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

Mitchell E. Allen, Edward Ross Pennington, Justin B. Perry, Sahil Dadoo, Marina Makrecka-Kuka, Maija Dambrova, Fatiha Moukdar, Hetal D. Patel, Xianlin Han, Grahame K. Kidd, Emily K. Benson, Tristan B. Raisch, Steven Poelzing, David A. Brown, Saame Raza Shaikh

Research output: Contribution to journalArticle

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 ischemia-reperfusion. 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.

Original languageEnglish (US)
Article number389
JournalCommunications Biology
Volume3
Issue number1
DOIs
StatePublished - Dec 1 2020

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Medicine (miscellaneous)

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    Allen, M. E., Pennington, E. R., Perry, J. B., Dadoo, S., Makrecka-Kuka, M., Dambrova, M., Moukdar, F., Patel, H. D., Han, X., Kidd, G. K., Benson, E. K., Raisch, T. B., Poelzing, S., Brown, D. A., & Shaikh, S. R. (2020). The cardiolipin-binding peptide elamipretide mitigates fragmentation of cristae networks following cardiac ischemia reperfusion in rats. Communications Biology, 3(1), [389]. https://doi.org/10.1038/s42003-020-1101-3