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Mitochondrial Structure-Function in health and disease

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dc.contributor.authorAllen, Mitchell Edisonen
dc.contributor.committeechairBrown, David A.en
dc.contributor.committeememberGrange, Robert W.en
dc.contributor.committeememberPoelzing, Stevenen
dc.contributor.committeememberSchmelz, Eva M.en
dc.contributor.departmentHuman Nutrition, Foods and Exerciseen
dc.date.accessioned2020-10-17T06:00:29Zen
dc.date.available2020-10-17T06:00:29Zen
dc.date.issued2019-04-25en
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
dc.description.abstractgeneralMitochondria, the powerhouses of the cell, form energy networks that produce over 90% of the body’s energy. Mitochondrial dysfunction is implicated across diseases, yet no FDA-approved treatments exist that improve mitochondrial energy production. In this study, we tested the effects of elamipretide, a peptide that localizes to mitochondria. Although elamipretide is currently in clinical trials for several diseases characterized by energetic deficiencies, its mechanism of action is not fully understood. Since mitochondrial structure and function are directly linked, we modeled heart attacks in cultured cells and rat hearts to test the hypothesis that elamipretide and a postulated analog, RYKF, glue damaged mitochondrial membranes back together to preserve structure and function during disease. In hearts subjected to a heart attack, elamipretide significantly protected mitochondrial energy production. Similarly, RYKF protected mitochondrial function in muscle cells exposed to peroxide stress. In damaged hearts imaged with electron microscopy, elamipretide and RYKF treatment significantly improved mitochondrial structure and notably, improved the interconnectedness of mitochondrial energy networks. Furthermore, elamipretide and RYKF improved the integrity of diseased mitochondrial membranes. Together, these data support our hypothesis that elamipretide and RYKF act as mitochondrial adhesion molecules to protect mitochondrial structure and sustain energy production during disease.en
dc.description.degreeDoctor of Philosophyen
dc.format.mediumETDen
dc.identifier.othervt_gsexam:19533en
dc.identifier.urihttp://hdl.handle.net/10919/100601en
dc.publisherVirginia Techen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectmitochondriaen
dc.subjectcristaeen
dc.subjectbioenergeticsen
dc.subjectstructure-functionen
dc.subjectischemia reperfusionen
dc.subjectelamipretideen
dc.titleMitochondrial Structure-Function in health and diseaseen
dc.typeDissertationen
thesis.degree.disciplineHuman Nutrition, Foods, and Exerciseen
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen
thesis.degree.leveldoctoralen
thesis.degree.nameDoctor of Philosophyen

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