| Popis: |
The cellular response to low oxygen tension (hypoxia) is orchestrated through an elegant pathway involving a number of molecular players and is well characterised in development, physiology and pathology. The hypoxia inducible factors (HIFs) comprise a family of transcription factors whose activity is responsible for mediating transcriptional responses to hypoxia and maintaining cellular oxygen homeostasis. Of particular interest, is the relationship between the HIFs and mitochondria. Mitochondria consume oxygen and generate chemical energy in the form of adenosine triphosphate (ATP). Mitochondrial function and the electron transport chain are necessary for the stabilisation of HIF-α protein in response to hypoxia and the transactivation of HIF target genes. Conversely, mitochondrial adaptation to hypoxia is controlled through a number of HIF target genes. However, the molecular relationship between the HIFs and mitochondria and vice versa is still emerging. Oxygen-dependent regulation of HIF-α protein stability is controlled by the prolyl hydroxylase domain (PHD) proteins. Using several approaches to stabilise and activate the HIFs, this thesis has explored the role of the oxygen-sensing machinery in regulating mitochondrial function. This work identifies altered subcellular localisation of the HIF-complex and PHD proteins. Additionally, manipulation of the oxygen-sensing pathway results in gross mitochondrial morphological and ultrastructural differences in addition to alterations in a number of mitochondrial parameters, including DNA maintenance, electron transport chain (ETC) protein expression, bioenergetics and autophagy. Together these data identify a novel role for members of the oxygen-sensing machinery in mitochondrial function. |
