Beikoghli Kalkhoran, Siavash; (2018) Imaging Mitochondrial Dynamics in the Adult Heart. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Background Mitochondrial dynamics, the phenomenon which incorporates inter-mitochondrial communication and changes in mitochondrial morphology is central to cellular homeostasis. Although the phenomenon of mitochondrial dynamics has been comprehensively studied under normal and pathological conditions in non-cardiac cells, and more recently in cardiac cell lines, its relevance to adult cardiomyocytes has not been so well-established and is investigated in this thesis. Methods and Results Using 2D and 3D electron microscopy, we initially evaluated the morphological features of the 3 different mitochondrial subpopulations (interfibrillar, peri-nuclear, subsarcolemmal) in adult rodent cardiomyocytes, and demonstrated that they are morphologically unique. These morphological characteristics were found to be altered under pathological conditions such as ischaemia or the genetic ablation of mitochondrial fusion proteins “mitofusins”. Using mice expressing the Dendra2 fluorescence probe, we then confirmed that mitochondrial fusion events (“the inter-mitochondrial communication”) occur in live adult cardiomyocytes, and the fusion rates differ according to the mitochondrial subpopulation. We next performed high throughput screening of a small molecule library and identified hydralazine (a drug used to treat hypertension and heart failure) to be a novel modulator of mitochondrial dynamics, acting to inhibit mitochondrial fission and protect against the detrimental effects of acute myocardial ischaemia/reperfusion injury by preserving mitochondrial dynamics. Conclusion This thesis has demonstrated that 2D and 3D changes in mitochondrial shape features, as well as alterations in inter-mitochondrial communication, are of high relevance to adult rodent cardiomyocytes. Hydralazine-induced cardioprotection in the setting of IRI demonstrates the significance of distinct aspects of mitochondrial dynamics and reveals the role they play in the normal functioning of adult cardiomyocytes.

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