Stanzani, Giacomo; (2024) The role of mitochondria in sepsis-induced cardiomyopathy. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Introduction: Sepsis is a dysregulated host response to an infection that leads to life threatening organ dysfunction. Sepsis-induced cardiomyopathy (SIC) is a common manifestation of sepsis and contributes to patients’ morbidity and mortality. Objectives My primary objective was to identify the mechanisms of SIC by developing an in vitro model focusing on the role of mitochondrial dysfunction. I hypothesised that SIC is associated with altered cellular homeostasis caused by mitochondrial abnormalities, which are mediated by circulating factors and can be replicated in vitro. Design: Firstly, I focused on developing an in vitro model of SIC. To achieve this, I exposed primary adult rat ventricular cardiomyocytes to septic serum generated through a clinically-relevant rat model of faecal peritonitis. I then monitored these cardiomyocytes, treated under various conditions, for changes in mitochondrial function. Secondly, I evaluated mitochondrial function in the same cardiomyocytes following selective activation of inflammatory pathways by comparing TLR4 and TLR9 agonism, and following mitochondrial complex I and II manipulation. Results: In my initial experiments, I generated viable primary adult rat cardiomyocytes and replicated the in vivo model of faecal peritonitis previously described by my host lab. Compared to control serum, exposure of cardiomyocytes to septic serum did not result in measurable changes in mitochondrial membrane potential or mitochondrial oxygen consumption in any of the conditions tested. TLR agonism led to higher NAD(P)H, but not FAD, oxidation and was associated with higher mitochondrial oxygen consumption. However, no differences could be identified between TLR4 and TLR9 agonism. Conclusions: The proposed in vitro model utilising septic serum failed to induce measurable mitochondrial dysfunction; without further characterisation, it should not be used to understand the role of mitochondria in SIC. In contrast, TLR agonism resulted in alterations in mitochondrial redox state and oxygen consumption, but no differences were seen between the two agonists evaluated.

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