179 6 iPSC-derived liver organoids as a tool to study Medium Chain Acyl-CoA Dehydrogenase deficienc Figure 4. Adaptations of mitochondrial and peroxisomal β-oxidation in MCADD in Mat-EHOs. (A) Schematic depiction of the hypothesized interplay between mitochondria and peroxisomes in the β-oxidation of medium chain fatty acids. In green, the targets analyzed in D-E. (B) Acyl-carnitines measured in supernatant collected after 24 hours in glucose-free medium supplemented with BSA-palmitate and L-carnitine. (C) C8/C10 ratio; For B-C, data represents 6 biological replicates for control and 4 for MCADD ± SEM (*P<0.05, **P<0.01 two-tailed unpaired t-test). (D) Relative gene expression of genes involved in the mitochondrial β-oxidation. (E) Relative gene expression of genes involved in the peroxisomal β-oxidation. For E and D, organoids were grown in glucose-free medium supplemented with BSA and L-carnitine. Data represents 6-7 biological replicates for control and 5-6 for MCADD ± SEM. (*P<0.05, **P<0.01, two-tailed unpaired t test). Control (grey) and MCADD (red). In agreement with the changes observed in the acyl-carnitine profile (Figure 4b), a recent in silico study, based on a detailed kinetic model of human fattyacid oxidation, predicted decreased levels of short-chain and C12-14 acyl-CoA and acyl-carnitines in MCADD28. Such decrease has been suggested to be associated with a concomitant depletion in the free coenzyme A (CoA) levels and, consequently, reduced entry of long-chain fatty acids into the pathway28,37. CoA is an essential intracellular cofactor involved in several metabolic pathways
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