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

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dc.contributor.authorAllen, Mitchell E.en
dc.contributor.authorPennington, Edward Rossen
dc.contributor.authorPerry, Justin B.en
dc.contributor.authorDadoo, Sahilen
dc.contributor.authorMakrecka-Kuka, Marinaen
dc.contributor.authorDambrova, Maijaen
dc.contributor.authorMoukdar, Fatihaen
dc.contributor.authorPatel, Hetal D.en
dc.contributor.authorHan, Xianlinen
dc.contributor.authorKidd, Grahame K.en
dc.contributor.authorBenson, Emily K.en
dc.contributor.authorRaisch, Tristan B.en
dc.contributor.authorPoelzing, Stevenen
dc.contributor.authorBrown, David A.en
dc.contributor.authorShaikh, Saame Razaen
dc.contributor.departmentHuman Nutrition, Foods, and Exerciseen
dc.contributor.departmentFralin Biomedical Research Instituteen
dc.contributor.departmentBiomedical Engineering and Mechanicsen
dc.contributor.departmentCenter for Drug Discoveryen
dc.date.accessioned2020-11-11T14:28:58Zen
dc.date.available2020-11-11T14:28:58Zen
dc.date.issued2020-07-17en
dc.description.abstractAllen and Pennington et al. show that the cardiolipin-binding peptide elamipretide mitigates disease-induced fragmentation of cristae networks following cardiac ischemia reperfusion in rats. This study suggests that elamipretide targets mitochondrial membranes to sustain cristae networks, improving their bioenergetic function. 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.en
dc.description.notesWe are grateful for the support provided by Kathy Lowe of the Virginia Tech Electron Microscopy Core. We are also thankful for the contributions of Ella Maru Studio for professional illustrations used in Fig. 6 of our manuscript. These studies were supported by research grants from the National Institutes of Health, NHLBI 1R01HL123647 (to S.R.S. and D.A.B.), R01HL141855 (to S.P.), R01HL102298 (to S.P.), R01HL138003 (to S.P.), P30DK056350 (to S.R.S.), Stealth BioTherapeutics (to D.A.B. and S.R.S.), USDA National Institute of Food and Agriculture Hatch Project 1017927 (to D.A. B.), and a Translational Obesity Research Fellowship from the Virginia Tech Interdisciplinary Graduate Education Program (to M.E.A.).en
dc.description.sponsorshipNational Institutes of Health, NHLBIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Heart Lung & Blood Institute (NHLBI) [1R01HL123647, R01HL141855, R01HL102298, R01HL138003, P30DK056350]; Stealth BioTherapeutics; USDA National Institute of Food and Agriculture Hatch Project [1017927]; Translational Obesity Research Fellowship from the Virginia Tech Interdisciplinary Graduate Education Programen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1038/s42003-020-1101-3en
dc.identifier.eissn2399-3642en
dc.identifier.issue1en
dc.identifier.other389en
dc.identifier.pmid32680996en
dc.identifier.urihttp://hdl.handle.net/10919/100835en
dc.identifier.volume3en
dc.language.isoenen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.titleThe cardiolipin-binding peptide elamipretide mitigates fragmentation of cristae networks following cardiac ischemia reperfusion in ratsen
dc.title.serialCommunications Biologyen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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