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Title: Investigating the role of mitochondrial dynamic proteins MiD49 and MiD51, as novel targets of cardioprotection
Author: Samangouei, Parisa
ISNI:       0000 0004 7659 7667
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2018
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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.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available