Weinrich Weinrich, Tobias; (2019) The mitochondrial ageing signature; seeing the light. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Mitochondrial dysfunction is a major feature of ageing, but also plays a role in pathological conditions, including inflammation. Mitochondria have been suggested as therapeutic targets, where improvements in mitochondrial function can lead to improvements in age-related physiological decline. The work described in this thesis involves the study of mitochondrial dysfunction in two models of ageing, Drosophila and primates. It reveals how mitochondrial dysfunction can be reverted with two different therapies and a putative method to assess mitochondrial function in vivo non-invasively. Also, the work revels some features of circadian mitochondrial function critical to such therapies. Aged Drosophila flies treated with two 670 nm protocols show interesting phenotypes. A short treatment impacts positively mitochondrial function while changes in behaviours are limited and short term. A longer treatment windows triggers, in addition to changes in mitochondrial and metabolite profiles, robust improvements in memory, locomotor and visual function. However, stress responses seem to be unaltered except for chilled coma recovery time. A trial supplementing 9-cis-β-carotene in Drosohila food expands median life span, and suggest a link with mitochondrial function. However, further research is required to understand this putative link between this carotene and mitochondrial function. As with other biological functions, mitochondrial function oscillates during the day. We show data that supports the concept that mitochondria, especially electron transport chain complexes, anticipate the light phase reaching its zenith a few hours later, while their activity is minimal during the dark phase. However, we found no oscillation in the expression levels of our analysed electron transport chain complexes genes. Cone photoreceptors in the retina are cells characterised by a high mitochondrial density. With ageing, however, photoreceptor physiological decline is not homogenous across the different types (S and M/L). We found no difference in cone photoreceptor numbers with ageing in our model (M. fasciularis) that could explain the observed differences in function. Additionally, stress related markers were investigated, but again, no differences could be observed between cone types. Mitochondrial flavoprotein autofluorescence can be used to assess mitochondrial function in vivo in the retina. Our data shows that mitochondria are responsive to changes in inspired oxygen concentration. However, mitochondrial function was unaltered in our animal model with specific retinal inflammation. Collectively, the findings in this thesis expand our understanding of how mitochondria contribute to the ageing process, and how we can modulate aged mitochondrial function to ameliorate the consequences of ageing. We also propose a method to study mitochondrial function in vivo¸ to further understand the role of this organelle in physiological and pathological conditions.

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