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dc.contributor.authorAllen, Mitchell Edisonen_US
dc.date.accessioned2020-10-17T06:00:29Z
dc.date.available2020-10-17T06:00:29Z
dc.date.issued2019-04-25
dc.identifier.othervt_gsexam:19533en_US
dc.identifier.urihttp://hdl.handle.net/10919/100601
dc.description.abstractMitochondrial structure and function are inextricably linked ("structure-function"), with decrements in structure-function evident across diseases. Barriers to new therapies include a complete understanding of the underlying molecular culprits, as well as effective mitochondria-targeted therapies that mitigate injury. In these works, we investigate the role of cristae-shaping factors like cardiolipin in health and disease. In a series of studies, we tested the effects of the cell-permeable tetrapeptides, elamipretide and a postulated peptide, (arginine-tyrosine-lysine-phenylalanine; "RYKF"), on the recovery of mitochondrial structure-function after injury. Elamipretide is a clinical-stage compound currently under investigation for genetic and age-related mitochondrial diseases, yet the mechanism of action is not completely understood. We used a combination of physiological models, mitochondrial imaging, and biomimetic membrane studies to test the hypothesis that elamipretide and RYKF-cardiolipin interactions improved mitochondrial structure-function. Post-ischemic treatment with elamipretide sustained mitochondrial function across electron transport chain complexes. Endogenous RYKF expression similarly improved mitochondrial respiration after peroxide and hypoxia nutrient deprivation injuries. Using two parallel electron microscopy paradigms, we show elamipretide and RYKF treatment led to maintenance of mitochondrial ultrastructure and notably, improved cristae interconnectedness. Finally, we utilized a novel biomimetic membrane system to model the pathological mitochondrial membrane and found that elamipretide and RYKF both improved biophysical pressure-area relationships through a mechanism that appears to involve aggregating cardiolipin. Our data indicate that targeting pathophysiological mitochondrial membranes with cationic, lipophilic peptides can improve bioenergetics by sustaining cristae networks and support interdependent relationships between mitochondrial structure and function.en_US
dc.format.mediumETDen_US
dc.publisherVirginia Techen_US
dc.rightsThis item is protected by copyright and/or related rights. Some uses of this item may be deemed fair and permitted by law even without permission from the rights holder(s), or the rights holder(s) may have licensed the work for use under certain conditions. For other uses you need to obtain permission from the rights holder(s).en_US
dc.subjectmitochondriaen_US
dc.subjectcristaeen_US
dc.subjectbioenergeticsen_US
dc.subjectstructure-functionen_US
dc.subjectischemia reperfusionen_US
dc.subjectelamipretideen_US
dc.titleMitochondrial Structure-Function in health and diseaseen_US
dc.typeDissertationen_US
dc.contributor.departmentHuman Nutrition, Foods and Exerciseen_US
dc.description.degreeDoctor of Philosophyen_US
thesis.degree.nameDoctor of Philosophyen_US
thesis.degree.leveldoctoralen_US
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen_US
thesis.degree.disciplineHuman Nutrition, Foods, and Exerciseen_US
dc.contributor.committeechairBrown, David A.en_US
dc.contributor.committeememberGrange, Robert W.en_US
dc.contributor.committeememberPoelzing, Stevenen_US
dc.contributor.committeememberSchmelz, Eva Mariaen_US


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