Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.627943
Title: Autophagy and mitochondrial quality control in homeostasis and disease
Author: MacVicar, Thomas D. B.
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2013
Availability of Full Text:
Access through EThOS:
Abstract:
Mitochondria are the powerhouses of eukaryotic cells and they must remain healthy in order to generate sufficient ATP for cellular function. Dysfunctional mitochondria pose a grave threat to high-energy demanding tissues and are associated with an array of human diseases. Mitochondria exist in a dynamic organelle network that is essential for their intracellular distribution and quality control. A damaged mitochondrion must first be exiled from the network by mitochondrial fission and next be neutralized by a process termed mitophagy. A number of mitophagy pathways exist to specifically target damaged or redundant mitochondria for engulfment by double-membrane autophagosomes in order to deliver them to the acidic lysosome for degradation. This dissertation explores the regulation and molecular mechanisms of the PINK1/Parkin mitophagy pathway. Mutated in several forms of Parkinson's disease, the PINK1 kinase and Parkin E3-ubiquitin ligase govern the selective degradation of dysfunctional mitochondria and they have been demonstrated to play key neuroprotective roles in vitro and in vivo. Here, the role of mitochondrial bioenergetics in regulating mitophagy is investigated. By employing a range of biochemical and imaging techniques in a cell-based model of Parkin-mediated mitophagy, the following data demonstrate how cells dependent on mitochondrial respiration can avoid mitophagy via intricate control of mitochondrial dynamics. In order to maintain the energy supply, respiring cells can resist mitophagy by preserving an interconnected mitochondrial network via inhibition of Drp1 and impaired OMA1-dependent OPA1 cleavage. This dissertation also questions the importance of close contact between the mitochondria and endoplasmic reticulum (ER) for the progression of Parkin-mediated mitophagy. A focused siRNA screen of ER-mitochondrial communication factors highlights a novel role for ER-mitochondrial Ca2+ signa ling during Parkin-mediated mitophagy. Together, the data presented in this dissertation place mitochondrial bioenergetic demand and Ca2+ flux as key players in the regulation of mitophagy. Further research will be required to identify whether these two regulatory arms are linked and will strengthen the therapeutic potential for positively modulating mitochondrial homeostasis in order to promote cell protection.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.627943  DOI: Not available
Share: