SS-31 aka Elamipretide
“Mitochondria are cellular hubs integral for metabolism, signaling, and survival. Mitochondrial dysfunction is centrally involved in the aging process and an expansive array of disease states. Elamipretide is a novel mitochondria-targeting peptide that is under investigation for treating several disorders related to mitochondrial dysfunction. This review summarizes recent data that expand our understanding of the mechanism of action (MOA) of elamipretide. Elamipretide is a potential first-in-class therapeutic that targets the inner mitochondrial membrane. Despite initial descriptions of elamipretide’s MOA involving reactive oxygen species scavenging, the last ten years have provided a significant expansion of how this peptide influences mitochondrial bioenergetics. The cardiolipin binding properties of elamipretide have been corroborated by different investigative teams with new findings about the consequences of elamipretide-cardiolipin interactions. In particular, new studies have shown elamipretide-mediated modulation of mitochondrial membrane electrostatic potentials and assembly of cardiolipin-dependent proteins that are centrally involved in mitochondrial physiology. These effects contribute to elamipretide’s ability to improve mitochondrial function, structure, and bioenergetics. In animal studies, elamipretide-mediated amelioration of organ dysfunction has been observed in models of cardiac and skeletal muscle myopathies as well as ocular pathologies. A number of clinical trials with elamipretide have been recently completed, and a summary of the results focusing on Barth syndrome, primary mitochondrial myopathy, and age-related macular degeneration, is also provided herein. Elamipretide continues to show promise as a potential therapy for mitochondrial disorders. New basic science advances have improved understanding of elamipretide’s MOA, enabling a better understanding of the molecular consequences of elamipretide-cardiolipin interactions.”
"By localizing to the IMM and associating with CL, elamipretide improves assembly of ETS complexes into respiratory supercomplexes and as a result, respiratory efficiency [55,56], thereby improving bioenergetics, reducing ROS production, and improving mitochondrial morphology in dysfunctional mitochondria.
Recent studies show that elamipretide interacts with proteins that are associated with the IMM, interact with CL, and are involved in oxidative phosphorylation. Elamipretide has also been recently shown to modulate mitochondrial membrane surface electrostatic properties, which may underpin its modulation of electron carrier properties and its ability to interact with ANT and ETS supercomplexes. These changes of membrane physical properties can themselves elicit improvements in overall mitochondrial function that are independent of alterations in constituent protein structure and function, and therefore reinforces elaimpretide’s ability to target mitochondrial health at multiple levels within the organelle itself.
Preclinical models of disease also show that elamipretide improves mitochondrial structure and function, enhances mitochondrial bioenergetics, and is associated with improvements in physiologic functions, such as cardiac and skeletal muscle performance, as well as improvements in age-related retinal dysfunction. Clinical trials also support elamipretide’s efficacy in mitochondrial-related diseases (eg, BTHS, mitochondrial myopathy, and AMD), although the results have been mixed, which may be due to a variety of factors including the difficulty in identifying appropriate endpoints, small patient populations, and inadequate treatment duration."
