Mitochondrial dysfunction has been identified as a key factor in the progression of Parkinson's disease. Mitochondrial dysfunction has been shown to induce stress pathways, leading to neuronal dysfunction and cell death. Our lab has previously identified that, in neurons, reconfiguring the mitochondria using supercomplex assembly factors is protective against excitotoxic stress. For this thesis, we sought to characterize the stress pathways and synaptic impairment in an in vitro mitochondrial dysfunction model. Then, to determine if we can rescue the deficits shown, we manipulated mitochondrial integrity using the inner mitochondrial membrane targeted isoform of MCL1, which has previously been shown to regulate cristae structure and mitochondrial supercomplex assembly. We demonstrate that the integrated stress response is activated upon mitochondrial dysfunction. Next, we show mitochondrial dysfunction leads to a downregulation of synaptic genes involved in neurotransmission. Finally, our results show that both the antiapoptotic outer mitochondrial membrane-targeted isoform, and MCL1-Matrix are able to prevent cell death in response to mitochondrial dysfunction; however, MCL1-Matrix confers greater reduction in ISR activation and reactive oxygen species production. These data suggest that manipulating mitochondrial integrity, using MCL1-Matrix, confers a broad protective effect against neuronal stressors and may be used as a novel approach to preventing Parkinson's disease.
| Identifer | oai:union.ndltd.org:uottawa.ca/oai:ruor.uottawa.ca:10393/44084 |
| Date | 21 September 2022 |
| Creators | Chen, Jingwei |
| Contributors | Slack, Ruth |
| Publisher | Université d'Ottawa / University of Ottawa |
| Source Sets | Université d’Ottawa |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
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