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dc.contributor.authorMaddalena, Lucas
dc.date.accessioned2016-10-28T15:51:39Z
dc.date.available2016-10-28T15:51:39Z
dc.identifier.urihttp://hdl.handle.net/10464/10675
dc.description.abstractThe mitochondrial pathway of apoptosis contributes to cell death and tissue degeneration in a variety of human diseases. Targeting the molecular events of this pathway represents a promising therapeutic strategy under pathological scenarios, particularly in tissues with limited regenerative capability (e.g. brain, heart). Recently, the small molecule ‘TPP-IOA’ was designed to target mitochondria and therein inhibit the peroxidase activity of cytochrome c that promotes activation of the apoptotic death pathway (Atkinson et al., Nat. Commun. 2011; 2:497). Therefore, TPP-IOA holds promise as a potential therapeutic agent in many pathological scenarios of cell loss. However, TPP-IOA’s target protein and organelle perform critical functions in aerobic ATP production via oxidative phosphorylation, and yet little is known about TPP-IOA’s interaction with mitochondrial energetics. This is an important consideration for TPP-IOA’s potential future therapeutic utility, as avoiding interference to mitochondrial energetics will be essential for many target cell types that feature a high rate of oxidative phosphorylation (e.g. neurons, cardiomyocytes). Using the purified protein target, isolated organelle target, and live cultured cells, this thesis investigated TPP-IOA’s interaction with fundamental components of energetics-related mitochondrial biology. Assessments with pure cytochrome c revealed that TPP-IOA can inhibit the respiration-associated reduction activity of cytochrome c, and that this occurred at concentrations marginally higher than those required to inhibit the protein’s pro-apoptotic peroxidase activity. In isolated rat liver mitochondria, TPP-IOA impaired oxidative phosphorylation via inhibition of both ADP-phosphorylating-respiration and FCCP-uncoupled respiration, and stimulation of non-phosphorylating respiration. Critically, TPP-IOA was unable to inhibit pro-apoptotic peroxidase activity at concentrations that avoided interference to oxidative phosphorylation, suggesting it may be unable to perform its desired pharmacological activity without causing toxicity to mitochondrial energetics. In live cultured cells, TPP-IOA caused effects associated with impaired oxidative phosphorylation, including a collapsed mitochondrial membrane potential, fragmented mitochondrial network morphology, and apparent loss of mitochondria. Furthermore, TPP-IOA effectively inhibited apoptotic death under lethal conditions in cells that preferentially utilized anaerobic glucose metabolism, but not in cells manipulated to be heavily reliant on oxidative phosphorylation and thus more sensitive to the perturbations to mitochondrial energetics. Altogether, these findings indicate that relative cellular dependence on oxidative phosphorylation is a critical factor influencing TPP-IOA’s pharmacological efficacy. Furthermore, potential therapeutic applications may be limited to pathologies involving predominantly less aerobic tissues/cell types or depressed aerobic metabolism. Additionally, these findings have broader implications for mitochondrial medicine based on similar mitochondrial drug targeting strategies.en_US
dc.language.isoengen_US
dc.publisherBrock Universityen_US
dc.subjectmitochondriaen_US
dc.subjectbioenergeticsen_US
dc.subjectmetabolismen_US
dc.subjectapoptosisen_US
dc.subjectcytochrome cen_US
dc.titleInteractions with bioenergetics by the mitochondria-targeted anti-apoptotic imidazole fatty acid derivative ‘TPP-IOA’.en_US
dc.typeElectronic Thesis or Dissertationen_US
dc.degree.nameM.Sc. Biological Sciencesen_US
dc.degree.levelMastersen_US
dc.contributor.departmentDepartment of Biological Sciencesen_US
dc.degree.disciplineFaculty of Mathematics and Scienceen_US
refterms.dateFOA2021-08-02T01:38:26Z


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