17 1 General Introduction none of these systems allow researchers to address the issue of patient heterogeneity, emphasizing the need for new experimental models to study MCADD in patient derived tissue. The role of peroxisomes in MCAD deficiency As mentioned above, MCAD deficiency is characterized by the accumulation of substrates that are normally metabolized by the medium-chain dehydrogenase. Under non-challenging conditions other dehydrogenases are able to prevent severe phenotypes. In contrast, catabolic conditions such as fasting and recurring illness can trigger accumulation of medium-chain fatty acids in MCAD deficient patients. Peroxisomes have been reported to metabolize a wide range of substrates including medium-chain acyl-CoAs when mitochondrial import of fatty acids is inhibited97. Interestingly, peroxisomes are equipped with all the enzymes required for the activation, import and oxidation of medium-chain fatty acids. A study reported that medium-chain acyl-CoAs can enter peroxisomes via ABCD3 (PMP70) prior to being oxidized by the peroxisomal β-oxidation. These results highlight peroxisomes as a potential route to metabolize medium-chain fatty acids in MCAD deficiency in order to prevent metabolite accumulation. Yet, no studies have reported on the role of peroxisomes in any of the mitochondrial dehydrogenase deficiencies (SCADD, MCADD or VLCADD). NEW EXPERIMENTAL AND COMPUTATIONAL MODELS TO STUDY SEVERE MALNUTRITION AND MCADD IN VITRO AND IN SILICO I have already introduced some of the more traditional models for the characterization and study of both severe malnutrition and MCADD. However, it is important to realize that all models are flawed and present both advantages and limitations. In the context of this thesis, I introduce two new tools for the study of the above-mentioned diseases. Here I introduce primary and iPSC-derived organoids as well as computational models to predict different metabolic outcomes. Organoids The development discovery of organoids in 200998 has entailed a change in the way we conceive the study of biology and biomedicine. Organoids are three-dimensional structures that can be derived from primary tissue as well
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