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Title: Controlling mitochondrial dynamics : population genetics and networks
Author: Hoitzing, Hanne
ISNI:       0000 0004 7229 1417
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2018
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Mitochondria form an essential component of nearly all eukaryotic cells, are implicated in numerous diseases and may play important roles in ageing. Mitochondrial populations are dynamic, controlled and heterogeneous, with different types -- both mutant and wildtype -- potentially coexisting in single cells. This thesis will study the dynamics of both mitochondria and their genetic material (mtDNA) to improve our understanding of the role of these dynamics in pathology and ageing. This study suggests, as well as critically evaluates, reasons for the existence of complex continuous mitochondrial networks using coarse-grained mathematical models, underlining a nonlinear relation between functionality and network structure. Understanding the link between morphology and function is important as disruption of the former is directly implicated in cellular dysfunction. We perform experiments in which we measure the influence of mitochondrial fusion and division events on integrated mitochondrial membrane potential, an indicator of functionality, and find evidence for its conservation. The cellular homeostatic control acting on a mitochondrial population is poorly understood; to address this, we study the influence of general feedback control strategies on mutant and wildtype mtDNA dynamics. We introduce a simple linear control mechanism that captures a wide variety of biologically observed dynamics, and study optimal parameterisations through the construction of an energy-based mitochondrial cost function. Not only cellular control, but also gene-therapeutic control of mtDNA is studied, allowing us to investigate optimal treatment strategies to reduce mutant loads. The cellular proportion of mutant mtDNA molecules, known as heteroplasmy, is crucial in mitochondrial disease and we study the influence of cellular mtDNA exchange on heteroplasmy dynamics and mutant expansion during ageing. We find that this exchange of genetic material can induce preferential mutant expansion during ageing (even in the face of selection against mutants) through a stochastically driven increase in cellular mean heteroplasmy levels.
Supervisor: Jones, Nick ; Johnston, Iain Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral