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Insights into the role of renin-angiotensin systems in regulating mitochondrial function

Astin, RJ; (2015) Insights into the role of renin-angiotensin systems in regulating mitochondrial function. Doctoral thesis , UCL (University College London). Green open access

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Abstract

The renin-angiotensin system (RAS) is an evolutionarily conserved enzyme system which plays a major role in circulatory homeostasis. This traditional concept of the RAS as a circulating enzyme system has, over the last two decades, been challenged. It is now well established that RAS exist within most tissues and operate independently of the circulating system, with the complexity of the RAS increasing as novel effector proteins, enzymes and receptors have been identified. It is now accepted that RAS can act intracellularly, and in some organs entire RAS exist within single cells. The functions of these RAS are still being elucidated, but data suggest a role in regulating metabolic efficiency. Mitochondria are intracellular organelles responsible for producing the main energy currency of the cell – adenosine triphosphate (ATP). Understanding of their functions has expanded to include cell signalling, regulating cell cycle, and modulating metabolic function. Over the last few years, the idea that RAS may influence mitochondrial function has gained credence. Mitochondrial number, replication and function all appear to be affected by RAS activity, whilst components of the RAS have been identified in association with mitochondria raising the possibility of a mitochondrial RAS. Thus, I examined the hypothesis that a RAS exists within mitochondria. This hypothesis was tested using four complimentary techniques. Existence of RAS proteins within the mitochondrial proteome was sought by interrogation of established databases and mass spectrometric analyses of mitochondria isolated from rat liver; no major RAS proteins were found. Attempts to identify a RAS receptor by immunochemistry failed, whilst radioligand binding studies revealed a binding site in membranes associated with mitochondria (MAM) but not mitochondria themselves. Finally, no effect of AngII on mitochondrial respiration could be found at physiological or supra-physiological concentrations. In conclusion, I could find no evidence of a mitochondrial RAS in rat liver suggesting the effects of the RAS on cellular metabolism are not mediated by direct interaction with mitochondria.

Type: Thesis (Doctoral)
Title: Insights into the role of renin-angiotensin systems in regulating mitochondrial function
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
URI: http://discovery.ucl.ac.uk/id/eprint/1471046
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