Abstract
Background
Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (MCADD) is the most frequent fatty acid oxidation (FAO) defect in humans. MCAD-deficient fibroblasts are more resistant to oxidative stress-induced cell death than other FAO defects and healthy controls.
Methods
Herein we investigate the antioxidant response and mitochondrial function in fibroblasts from MCAD-deficient patients (c.985 A>G/c.985 A>G) and healthy controls.
Results
MCAD-deficient fibroblasts showed increased level of mitochondrial superoxide, while lipids were less oxidatively damaged, and higher amount of manganese superoxide dismutase were detected compared to healthy controls, showing forceful antioxidant system in MCADD. We showed increased maximal respiration and reserve capacity in MCAD-deficient fibroblasts compared to controls, indicating more capacity through the tricarboxylic acid (TCA) cycle and subsequently respiratory chain. This led us to study the pyruvate dehydrogenase complex (PDC), the key enzyme in the glycolysis releasing acetyl-CoA to the TCA cycle. MCAD-deficient fibroblasts displayed not only significantly increased PDC but also increased lipoylated PDC protein levels compared to healthy controls.
Conclusions
Based on these findings, we raise the interesting hypothesis that increased PDC-bound lipoic acid, synthesized from accumulated octanoic acid in MCADD, may affect the cellular antioxidant pool in MCADD.
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Acknowledgements
We thank the Faculty of Health Sciences at Aarhus University and the Danish Council for Independent Research (Grant Nos. #4004-00548 and #11-107331) for financial support.
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Z.N.: experimental design, performed the experiments, data analysis, and writing the first draft of the manuscript. R.I.D.B.: performed the mass spectrometric analysis. P.F.-G.: MitoSOX and lipid peroxidation data analysis, set up the Seahorse profile protocol, and revised the manuscript. J.H.: performed the acylcarnitine analysis and revised the manuscript. 5. F.W.: performed the pyruvate dehydrogenase activity measurement. T.J.C.: experimental design, report editing, and revising the manuscript. N.G. and R.K.J.O.: experimental design, report editing, data analysis, and critically revising the manuscript.
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Nochi, Z., Birkler, R.I.D., Fernandez-Guerra, P. et al. Increased antioxidant response in medium-chain acyl-CoA dehydrogenase deficiency: does lipoic acid have a protective role?. Pediatr Res 88, 556–564 (2020). https://doi.org/10.1038/s41390-020-0801-1
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DOI: https://doi.org/10.1038/s41390-020-0801-1
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