Cabolis, Katerina; (2023) The effects of iron deficiency and iron repletion on mitochondrial function: An in vivo study. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Iron plays a central role in mitochondrial energy production, and this thesis provides insight into the mechanism by which mitochondria of energy demanding tissues are affected by iron deficiency and intravenous iron repletion in the mouse. Administration of an iron-deficient diet in mice led to iron deficiency, and in some cases anaemia. This deficiency was tested by measuring haemoglobin, serum ferritin, cardiac iron, and spleen iron concentrations and comparing them with a group of mice fed a control diet. Using biochemical assays and high resolution respirometry, it was shown that iron deficiency induced a decrease in activity of some, but not all, mitochondrial complexes within cardiac muscle, which is restored following intravenous iron repletion. Mitochondrial function in skeletal muscle tissue, namely the soleus and not the quadriceps, decreased in response to iron deficiency, but was partially restored following intravenous iron repletion. Iron deficiency also led to a decrease in in-gel activity of supramolecular complex II of the soleus, which remained uncorrected following iron repletion. Immunohistochemistry and western blot analysis of skeletal muscle tissue demonstrated that these functional changes occur in the absence of structural differences, i.e., the number of mitochondria, or the connectedness of mitochondria. Changes in cortical oxygenation and metabolism were assessed non-invasively, using broadband near-infrared spectroscopy. Iron deficient mice show a metabolic vulnerability, and an attenuated response in changes of deoxygenated haemoglobin during exposure to hypoxia, while iron repleted mice demonstrate an enhanced metabolic recovery following hypoxia. Additionally, iron deficiency induced a drop in synaptic marker expression in the brain, which was partially restored after repletion in certain areas of the brain. This research validated a murine model of adult iron deficiency and intravenous iron repletion and provided new insights into the effects iron deficiency and intravenous iron repletion on mitochondrial physiology.

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