Samangouei, Parisa;
(2018)
Investigating the role of mitochondrial dynamic proteins MiD49 and MiD51, as novel targets of cardioprotection.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Background Acute myocardial infarction and the heart failure that often ensues are the leading causes of death and disability worldwide. As such, novel therapeutic strategies are required to protect the heart from acute ischaemia-reperfusion injury (IRI). Mitochondria play a central role in determining the fate of cardiomyocytes, during acute myocardial IRI. Genetic and pharmacological inhibition of Drp1-mediated mitochondrial fission has been shown to reduce cardiomyocyte death, during acute IRI. Accordingly, we investigated the role of the newly described mitochondrial-specific Drp1 receptors, MiD49 and MiD51, as novel targets for cardioprotection. We hypothesised that inhibition of MiD49 and MiD51 would render the heart more resistant to acute IRI, and provide novel therapeutic targets for cardioprotection. Methods and Results 1. In cardiac cell-lines, the genetic knockdown (KD) of both MiD49 and MiD51 promoted mitochondrial elongation, inhibited mitochondrial permeability transition pore opening, reduced cell death and prevented mitochondrial calcium overload during simulated IRI, when compared to control cells. 2. In adult mice, MiD49 deficiency had no significant effect on mitochondrial morphology, cardiac size and function, or myocardial infarct size, when compared to wild-type littermates. The effect of dual cardiac-specific genetic ablation of MiD49 and MiD51 in the heart on the susceptibility to acute IRI is currently being investigated. 3. We have developed a biophysical assay to high-throughput screen for novel small molecule inhibitors of the interaction between Drp1 and MiD49 and MiD51, as a therapeutic strategy for inhibiting mitochondrial fission. Conclusions and Further studies For the first time, we provide evidence for the role of MiD49 and MiD51 as novel therapeutic targets for cardioprotection. Studies are ongoing to validate their roles in the adult heart. In order to provide a novel therapeutic strategy for inhibiting mitochondrial fission as a cardioprotective strategy, we aim to identify novel small molecule inhibitors of the interaction between Drp1 and MiD49/MiD51.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Investigating the role of mitochondrial dynamic proteins MiD49 and MiD51, as novel targets of cardioprotection |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2018. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/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 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 Population Health Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Pre-clinical and Fundamental Science |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10062814 |
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