Contemporary insights into elamipretide’s mitochondrial mechanism of action and therapeutic effects

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. Proposed mechanism of elamipretide in dysfunctional mitochondria. Abbreviations: ADP = adenosine diphosphate; ATP = adenosine triphosphate; IMM = inner mitochondrial membrane; ROS = reactive oxygen species. • Mitochondria electron transport system (ETS) produces essential cellular energy. • ETS is located on cardiolipin (CL)-rich cristae of inner mitochondrial (MITO) membrane. • In disease, elamipretide binds to CL, improving MITO structure, function and dynamics. • In animals, elamipretide improves MITO function in cardiac and skeletal myopathies. • In humans, elamipretide improves symptoms of Barth syndrome myopathy.