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

Abstract

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.

Keywords: Barth syndrome; Cardiolipin; Elamipretide; MOA; Mechanism; Mitochondria.

Fig. 1.

Representative transmission electron microscopy images of sections of cardiac mitochondria isolated from healthy (wildtype), diseased (TAFAZZIN knockdown), and elamipretide-treated disease mice [13].

Fig. 2.

NMR-detected interaction of amino acids of elamipretide with (A) cardiolipin [20] and (B) elamipretide interactions with a CL-containing lipid bilayer evaluated by molecular dynamics simulations [21]. Abbreviations: CL = cardiolipin.

Fig. 3.

Proposed mechanisms by which the down-regulation of the surface potential on mitochondrial membranes alter lipid bilayer properties. (1) Alteration of the distribution of divalent cations, such as Ca²⁺, which interact strongly with CL. (2) Decrease in the mitotoxic interaction of basic proteins with CL-rich mitochondrial membranes through alteration of lipid bilayer properties, such as demixing and sequestration of CL, resulting in adverse effects on membrane integrity and lipid-protein interactions as well as lipid peroxidation. (3) Alterations in the physical properties of CL-containing bilayers [21]. Abbreviations: CL = cardiolipin; SS-31 = elamipretide.

Fig. 4.

Permeabilized cardiomyocytes exposed to lower external pH demonstrated that permeability of old mitochondria was greater than that of young mitochondria, but elamipretide restored mitochondrial pH stress resistance in permeabilized aged cardiomyocyte mitochondria and reduced proton leakage [33]. Abbreviations: SS-31 = elamipretide.

Fig. 5.

Mitochondrial function is impaired in explanted failing pediatric and human hearts. In explanted tissue from patients with heart failure, elamipretide was associated with improvements in supercomplex coupling control factor (Panel A), respiratory control ratio (Panel B), CI activity (Panel C), and CIV activity (Panel D) [12]. Abbreviations: CI = complex I; CIV = complex IV.

Fig. 6.

Model of the effect of elamipretide affects supercomplex assembly and ETS efficiency [12]. Abbreviations: ATP = adenosine triphosphate.