212 Chapter 7 coding for enzymes involved the metabolism of CoA, both in the peroxisome and mitochondria. These results point towards a peroxisomal contribution to MCADD and emphasize the need to further characterize the interplay of both organelles in the disease. For this study, and to set up the model, we purposefully selected fibroblast from symptomatic patients. For that reason, we believe that differentiation of fibroblast from a larger number of patients, including symptomatic and asymptomatic, will provide broader view of the adaption mechanisms of peroxisomes in the disease. PART 3. CONCLUDING REMARKS AND FUTURE DIRECTIONS In conclusion, this work illustrates the potential of new translational models to understand and characterize disorders affecting mitochondrial and peroxisomal fatty-acid metabolism. I present two in vitro and two in silico models for the study of malnutrition and MCADD and introduce them as tools for the study of the pathophysiology of the diseases and discovery of therapeutic approaches. As an proof-of-principle, the intestinal model has already been used to test the effect of amino-acid restriction on mitochondrial homeostasis and intestinal permeability1. Moreover, as shown in chapter 2 and 4, the organoid models can be used to test different therapeutic and pharmacological interventions. Future studies, including higher number of compounds should be performed to find the best approach to minimize peroxisomal and mitochondrial defects in malnutrition. In the case of MCADD, we aim to perform further studies including RNAseq and untargeted proteomics to understand the differences between MCADD and control organoids. Furthermore, we intend to establish organoids from asymptomatic patients in order to compare them to the symptomatic ones. We believe that this approach will help us uncover and understand potential adaptation mechanisms in MCADD.
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