Peroxisomal membrane dynamics in health and disease
Date: 13 January 2020
University of Exeter
PhD in Biological Sciences
Peroxisomes are oxidative subcellular organelles present in the majority of eukaryotic cells, with key functions in lipid metabolism, reactive oxygen species (ROS) homeostasis, and production of ether phospholipids (myelin lipids). Modulation of peroxisome number in the cell through coordinated proliferation and degradation is crucial ...
Peroxisomes are oxidative subcellular organelles present in the majority of eukaryotic cells, with key functions in lipid metabolism, reactive oxygen species (ROS) homeostasis, and production of ether phospholipids (myelin lipids). Modulation of peroxisome number in the cell through coordinated proliferation and degradation is crucial for supporting these functions, with peroxisomes rapidly responding to environmental changes in order to maintain cell vitality. As a result, patients with defects in peroxisome proliferation present with a range of symptoms and severity, with vision/hearing loss, neurological defects, seizures, and organ dysfunction being common in peroxisome biogenesis disorders. To proliferate, peroxisomes follow a multi-step process of growth and division, whereby (i) the peroxisome membrane is elongated, (ii) this elongation is constricted at several points to produce a ‘beads on a string’ morphology, and (iii) the membrane undergoes scission at these constriction points to produce new peroxisomes. This process requires extensive remodelling of the peroxisomal membrane, through the action of dedicated division machinery. Our knowledge of the key processes underlying the regulation of this membrane remodelling and the contribution of alterations to membrane dynamics to health and disease are still not well understood. In this thesis, a literature review is presented describing knowns and unknowns in the peroxisome field, with particular focus on the role peroxisome membrane dynamics play in maintaining peroxisome function, and the role of these dynamics in human health and disease. Results chapters begin first by investigating alterations to peroxisomal membrane dynamics in response to the mitochondrial respiratory chain inhibitor rotenone, to understand the resistance of peroxisomes to mitochondria-derived ROS. Surprisingly, alterations to the peroxisome compartment are due to the microtubule-destabilising ability of rotenone, and peroxisomes are unaffected by mitochondrial ROS, despite this not being the case vice versa. The implication of these findings in understanding the peroxisome-mitochondria redox relationship are discussed, in addition to highlighting the importance of investigating peroxisome membrane dynamics in in cellulo models of disease. Second, alterations to peroxisomal membrane dynamics in response to lack of division protein MFF are investigated. It is revealed that despite completely normal biochemical parameters, there are more underlying alterations to the peroxisomes than hyper-elongation, and that MFF has a crucial role in the maturation of peroxisomes. In addition, these findings suggest that peroxisomal import complex protein PEX14 may play a role in peroxisomal membrane dynamics, by stabilising elongated peroxisomal tubules through interaction with the cytoskeleton. Third, an interdisciplinary, combined experimental-modelling approach is used to characterise alterations to peroxisomal membrane dynamics, using peroxisomes with a block in division (loss of function of MFF), and peroxisomes with altered membrane dynamics (elongation through expression of Rho GTPase MIRO1), as case studies. The key cellular processes underlying the regulation of peroxisome growth and division are highlighted, and findings from this chapter provide a proof-of-concept that this interdisciplinary approach is useful not only for characterisation and understanding mechanisms of membrane dynamics, but as a prediction tool to help suggest future therapeutics. Finally, a discussion of the key findings of this thesis and their implications is presented, highlighting the real importance of studying peroxisome membrane dynamics through interdisciplinary approaches such as the ones employed here.
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