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Title: Mitochondrial function and dynamics in demyelinated axons
Author: Peters, F.
ISNI:       0000 0004 7225 160X
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2017
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Demyelination is a pathological process which causes profound changes in the physiology of axons. Post mortem evidence suggests that mitochondrial content is increased in demyelinated axons which has led to the widely accepted theory that loss of myelin causes an increase in axonal energy demand which in turn can be satisfied by a larger number of mitochondria. However, demyelinated axons are known to undergo a series of changes from conduction block early on in demyelination to altered modes of conduction and finally remyelination and return of normal conduction. Little is known about how these different states influence axonal mitochondria. In this thesis, mitochondrial function and dynamics were investigated throughout the time course of lysolecithin-mediated de- and remyelination in the saphenous nerve in vivo. First, the time course of anatomical and electrophysiological changes after application of lysolecithin was mapped out using semi-thin resin sections and recordings of compound action potentials. Then, mitochondrial dynamics and membrane potential were measured at various time points during the onset and resolution of demyelination. Mitochondrial transport was significantly reduced during the first week of demyelination, preceding the accumulation of stationary mitochondria in the axon. At the same time, mitochondrial membrane potential was significantly increased, particularly at the earliest time points investigated (days 2 and 4). Interestingly, all changes including the abovementioned accumulation of mitochondria took place before the return of conduction and putative increase in energy demand. In order to understand better the processes underlying these changes, the role of two known modifiers of mitochondrial dynamics were investigated: action potential conduction and intra-axonal calcium. A 6h conduction block was induced using bupivacaine and confirmed using electrophysiological stimulation but did not lead to any of the changes seen in the early phases of demyelination. On the other hand, calcium imaging using the genetically encoded calcium sensor Tn-XXL revealed a slight but consistent increase in intra-axonal calcium in demyelinated axons, both at the time point with the highest increase in mitochondrial membrane potential (day 2) and at the time point with the highest mitochondrial density (day 8). Taken together, these findings point to impaired axonal calcium homeostasis, rather than changes in energy demand, as the main driving force behind mitochondrial changes in demyelination. The fact that mitochondrial transport remained impaired until later in the remyelination process may have implications for the long term survival of chronically demyelinated axons.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available