McKenna, Helen Therese; (2020) The bioenergetic and redox phenotype in human critical illness. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

A multitude of pathologies may progress to a state called ‘critical illness’, the hallmark of which is multiple organ failure. Supportive therapy is based on the hypothesis that organ failure results from bioenergetic collapse but attempts to restore energetic capacity through augmentation of systemic oxygen transport have failed to improve survival. The potential relevance of cellular adaptation for survival in critical illness has not been considered. This thesis explored the hypothesis that survival from critical illness could be related to dynamic changes in cellular bioenergetic and redox phenotype. Instead of bioenergetic collapse, skeletal muscle from critically ill patients demonstrated a profile of modifications consistent with cellular hypoxic adaptation, including: greater coupling efficiency of oxidative phosphorylation; selective reduction in respiratory capacity supported by complex I and fatty acid oxidation (FAO), accompanied by a switch from the tricarboxylic acid cycle towards glycolysis, and downstream impairment in FAO and accumulation of medium and long chain carnitines, in comparison to reference patients. The overall redox status in skeletal muscle was more reduced in in critically ill patients than reference patients, suggesting an enhanced reductive drive. Survivors and non survivors exhibited distinct phenotypes, the nature of which were time-specific. Within 48 hours of developing organ failure, survivors had lower skeletal muscle complex I capacity and lower plasma antioxidant capacity, but 7 days later these differences had resolved, and survivors now demonstrated lower plasma lipid peroxidation than non survivors. Specific bioenergetic modifications in skeletal muscle and plasma redox status in critical illness were related to aspects of microcirculatory function but not systemic indices of oxygenation. Dynamic adaptation in microscopic biological functions, such as bioenergetics, metabolism and redox, may underpin human resilience to life-threatening stress. This work calls for further investigation into cell-based strategies of human life-support.

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