Evaluating and targeting mitochondrial dynamics and plasticity in conditions of mitochondrial dysfunction
dc.contributor.author | Bagshaw, Olivia Rita Marie | |
dc.date.accessioned | 2022-08-15T17:29:58Z | |
dc.date.available | 2022-08-15T17:29:58Z | |
dc.identifier.uri | http://hdl.handle.net/10464/16496 | |
dc.description.abstract | Mitochondria represent dynamic structures which undergo various changes in morphology in order to rapidly respond to changes in cellular physiology. Changes in mitochondrial dynamics are observed in various pathological events and represent a potential target for therapeutics. In this thesis, I first investigated the role of zinc supplementation on rat aortic endothelial (RAENDO) and smooth muscle (RASMC) cell mitochondrial form and function to elucidate the underlying mechanisms by which zinc prevents the development of smooth muscle neointimal hyperplasia in vivo. I discovered that zinc differentially alters the gene expression of several mitochondria-associated genes in cells treated with ZnSO4 for 7 days. In agreement with this, an increase in mitochondrial network fragmentation (fission) is observed in RAENDO cells, whereas fusion is observed in RASMC cells with zinc treatment. I determined that cell-type specific differences in zinc storage and buffer capacity necessitating different mitochondrial quality control mechanisms may underscore differential responses to zinc exposure in vivo. These results highlight mitochondria as an important target for the treatment or prevention of neointimal hyperplasia in vivo. The potential to modulate mitochondrial network morphology to alter cellular function lead to the second study of this thesis, in which a mitochondrial-targeting moiety, triphenylphosphonium (TPP), is employed to target mitochondrial lipid composition. Here, I evaluated the use of TPP-linoleic acid (TPP-LA) to modulate mitochondrial cardiolipin (CL) composition in a tafazzin knockout (TAZKO) mouse myoblast model of Barth syndrome, a disease characterized by abnormal CL composition. My results indicate that TPP-LA non-significantly enhances mitochondrial membrane potential and apparent fusion in TAZKO and isogenic wildtype (WT) cells. CL analyses reveal that TPP-LA administration for 14 days during differentiation may rescue the CL profile of TAZKO cells. TPP-LA treatment also enhances biochemical differentiation in WT cells but fails to rescue differentiation in TAZKO cells. These results highlight the complex relationship between mitochondrial lipid composition and modulation of mitochondrial dynamics. Taken together, these two projects highlight the plastic nature of mitochondria, their role in pathological conditions and potential as therapeutic targets. | en_US |
dc.language.iso | eng | en_US |
dc.publisher | Brock University | en_US |
dc.subject | mitochondrial dynamics | en_US |
dc.subject | barth syndrome | en_US |
dc.subject | zinc | en_US |
dc.subject | biodegradable materials | en_US |
dc.subject | cardiolipin | en_US |
dc.title | Evaluating and targeting mitochondrial dynamics and plasticity in conditions of mitochondrial dysfunction | en_US |
dc.type | Electronic Thesis or Dissertation | en |
dc.degree.name | M.Sc. Biological Sciences | en_US |
dc.degree.level | Masters | en_US |
dc.contributor.department | Department of Biological Sciences | en_US |
dc.degree.discipline | Faculty of Mathematics and Science | en_US |
refterms.dateFOA | 2022-08-15T17:29:59Z |