS-31) Ameliorates Isoflurane-Induced Long-Term Impairments of Mitochondrial Morphogenesis and Cognition in Developing Rats. Frontiers in Cellular Neuroscience, 11. https://doi.org/10.3389/fncel.2017.00119.
6. Zuo, Y., Yin, L., Cheng, X., Li, J., Wu, H., Liu, X., Gu, E., & Wu, J. (2020). Elamipretide Attenuates Pyroptosis and Perioperative Neurocognitive Disorders in Aged Mice. Frontiers in Cellular Neuroscience, 14. https://doi.org/10.3389/fncel.2020.00251.
7. Tarantini, S., Valcarcel‐Ares, N., Yabluchanskiy, A., Fulop, G., Hertelendy, P., Gautam, T., Farkas, E., Perz, A., Rabinovitch, P., Sonntag, W., Csiszar, A., & Ungvari, Z. (2018). Treatment with the mitochondrial‐targeted antioxidant peptide SS‐31 rescues neurovascular coupling responses and cerebrovascular endothelial function and improves cognition in aged mice. Aging Cell, 17. https://doi.org/10.1111/acel.12731.
8. Campbell, M., Duan, J., Samuelson, A., Gaffrey, M., Merrihew, G., Egertson, J., Wang, L., Bammler, T., Moore, R., White, C., Kavanagh, T., Voss, J., Szeto, H., Rabinovitch, P., MacCoss, M., Qian, W., & Marcinek, D. (2019). Improving mitochondrial function with SS-31 reverses age-related redox stress and improves exercise tolerance in aged mice.. Free radical biology & medicine, 134, 268-281 . https://doi.org/10.1016/j.freeradbiomed.2018.12.031.
9. Campbell, M., Gaffrey, M., Egertson, J., Merrihew, G., Pérez, M., Wang, L., Villén, J., MacCoss, M., Qian, W., & Marcinek, D. (2018). Reversal of age related post-translational modifications improves mitochondrial and skeletal muscle function through redox dependent mechanisms. Free Radical Biology and Medicine. https://doi.org/10.1016/J.FREERADBIOMED.2018.10.305.
10. Chiao, Y., Zhang, H., Sweetwyne, M., Whitson, J., Ting, Y., Basisty, N., Pino, L., Quarles, E., Nguyen, N., Campbell, M., Zhang, T., Gaffrey, M., Merrihew, G., Wang, L., Yue, Y., Duan, D., Granzier, H., Szeto, H., Qian, W., Marcinek, D., MacCoss, M., & Rabinovitch, P. (2020). Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice. eLife, 9. https://doi.org/10.1101/2020.01.02.893008.
11. Whitson, J., Martín-Pérez, M., Zhang, T., Gaffrey, M., Merrihew, G., Huang, E., White, C., Kavanagh, T., Qian, W., Campbell, M., MacCoss, M., Marcinek, D., Villén, J., & Rabinovitch, P. (2021). Elamipretide (SS-31) treatment attenuates age-associated post-translational modifications of heart proteins. GeroScience, 43, 2395 – 2412. https://doi.org/10.1007/s11357-021-00447-6.
12. Nie, Y., Li, J., Zhai, X., Wang, Z., Wang, J., Wu, Y., Zhao, P., & Yan, G. (2023). Elamipretide(SS-31) Attenuates Idiopathic Pulmonary Fibrosis by Inhibiting the Nrf2-Dependent NLRP3 Inflammasome in Macrophages. Antioxidants, 12. https://doi.org/10.3390/antiox12122022.
13. Zhang, X., Bowen, E., Zhang, M., Szeto, H., Deng, X., & Rodeo, S. (2022). SS-31 as a Mitochondrial Protectant in the Treatment of Tendinopathy. The Journal of Bone and Joint Surgery, 104, 1886 – 1894. https://doi.org/10.2106/JBJS.21.01449.