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Title: The effect of circulating humoral factors on mitochondria in septic AKI
Author: Pollen, Sean James
ISNI:       0000 0004 9359 2497
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2020
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Mitochondrial modulation of cellular bioenergetics has been posited as a mechanism to explain the apparent paradox between the clinical and biochemical presentation of septic AKI, despite minimal cell death, maintenance of tissue oxygenation and eventual recovery of organ function. Additionally, in vitro studies show that exposing naïve tissue to septic serum alone causes mitochondrial dysfunction. To investigate this, I revalidated my host laboratory’s long-term in vivo model of sepsis from which serum and other tissues were collected. Serum from septic animals collected at 24 hours were added to naïve kidney slices to characterise changes in mitochondrial function over 90 minutes that may be induced by potential humoral mediators present in septic serum. Pooled serum from sham operated animals acted as controls. Following characterisation, proposed modulators of the changes observed were included in experiments to potentially mitigate the dysfunction caused by exposure to septic serum. Septic serum increased mitochondrial reactive oxygen species (ROS) generation, decreased mitochondrial membrane potential (MMP), and shifted NADH redox state towards oxidation. This suggests increased uncoupling. Scavenging ROS prevented these changes and largely reversed them when administered part-way through exposure. Inhibition of uncoupling partially prevented the changes in MMP and redox state, although it exacerbated ROS generation. Serum fractionation suggested that components ≥50 kDa were primarily responsible for the changes observed. Inclusion of exogenous fresh albumin partially prevented the dysfunction. Septic serum also reduced mitochondrial respiration and respiratory complex enzyme activities in exposed tissue. Humoral factors in septic serum were shown to cause mitochondrial dysfunction in kidney slices from naïve, control, unoperated animals. ROS appears to be a key mediator of these changes, scavenging of which may prove protective. Uncoupling may however representative a negative feedback, reducing ROS and protecting the cell from oxidative damage. Exploring further which specific components of the serum cause mitochondrial dysfunction and the mechanisms through which exogenous albumin attenuates mitochondrial dysfunction are also warranted.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available