Carbohydrates/sugars, fats, and proteins are the macronutrients for the body. During fasting, fat stores represent an important energy source and can be broken down to be used as fuel by a process called mitochondrial fatty acid β-oxidation (mFAO). This constitutes a cyclic sequence of chemical reactions, in which a fatty acid molecule is shortened by two carbons in each cycle and energy is harvested. Such reactions are catalyzed by specialized proteins called “enzymes”.
In disease, if one enzyme is absent or dysfunctional, the reactions that are performed by it, either do not happen or happen at a lower speed. As a consequence, in the context of mFAO, less energy would be extracted from fat, more fat-derived biochemical compounds would accumulate in the body, and the nutrient balance would be disturbed. The lack or insufficient levels of a functional enzyme is called a deficiency. This thesis of Ligia Kiyuna is focused on medium-chain acyl-CoA dehydrogenase deficiency (MCADD), a rare inherited metabolic disorder in which the patients have a variant in the gene that encodes the MCAD enzyme. I investigated how the loss of a functional MCAD, one of the enzymes in the mFAO pathway, can disturb the nutrient balance and lead to the onset of disease symptoms (e.g. hypoglycemia). As a secondary result of my studies, together with colleagues, I developed and characterized novel in vitro and ex vivo (animal free) disease models to pave the way for their use in future studies of MCADD and other inherited metabolic disorders.
