178 Chapter 6 the EHOs, in Mat-EHOs short-chain acyl-carnitine (C2) and long-chain myristoylcarnitine (C14) were downregulated (Figure 4b). Interestingly, we observed that several genes encoding mitochondrial β-oxidation enzymes were downregulated in the MCADD Mat-EHOs relative to controls, including medium-chain ketoacyl-CoA thiolase (MCKAT) (encoded by ACAA2), hydroxyacyl-coenzyme A dehydrogenase (M/SCHAD) (encoded by HADH) and carnitine/acylcarnitine carrier protein (CACT) (encoded by SLC25A20) (Figure 4d). Given the ability of peroxisomes to oxidize MCFA, it has been hypothesized that in the absence of MCAD, excess medium-chain acyl-CoAs can also be channeled to peroxisomes, where they undergo further β-oxidation until C6-acyl-CoA, which may be shuttled back into the mitochondria to be oxidized by SCAD29 (Figure 4a). For the peroxisomal β-oxidation, the genes encoding for the transporters ABCD1 and ABCD3 (ATP binding cassette transporter subfamily D; ABCD1 and ABCD3), the oxidase ACOX1 (acyl-CoA oxidase 1; ACOX1), DBP and LBP (D-bifunctional protein and L-bifunctional protein; HSD17B4 and EHHDAH, respectively) and the thiolases ACAA1 and SCPx (ACAA1 and SCP2, respectively) were evaluated (Figure 4e). Apart from a non-significant decline in ACOX1 expression, other measured genes were not regulated in MCADD organoids. In conclusion, all the observed adaptations showed downregulation, rather than upregulation of putative compensatory pathways.
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