On the Regulation of Mitochondrial Fusion, Fission and Mitochondrial DNA
| dc.contributor.advisor | Shutt, Timothy E. | |
| dc.contributor.author | Sabouny, Rasha | |
| dc.contributor.committeemember | Sinasac, David S. | |
| dc.contributor.committeemember | Schriemer, David C. | |
| dc.contributor.committeemember | Corcoran, Jennifer A. | |
| dc.contributor.committeemember | Hoppins, Suzanne C, | |
| dc.date | 2020-06 | |
| dc.date.accessioned | 2020-04-16T15:40:54Z | |
| dc.date.available | 2020-04-16T15:40:54Z | |
| dc.date.issued | 2020-04-13 | |
| dc.description.abstract | Mitochondria are functionally and structurally fascinating organelles, well known for their role as the cellular powerhouse. Unlike other membrane bound organelles, mitochondria maintain their own genome (mtDNA), which is present in hundreds of copies per cell, packaged into nucleo-protein structures known as nucleoids. An important regulator of mitochondrial function is their dynamic nature, whereby ongoing fusion and fission events remodel mitochondrial network morphology and influence mitochondrial activity. Dynamic fusion and fission forces are also key for distributing mtDNA nucleoids throughout mitochondrial networks and the maintenance of mtDNA copy number. Notably, mutations in core mitochondrial fusion (MFN2, OPA1) and fission (DRP1) proteins lead to enlarged nucleoids, mtDNA depletion and cause severe mitochondrial diseases. However, we do not completely understand how or why these processes are important for mtDNA. Additionally, there remains a lot to be learned about the molecular regulators mediating fusion and fission of mitochondrial networks. This project set out to characterize novel mitochondrial fusion and fission factors and further understand how defective fusion and fission regulation influence mtDNA dynamics. The work outlined in this thesis showcases three nuclear-encoded mitochondrial disease genes (FBXL4, MSTO1 & MYH14) implicated as regulators of mitochondrial morphology and shown to be important for mtDNA regulation. Firstly, this work characterizes an established mtDNA depletion syndrome gene, FBXL4 and provides the first evidence that FBXL4 protein is a mitochondrial fusion regulator. Secondly, MSTO1, a recently described cytosolic fusion regulator, is highlighted as perturbations in MSTO1 pro-fusion activity gives rise to mtDNA depletion and altered nucleoid distribution. Lastly, the largely uncharacterized non-muscle myosin protein, NMIIC, encoded by MYH14, is highlighted as novel component of the mitochondrial fission machinery. A pathogenic mutation in MYH14 causing peripheral neuropathy reduces fission and adversely affects the distribution of mtDNA nucleoids, particularly at the cell periphery. Through genetic and pharmacological rescue approaches to restore mitochondrial network morphology in these models, this work contributes to our understanding on the interplay between fusion and fission dynamics and mtDNA maintenance. | en_US |
| dc.identifier.citation | Sabouny, R. (2020). On the Regulation of Mitochondrial Fusion, Fission and Mitochondrial DNA (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. | en_US |
| dc.identifier.doi | http://dx.doi.org/10.11575/PRISM/37680 | |
| dc.identifier.uri | http://hdl.handle.net/1880/111801 | |
| dc.publisher.faculty | Cumming School of Medicine | en_US |
| dc.publisher.institution | University of Calgary | en |
| dc.rights | University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission. | en_US |
| dc.subject | Mitochondria, Mitochondrial Dynamics, Fusion, Fission, Mitochondrial DNA, mtDNA, FBXL4, MSTO1, MYH14 | en_US |
| dc.subject.classification | Biology--Cell | en_US |
| dc.subject.classification | Genetics | en_US |
| dc.subject.classification | Biology--Molecular | en_US |
| dc.subject.classification | Neuroscience | en_US |
| dc.subject.classification | Human Development | en_US |
| dc.subject.classification | Biochemistry | en_US |
| dc.title | On the Regulation of Mitochondrial Fusion, Fission and Mitochondrial DNA | en_US |
| dc.type | doctoral thesis | en_US |
| thesis.degree.discipline | Medicine – Biochemistry and Molecular Biology | en_US |
| thesis.degree.grantor | University of Calgary | en_US |
| thesis.degree.name | Doctor of Philosophy (PhD) | en_US |
| ucalgary.item.requestcopy | true | en_US |