SS-31, a Mitochondria-Targeting Peptide, Ameliorates Kidney Disease

Abstract

Mitochondria are essential for eukaryotic cell activity and function, and their dysfunction is associated with the development and progression of renal diseases. In recent years, there has been a rapid development in mitochondria-targeting pharmacological strategies as mitochondrial biogenesis, morphology, and function, as well as dynamic changes in mitochondria, have been studied in disease states. Mitochondria-targeting drugs include nicotinamide mononucleotide, which supplements the NAD+ pool; mitochondria-targeted protective compounds, such as MitoQ; the antioxidant coenzyme, Q10; and cyclosporin A, an inhibitor of the mitochondrial permeability transition pore. However, traditional drugs targeting mitochondria have limited clinical applications due to their inability to be effectively absorbed by mitochondria in vivo and their high toxicity. Recently, SS-31, a mitochondria-targeting antioxidant, has received significant research attention as it decreases mitochondrial reactive oxygen species production and prevents mitochondrial depolarization, mitochondrial permeability transition pore formation, and Ca²⁺-induced mitochondrial swelling, and has no effects on normal mitochondria. At present, few studies have evaluated the effects of SS-31 against renal diseases, and the mechanism underlying its action is unclear. In this review, we first discuss the pharmacokinetics of SS-31 and the possible mechanisms underlying its protective effects against renal diseases. Then, we analyze its renal disease-improving effects in various experimental models, including animal and cell models, and summarize the clinical evidence of its benefits in renal disease treatment. Finally, the potential mechanism underlying the action of SS-31 against renal diseases is explored to lay a foundation for future preclinical studies and for the evaluation of its clinical applications.

Figure 1

Mechanism of action of SS-31 against kidney disease. Mitochondria produce ATP and ROS through an electron transport chain consisting of complexes I to V. Ischemia, hypoxia, hyperglycemia, drugs, obstruction, genetic, and other risk factors can affect the kidneys, causing mitochondrial dysfunction and kidney disease. SS-31 protects mitochondrial structure, scavenges ROS, increases ATP supply, reduces cytochrome C release, and inhibits mPTP opening and calcium overload by binding to cardiolipin in the inner membrane of mitochondria, thereby exerting anti-oxidative stress, anti-inflammatory, antifibrotic, antiapoptotic, and autophagic effects.

Figure 2

SS-31 potential protective mechanisms and signaling pathways. SS-31 concentrates on the inner mitochondrial membrane, by scavenging ROS, increasing ATP synthesis, and inhibiting mPTP opening; it can reduce lipid peroxidation, thereby improving ferroptosis, apoptosis, necrosis, and pyroptosis. In addition, SS-31 may also regulate apoptosis through PKC, MAPK, and NF-κB signaling pathways.