The cardiolipin-binding peptide elamipretide mitigates fragmentation of cristae networks following cardiac ischemia reperfusion in rats

Abstract

Mitochondrial dysfunction contributes to cardiac pathologies. Barriers to new therapies include an incomplete understanding of underlying molecular culprits and a lack of effective mitochondria-targeted medicines. Here, we test the hypothesis that the cardiolipin-binding peptide elamipretide, a clinical-stage compound under investigation for diseases of mitochondrial dysfunction, mitigates impairments in mitochondrial structure-function observed after rat cardiac ischemia-reperfusion. Respirometry with permeabilized ventricular fibers indicates that ischemia-reperfusion induced decrements in the activity of complexes I, II, and IV are alleviated with elamipretide. Serial block face scanning electron microscopy used to create 3D reconstructions of cristae ultrastructure reveals that disease-induced fragmentation of cristae networks are improved with elamipretide. Mass spectrometry shows elamipretide did not protect against the reduction of cardiolipin concentration after ischemiareperfusion. Finally, elamipretide improves biophysical properties of biomimetic membranes by aggregating cardiolipin. The data suggest mitochondrial structure-function are interdependent and demonstrate elamipretide targets mitochondrial membranes to sustain cristae networks and improve bioenergetic function.

Metabolomic biomarkers from patients with Barth syndrome treated with elamipretide: insights from the TAZPOWER study

“…Additionally, improved bioenergetic efficiency would reduce the overall need for carbon substrates to support metabolism, which may also contribute to the reductions in various metabolite concentrations observed. These suppositions are in agreement with prior pre-clinical [11,13,49,50] and clinical [51,52] data in settings other than Barth syndrome, indicating that elamipretide treatment can bring about a more efficient bioenergetic state.…”

“…The loss of mature cardiolipin in Barth syndrome results in cascades of cellular dysfunction, including loss of energy and redox homeostasis, calcium overload, and cell death (for review see Sabbah [3]). Improved mitochondrial structure [13] and ETC/supercomplex function [33] with elamipretide are also expected to improve the local availability of oxidized FAD and NAD + cofactors essential for complete β-oxidation of fats [47,48]. All of these factors may contribute to the decreases in plasma and urine acylcarnitines, as well as the trends for lower acetylcarnitine, 3-methylglutaconate, and 3-hydroxybutyrate observed in this study.…”

“…Patients with Barth syndrome have increased levels of immature cardiolipin (monolysocardiolipin), decreased remodeled cardiolipin, and resulting mitochondrial dysfunction [3]. Across numerous pre-clinical models, elamipretide has been shown to improve mitochondrial structure and function in a cardiolipin-dependent manner [13,14], resulting in improved heart and skeletal muscle function.…”

A phase 2/3 randomized clinical trial followed by an open-label extension to evaluate the effectiveness of elamipretide in Barth syndrome, a genetic disorder of mitochondrial cardiolipin metabolism

“…There, it binds to cardiolipin via electrostatic and hydrophobic interactions, 15 and is hypothesized to sustain the cristae network and remediate bioenergetic dysfunction. 16 SS-31 has shown benefit in preclinical mitochondrial disorders and heart failure. 15,[17][18][19][20] We performed a randomized, double-blind, placebocontrolled crossover trial with an open-label extension to test the clinical efficacy and safety of daily administration of elamipretide in individuals with genetically confirmed Barth syndrome.…”

In Vivo Mitochondrial ATP Production Is Improved in Older Adult Skeletal Muscle After a Single Dose of Elamipretide in a Randomized Trial

“…Early studies inaccurately described ELAM as having antioxidant properties, [19][20][21] although more recent work has demonstrated that ELAM actually reduces production of superoxide and H2O2 particularly where overproduction resulted from dysfunctional mitochondria [22,23]. Studies in isolated mitochondria, cells and intact organs reveal improved ETC flux, reduced mitochondrial generation of reactive oxygen species (ROS; H2O2), and elevated ATP generation with ELAM treatment after ischemic insult and heart failure [16,24,25]. In skeletal muscle, treatment with ELAM prevented the increase in mitochondrial oxidative stress and muscle wasting associated with disuse atrophy in mouse hindlimb and diaphragm.…”