SS-31 (Szeto-Schiller-31), also known as MTP-131, is a tetrapeptide that has garnered interest for its potential properties related to mitochondrial dysfunction. With a unique characteristic of holding a cationic 3+ charge at physiological pH, this molecule appears to permeate cell membranes with ease and potentially traverses the blood-brain barrier. It has been suggested to rapidly exit cells, despite not being a substrate for P-glycoprotein. One of the most researched attributes of SS-31 is its potential to accumulate in the inner mitochondrial membrane at concentrations that appear to be over 1000 times greater than in plasma. There, the peptide may display a potential affinity for cardiolipin, an anionic phospholipid exclusively found in the inner mitochondrial membrane. This binding has been suggested to disrupt the interactions between cardiolipin and cytochrome C, leading to a reduction in the oxidative inactivation of cardiolipin by cytochrome C. The mechanism may involve inhibiting the peroxidase activity of cytochrome c, while preserving Met80-heme ligation and favoring its electron carrier activity by SS-31. Given that cardiolipin has been suggested to play a pivotal role in optimizing mitochondrial electron transport and ATP production, this disruption has significant potential. It may help in the formation of mitochondrial cristae, ensuring efficient oxidative phosphorylation and minimizing the leakage of reactive oxygen species.
 
SS-31 and Aging
SS-31 may exhibit potential actions against aging, as posited by a trial examining the actions of the peptide on cardiac proteins in aged murine models. The study delved into the potential of SS-31 on post-translational modifications of heart proteins. The myocardium of aged murine models had an apparent rise in the oxidation of protein thiols (sulfur-containing groups in proteins), indicated by the enhanced S-glutathionylation of cysteine residues, especially when compared to young murine models. An 8-week intervention with SS-31 appeared to almost entirely reverse this age-associated proteomic oxidation. The authors commented that significant shifts were apparently detected, predominantly in proteins purported as important for mitochondrial or cardiac function. Further, age-correlated modifications in the murine heart appeared to undergo partial reversal post SS-31 exposure. More specifically, the researchers noted “changes in the mouse heart phosphoproteome that were associated with age, some of which were partially restored with elamipretide.” Thus, the findings suggest that alterations in the thiol redox state and phosphorylation status could be pathways through which aging may impact murine heart functionality. Importantly, these age-induced changes seem to be mitigated with SS-31 influence.
 
SS-31 and Neuroprotection
SS-31 has been suggested to provide neuroprotection in a range of experimental models. Its function as a mitochondrial reactive oxygen species (ROS) scavenger and the inherent mechanisms in neuronal injury remain elusive. Yet, one trial aimed to delve into the neuroprotective potential of SS-31 and comprehend any apparent mitochondrial alterations using murine models of neuronal injury. Murine models were categorized into sham, neuronal injury, neuronal injury + vehicle, and neuronal injury + SS-31 groups. The peptide SS-31 or vehicle was introduced post-neuronal injury, and brain specimens were procured 24 hours thereafter for analysis. The introduction of SS-31 appeared to counteract mitochondrial impairment and lessened secondary neuronal injury. It may directly reduce the reactive oxygen species content, rejuvenate the activity of superoxide dismutase (SOD), lower malondialdehyde (MDA) levels, and curb the release of cytochrome C, thereby mitigating potential neurological impairments, brain hydration, DNA destruction, and neural apoptosis. Additionally, SS-31 appeared to have reinstated the SIRT1 expression and amplified the nuclear relocation of PGC-1α, as suggested by Western blot and immunohistochemistry. Collectively, these findings suggest that SS-31 enhances mitochondrial function and may confer neuroprotection in murine models post-neuronal injury, possibly via augmented mitochondrial rebirth.
 
SS-31 and Metabolic Conditions
Studies have investigated the potential mechanisms and effects of SS-31 on leukocytes from models with type 2 diabetes (T2D), focusing on oxidative stress, endoplasmic reticulum (ER) stress, and autophagy. The trial included samples from models of type 2 diabetes and controls. Key metrics such as anthropometric and analytical measurements were considered. Results indicated that leukocytes from the T2D models exhibited increased levels of reactive oxygen species (ROS), elevated calcium content, and pronounced expression of ER stress markers like GRP78 and CHOP. However, exposure to SS-31 appeared to significantly mitigate these elevated levels, hinting at its possible protective effects. Similarly, SS-31 appeared to have led to a decrease in BECN1 gene expression, along with reductions in Beclin1 and LC3 II/I protein expressions. Conversely, the protein levels of p62, which were found to be reduced in type 2 diabetes models, appeared rejuvenated post SS-31 exposure. An interesting observation was that SS-20, a compound without antioxidant activity, did not manifest any noticeable change in the parameters studied. Additionally, SS-31 may have exhibited properties that impacted leukocyte-endothelium interactions. Specifically, in type 2 diabetes models, it appeared to reduce rolling flux and leukocyte adhesion, while enhancing rolling velocity. Thus, the researchers commented that “SS-31 exerts potentially beneficial effects on leukocytes of T2D patients modulating oxidative stress and autophagy, and ameliorating endoplasmic reticulum stress.”
 
SS-31 and Kidney Function
Ischemia is a pathological condition which leads to organ injury such as acute kidney injury as a result of ATP depletion. Thus, swift recovery of ATP upon reperfusion is vital to reduce tissue damage. However, ATP recovery is often delayed since ischemia damages the mitochondrial cristae membranes, which are essential for mitochondrial ATP synthesis. The mitochondria-targeted compound SS-31 has been suggested to quicken ATP recovery post-ischemia and potentially diminish acute kidney injury. In one investigation, scientists utilized a polarity-sensitive fluorescent analog of SS-31 to show that SS-31 may bind with high affinity to cardiolipin that is crucial for cristae formation. Moreover, the SS-31/cardiolipin complex appeared to shield its heme iron and thus impede cytochrome C peroxidase activity, a reaction responsible for cardiolipin peroxidation leading to mitochondrial damage during ischemia. When murine models were exposed to SS-31, it appeared to safeguard the cristae membranes during renal ischemia, averting mitochondrial swelling. Immediate recovery of ATP upon reperfusion may also enable the speedy repair of ATP-dependent processes, such as the reformation of the actin cytoskeleton and cell polarity. This swift ATP recovery may also work to suppress apoptosis, fortify tubular barrier function, and alleviate renal dysfunction. Thus, Szeto-Schiller-31 may potentially preserve mitochondrial cristae by engaging with cardiolipin on the inner mitochondrial membrane.
 
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