Howden, Jack Hartley;
(2021)
New insights into mitochondrial quality control mechanisms in neurons and astrocytes.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Mitochondria play essential roles in ATP generation, calcium buffering and apoptotic signalling. In complex neuronal networks of the CNS, mitochondrial quality control systems are essential to maintain a functional mitochondrial network in neurons and glia. The clearance of dysfunctional mitochondria is termed mitophagy and mutations in this pathway are linked to Parkinson’s Disease. This thesis investigated the mitophagy pathway in astrocytes and neurons and identified clear differences in the spatiotemporal regulation, showing that mitophagy occurs quicker and is less spatially restricted in astrocytes compared to neurons. Additionally, it was found that astrocytic mitophagy is dependent on glycolysis. Furthermore, with the use of genetic mouse models, the role of Miro1 in mitophagy in astrocytes and neurons was investigated. This thesis identified a redundancy in the requirement of Miro1 for the mitophagic process in astrocytes yet highlighted its importance for neuronal mitochondrial homeostasis in vitro and in vivo. The loss of Miro1 delayed neuronal mitophagy in vitro and the long-term disruption of mitochondrial quality control in principal neurons lacking Miro1 in vivo led to upregulation of Mfn1/2, remodelling of the mitochondrial network and induction of the integrated stress response. Altogether, this thesis provides important new insights into the cell type-specific regulation of mitochondrial quality control in astrocytes and neurons and outlines how disrupted mitochondrial homeostasis in the CNS can lead to neurodegenerative pathology.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | New insights into mitochondrial quality control mechanisms in neurons and astrocytes |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10134743 |
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