SS-31, also recognized as MTP-131, represents a tetrapeptide that has attracted considerable attention  in the research community due to its prospective implications in mitochondrial dysfunction.(1)

Distinguishing itself with a distinctive cationic 3+ charge under physiological pH conditions, this molecule exhibits potentially notable cell membrane permeability and a plausible ability to traverse the blood-brain barrier. Intriguingly, SS-31 is observed to rapidly exit cells, despite lacking substrate status for P-glycoprotein.

Among the extensively investigated features of SS-31 is its apparent capacity to accumulate within the inner mitochondrial membrane, surpassing concentrations seen in plasma by over 1000-fold. Within this context, the peptide is suggested to host a potential affinity for cardiolipin—an anionic phospholipid exclusively present in the inner mitochondrial membrane. This binding interaction is proposed to disrupt the association between cardiolipin and cytochrome C, leading to a diminution in the oxidative inactivation of cardiolipin by cytochrome C.


Mechanism of Action

This intricate modulation appears to not only restrain cytochrome c peroxidase activity but may also uphold the integrity of Met80-heme ligation, favorably steering cytochrome c towards its role as an electron carrier under the influence of SS-31. The disruption’s significance lies in its potential to influence the intricate orchestration of mitochondrial processes.

By fortifying cardiolipin-mediated optimization of electron transport and ATP synthesis, it holds the promise of sculpting mitochondrial cristae, a crucial element in safeguarding efficient oxidative phosphorylation, while concurrently mitigating the release of reactive oxygen species, thereby contributing to cellular homeostasis.

SS-31 Peptide and Tendinopathies

Exploration into the impact of SS-31 on mitochondrial function in tenocytes, the cells of tendons, has been a focal point of research. One hypothesis posits that SS-31 holds the potential to enhance mitochondrial function in tenocytes derived from tendinopathy models. In a particular study, tenocytes were sourced from both functional hamstring tendons and degenerative supraspinatus tendons.(2)

These cells underwent cultivation and were then categorized into four groups, including SS-31-exposed and unexposed tenocytes within each category. Diverse outcome metrics were employed, encompassing measurements related to mitochondrial potential, intricate mitochondrial visualization through transmission electron microscopy, and evaluations of reactive oxygen species, superoxide dismutase activity, gene expression, and cell viability.

The study’s findings suggested a higher proportion of degenerative tenocytes with depolarized mitochondria. Notably, after exposure to SS-31, there appeared to be a reduction in this proportion. Transmission electron microscopy indicated that degenerative tenocytes exhibited a lower count of mitochondria, which were also smaller in size; however, SS-31 seemed to ameliorate these morphological deficiencies. While there was no marked difference in reactive oxygen species levels between the two tenocyte types, the activity of superoxide dismutase was noticeably lower in the degenerative group, exhibiting an increase post-SS-31 introduction, suggesting potential restoration of mitochondrial functionality.

Moreover, specific genes associated with matrix remodeling and fatty infiltration displayed heightened activity in degenerative tenocytes, which decreased following exposure to SS-31 peptide. Intriguingly, genes linked to cellular responses to hypoxic conditions and apoptosis regulation exhibited increased activity in the degenerative group, hinting at the potential multifaceted action of SS-31 in mitigating mitochondrial dysfunction in tenocytes. These observations, cultivated through murine models, present promising directions for future research in this domain.

SS-31 Peptide and Renal Function

Ischemia, a pathological condition resulting in organ injury such as acute kidney injury due to ATP depletion, necessitates rapid ATP recovery upon reperfusion to minimize tissue damage. Unfortunately, ischemia-induced damage to mitochondrial cristae membranes, critical for mitochondrial ATP synthesis, is considered to often lead to delayed ATP recovery. The mitochondria-targeted compound SS-31 is proposed to expedite ATP recovery post-ischemia, potentially mitigating acute kidney injury.

In a study, scientists employed a polarity-sensitive fluorescent analog of SS-31, indicating its potential high-affinity binding to cardiolipin, a crucial element for cristae formation.(3) The SS-31/cardiolipin complex appeared to protect heme-iron, inhibiting cytochrome C peroxidase activity—a process responsible for cardiolipin peroxidation and subsequent mitochondrial damage during ischemia. Exposure of SS-31 to murine models appeared to preserve cristae membranes during renal ischemia, preventing mitochondrial swelling.

The apparent immediate recovery of ATP upon reperfusion facilitated by SS-31 may expedite the repair of ATP-dependent processes, including the reformation of the actin cytoskeleton and cell polarity. This rapid ATP recovery may also contribute to the suppression of apoptosis, reinforcement of tubular barrier function, and alleviation of renal dysfunction. Hence, researchers suppose that SS-31 may hold the potential to safeguard mitochondrial cristae by engaging with cardiolipin on the inner mitochondrial membrane.

SS-31 Peptide and Neurological Resilience

In various experimental models, SS-31 has been proposed as a potential agent for neuroprotection, although its precise role as a mitochondrial reactive oxygen species (ROS) scavenger and the underlying mechanisms in neuronal injury remain elusive. A specific trial aimed to investigate the neuroprotective capabilities of SS-31 and understand any discernible mitochondrial alterations in murine models of neuronal injury.(4)

Murine models were divided into sham, neuronal injury, neuronal injury + vehicle, and neuronal injury + SS-31 groups. Following neuronal injury, SS-31 or vehicle was introduced, and brain specimens were collected 24 hours later for analysis. The introduction of SS-31 seemed to counteract mitochondrial impairment and reduce secondary neuronal injury. It exhibited a direct reduction in reactive oxygen species content, restoration of superoxide dismutase (SOD) activity, decrease in malondialdehyde (MDA) levels, and suppression of cytochrome C release, potentially mitigating neurological impairments, brain hydration, DNA damage, and neural apoptosis.

Furthermore, SS-31 appeared to restore SIRT1 expression and enhance the nuclear relocation of PGC-1α, as indicated by Western blot and immunohistochemistry. Overall, these findings suggest that SS-31  may potentially enhance mitochondrial function and may confer neuroprotection in murine models post-neuronal injury, possibly through augmented mitochondrial rejuvenation.

SS-31 Peptide and Cell Aging

In the context of the cell cycle, SS-31 demonstrates potential anti-aging effects, as suggested by a study exploring its impact on cardiac proteins in aged murine models.(5)

This investigation focused on SS-31’s potential influence on post-translational modifications of heart proteins. The myocardium of aged murine models exhibited a noticeable increase in protein thiol oxidation, specifically enhanced S-glutathionylation of cysteine residues, especially when compared to their younger counterparts. Following an 8-week intervention with SS-31, this age-related proteomic oxidation appeared nearly completely reversed. Notably, significant alterations were detected primarily in proteins crucial for mitochondrial or cardiac function.

Furthermore, age-associated modifications in the murine heart seemed to undergo partial reversal after exposure to SS-31. The researchers observed “changes in the mouse heart phosphoproteome that were associated with age, some of which were partially restored with elamipretide.”(5)

These findings suggest that changes in thiol redox state and phosphorylation status may represent pathways through which cell aging influences murine heart functionality. Importantly, the influence of SS-31 appears to mitigate these age-induced alterations.

SS-31 Peptide and Oxidative Stress

The central role of oxidative stress in various pathologies, including retinopathy, prompted an investigation into the impact of SS-31 in a murine model of diabetic retinopathy.(6)

Two weeks post-diabetes induction, these models were exposed to SS-31 or saline for a four-month period. The assessment of the inner blood retinal barrier’s structural integrity involved Evans blue dye (EBD) perfusion. Immunofluorescent staining examined the distribution of claudin-5 and occludin (maintainers of tissue barrier integrity), along with markers of oxidative stress and damage—acrolein, 8-OHdG, and nitrotyrosine—in retinal tissues. Transmission electron microscopy scrutinized intricate retinal structures. Western blot techniques evaluated the levels of proteins associated with cell growth and apoptosis, including VEGFR2, Trx-2, Bcl-2, Bax, caspase-3, p53, and NF-κB.

Four months post-exposure, murine models receiving SS-31 exhibited notable improvements, including enhanced retinal cell structures, refined capillary basement membrane composition, reduced inner blood retinal barrier permeability, more consistent staining for claudin-5 and occludin, and decreased levels of acrolein, 8-OHdG, nitrotyrosine, Bax, caspase-3, p53, and NF-κB. In contrast, levels of Trx-2 (which protects from oxidative stress) and Bcl-2 (which protects from cell death) appeared to be elevated. These findings suggest that SS-31 may potentially reinforce retinal structures and mitigate the degradation of the inner blood retinal barrier.

SS-31 and Mitochondrial Revitalization in Aging Skeletal Muscles

Mitochondrial dysfunction is considered to play a role in various pathological processes and unfavorable physiological phenomena, such as sarcopenia, the age-related reduction in muscle tissue size.(7)

To explore the potential of enhancing mitochondrial function as a countermeasure, a study investigated the impact of SS-31 on redox balance and skeletal muscle cell functionality in aged murine models. Young and older female C57BL/6Nia murine models underwent an 8-week exposure to SS-31, with assessments of mitochondrial function employing optical and magnetic resonance spectroscopy.

The findings suggested that SS-31 might counteract the age-related decline in peak mitochondrial ATP production and enhance the efficiency of oxidative phosphorylation (P/O). Notably, despite this mitochondrial enhancement, protein expression in the mitochondria remained constant or even decreased in the exposed older murine models. Respiration in permeabilized gastrocnemius muscle fibers appeared to exhibit no significant difference between the older and SS-31-exposed older models. Additionally, SS-31 was proposed to realign redox homeostasis in aged skeletal muscle cells, leading to a more balanced glutathione redox status. Thiol redox proteomics indicated a significant reversal of cysteine S-glutathionylation post-translational modifications across the skeletal muscle proteome.

Furthermore, gastrocnemius muscle cells in SS-31-exposed older murine models exhibited potentially increased fatigue resistance and apparent mass enhancement compared to unexposed controls. These findings suggest that SS-31 peptide holds promise in ameliorating age-related mitochondrial dysfunction and enhancing skeletal muscle performance.

SS-31 Peptide and Cachexia

Examining its potential against cachexia, a complex condition characterized by diminished oxidative capability and low intracellular ATP due to compromised mitochondrial functionality, one study focused on SS-31’s impact on muscle degradation and metabolic disturbances in C26-bearing (colon adenocarcinoma model) murine models, some subjected to combined exposure of oxaliplatin and 5-fluorouracil for additional cachexia induction.(8)

C26-bearing murine models exhibited mitochondrial impairments linked to alterations in cardiolipin fatty acid chains. Targeting cardiolipin with SS-31 suggested a moderate reduction in overall body wasting and significant prevention of glycolytic myofiber area reduction. Moreover, SS-31 appeared to enhance muscle mitochondrial succinate dehydrogenase (SDH) activity and successfully restore intracellular ATP concentrations, although it did not counteract the loss of mitochondrial proteins.

Progressive increases in SS-31 exposure in C26 OXFU murine models appeared to result in short-lived positive outcomes in body and muscle weight retention before entering a non-responsive, terminal stage by day 28. Remarkably, SS-31 appeared to hold potential in thwarting the loss of mitochondria and aberrant autophagy/mitophagy processes. In-depth metabolome analyses of skeletal muscles, liver, and plasma suggested significant disruptions in energy and protein metabolic pathways in C26 murine models. SS-31 exhibited a potential to partially regulate metabolomes in skeletal muscles and the liver, suggesting an enhancement in systemic energy equilibrium.

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  1. Pang, Y., Wang, C., & Yu, L. (2015). Mitochondria-Targeted Antioxidant SS-31 is a Potential Novel Ophthalmic Medication for Neuroprotection in Glaucoma. Medical hypothesis, discovery & innovation ophthalmology journal, 4(3), 120–126.
  2. Zhang, X., Zhang, Y., Zhang, M., Nakagawa, Y., Caballo, C. B., Szeto, H. H., Deng, X. H., & Rodeo, S. A. (2022). Evaluation of SS-31 as a Potential Strategy for Tendinopathy Treatment: An In Vitro Model. The American journal of sports medicine, 50(10), 2805–2816.
  3. Birk, A. V., Liu, S., Soong, Y., Mills, W., Singh, P., Warren, J. D., Seshan, S. V., Pardee, J. D., & Szeto, H. H. (2013). The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipin. Journal of the American Society of Nephrology : JASN, 24(8), 1250–1261.
  4. Zhu, Y., Wang, H., Fang, J., Dai, W., Zhou, J., Wang, X., & Zhou, M. (2018). SS-31 Provides Neuroprotection by Reversing Mitochondrial Dysfunction after Traumatic Brain Injury. Oxidative medicine and cellular longevity, 2018, 4783602.
  5. Whitson, J. A., Martín-Pérez, M., Zhang, T., Gaffrey, M. J., Merrihew, G. E., Huang, E., White, C. C., Kavanagh, T. J., Qian, W. J., Campbell, M. D., MacCoss, M. J., Marcinek, D. J., Villén, J., & Rabinovitch, P. S. (2021). Elamipretide (SS-31) treatment attenuates age-associated post-translational modifications of heart proteins. GeroScience, 43(5), 2395–2412.
  6. Escribano-López, I., de Marañon, A. M., Iannantuoni, F., López-Domènech, S., Abad-Jiménez, Z., Díaz, P., Solá, E., Apostolova, N., Rocha, M., & Víctor, V. M. (2019). The Mitochondrial Antioxidant SS-31 Modulates Oxidative Stress, Endoplasmic Reticulum Stress, and Autophagy in Type 2 Diabetes. Journal of clinical medicine, 8(9), 1322.
  7. Birk, A. V., Liu, S., Soong, Y., Mills, W., Singh, P., Warren, J. D., Seshan, S. V., Pardee, J. D., & Szeto, H. H. (2013). The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipin. Journal of the American Society of Nephrology : JASN, 24(8), 1250–1261.
  8. Ballarò, R., Lopalco, P., Audrito, V., Beltrà, M., Pin, F., Angelini, R., Costelli, P., Corcelli, A., Bonetto, A., Szeto, H. H., O’Connell, T. M., & Penna, F. (2021). Targeting Mitochondria by SS-31 Ameliorates the Whole Body Energy Status in Cancer- and Chemotherapy-Induced Cachexia. Cancers, 13(4), 850.
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