{"id":{"repo_id":"vt","oai_identifier":"oai:vtechworks.lib.vt.edu:10919/100601"},"canonical_url":"https://search.dev.ndltd.org/etd/vt/oai:vtechworks.lib.vt.edu:10919/100601","repository":{"repo_id":"vt","name":"Virginia Tech","base_url":"https://vtechworks.lib.vt.edu/oai/request"},"display":{"title":"Mitochondrial Structure-Function in health and disease","abstract":"Mitochondrial 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.","abstract_html":"Mitochondrial 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.","abstract_has_math":false,"creators":["Allen, Mitchell Edison"],"institution":"Virginia Tech","degree_name":"Doctor of Philosophy","degree_level":"doctoral","degree_discipline":"Human Nutrition, Foods, and Exercise","degree_department":"Human Nutrition, Foods and Exercise","school":null,"contributors":[],"advisors":[],"committee_chairs":["Brown, David A."],"committee_members":["Grange, Robert W.","Poelzing, Steven","Schmelz, Eva M."],"year":2019,"date_issued":"2019-04-25","date_published":"2019-04-25","updated_at":"2026-07-22T22:18:44Z","subjects":["mitochondria","cristae","bioenergetics","structure-function","ischemia reperfusion","elamipretide"],"languages":[],"rights":["In Copyright"],"rights_urls":["http://rightsstatements.org/vocab/InC/1.0/"],"identifier_entries":[{"key":"dc:identifier.other","label":"Dc Identifier Other","values":["vt_gsexam:19533"],"render_values":[{"text":"vt_gsexam:19533","href":null,"code":true}]}]},"links":{"outbound_url":"http://hdl.handle.net/10919/100601","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.committeechair","label":"Committee Chair","values":["Brown, David A."]},{"key":"dc:contributor.committeemember","label":"Committee Member","values":["Grange, Robert W.","Poelzing, Steven","Schmelz, Eva M."]},{"key":"dc:contributor.department","label":"Department","values":["Human Nutrition, Foods and Exercise"]},{"key":"dc:creator","label":"Author","values":["Allen, Mitchell Edison"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2020-10-17T06:00:29Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2020-10-17T06:00:29Z"]},{"key":"dc:date.issued","label":"Date","values":["2019-04-25"]},{"key":"dc:publisher","label":"Institution","values":["Virginia Tech"]},{"key":"dc:type","label":"Dc Type","values":["Dissertation"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Human Nutrition, Foods, and Exercise"]},{"key":"thesis:degree_level","label":"Degree Level","values":["doctoral"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Doctor of Philosophy"]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["Virginia Polytechnic Institute and State University"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["mitochondria","cristae","bioenergetics","structure-function","ischemia reperfusion","elamipretide"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:rights","label":"Dc Rights","values":["In Copyright"]},{"key":"dc:rights.uri","label":"Rights URI","values":["http://rightsstatements.org/vocab/InC/1.0/"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.other","label":"Dc Identifier Other","values":["vt_gsexam:19533"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["http://hdl.handle.net/10919/100601"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Mitochondrial 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."]},{"key":"dc:description.abstractgeneral","label":"General Abstract","values":["Mitochondria, 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."]},{"key":"dc:description.degree","label":"Dc Description Degree","values":["Doctor of Philosophy"]},{"key":"dc:format.medium","label":"Dc Format Medium","values":["ETD"]},{"key":"dc:title","label":"Title","values":["Mitochondrial Structure-Function in health and disease"]}]}],"canonical_facts":{"dc:contributor.committeechair":["Brown, David A."],"dc:contributor.committeemember":["Grange, Robert W.","Poelzing, Steven","Schmelz, Eva M."],"dc:contributor.department":["Human Nutrition, Foods and Exercise"],"dc:creator":["Allen, Mitchell Edison"],"dc:date.accessioned":["2020-10-17T06:00:29Z"],"dc:date.available":["2020-10-17T06:00:29Z"],"dc:date.issued":["2019-04-25"],"dc:description.abstract":["Mitochondrial 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."],"dc:description.abstractgeneral":["Mitochondria, 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."],"dc:description.degree":["Doctor of Philosophy"],"dc:format.medium":["ETD"],"dc:identifier.other":["vt_gsexam:19533"],"dc:identifier.uri":["http://hdl.handle.net/10919/100601"],"dc:publisher":["Virginia Tech"],"dc:rights":["In Copyright"],"dc:rights.uri":["http://rightsstatements.org/vocab/InC/1.0/"],"dc:subject":["mitochondria","cristae","bioenergetics","structure-function","ischemia reperfusion","elamipretide"],"dc:title":["Mitochondrial Structure-Function in health and disease"],"dc:type":["Dissertation"],"thesis:degree_discipline":["Human Nutrition, Foods, and Exercise"],"thesis:degree_level":["doctoral"],"thesis:degree_name":["Doctor of Philosophy"],"thesis:institution_name":["Virginia Polytechnic Institute and State University"]},"updated_at":"2026-07-22T22:18:44Z"}