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Pollard, Amelia K. (2017) The role of mitochondria in ageing. PhD thesis, University of Nottingham.

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Abstract

Cognitive decline coupled with functional loss of skeletal muscle strength is a quietly devastating reality for long-lived populations. Ageing is a complex process resulting in the progressive deterioration of biological functions, however the exact mechanisms of ageing are currently unclear. Mitochondrial dysfunction is a characteristic feature of ageing and age-related disease. This thesis explored the age-related changes to biochemical profile of the mitochondrion.

Firstly, mitochondrial function measured through complex I activity was examined with ageing and compared to that of neurodegenerative disease in different regions of the brain. Complex I activity is significantly reduced in aged animals and affects all brain regions similarly. In contrast, complex I activity in the neurodegenerative disease mouse model pcd5J showed region specific reductions in activity.

Secondly, the mitochondrial proteome isolated from young (8 weeks) and middle-aged/old (78 weeks) mouse brain and skeletal muscle were profiled. The mitochondrial proteome exhibited specific changes with ageing. Of particular interest was carbonic anhydrase II, which showed significantly increased protein levels in aged brain mitochondria. Furthermore, elevated carbonic anhydrase II had a detrimental effect on lifespan. It could be postulated that carbonic anhydrase inhibitors could be used to modulate age-related impairments and disease.

Thirdly, the lipidomic profile of young (8 weeks) and middle-aged/old (78 weeks) mouse brain and skeletal muscle were investigated. The brain mitochondrial lipidome showed reduced levels of fatty acids with ageing while skeletal muscle mitochondria exhibited a decreased abundance of phosphatidylethanolamines, but a pronounced increase of triglyceride levels. Reduced levels of phosphatidylethanolamines are associated with accelerated ageing. This study revealed possible lipid biomarkers of the ageing process that could be utilised to treat mitochondrial dysfunction.

Finally, the biochemical profile of the mouse mitochondrion was also compared to that of an exceptionally long-lived mammal, the common pipstrelle bat (P.pipistrellus). This study uncovered for the first time that bats exhibit distinct mitochondrial profiles consistent with an intrinsic resistance to the ageing processes.

Taken together this thesis highlights age-related changes in the mitochondrial biochemical profile that could be targeted to ameliorate functional decline and thereby maximise healthspan.

Item Type:	Thesis (University of Nottingham only) (PhD)
Supervisors:	Chakrabarti, Lisa Barrett, David
Subjects:	S Agriculture > SF Animal culture
Faculties/Schools:	UK Campuses > Faculty of Medicine and Health Sciences > School of Veterinary Medicine and Science
Item ID:	42425
Depositing User:	Pollard, Amelia
Date Deposited:	07 Nov 2019 14:06
Last Modified:	06 May 2020 13:16
URI:	https://eprints.nottingham.ac.uk/id/eprint/42425

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