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Cells 2019, 8(2), 106; https://doi.org/10.3390/cells8020106

ETF-QO Mutants Uncoupled Fatty Acid β-Oxidation and Mitochondrial Bioenergetics Leading to Lipid Pathology

1
Ph.D. Program in Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
2
School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
3
Department of Pediatrics, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
4
Department of Pediatrics, Shuang Ho Hospital, Taipei Medical University, New Taipei 23561, Taiwan
5
Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
6
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
*
Author to whom correspondence should be addressed.
Received: 11 December 2018 / Revised: 24 January 2019 / Accepted: 28 January 2019 / Published: 31 January 2019
(This article belongs to the Special Issue Lipid Droplets in Disease)
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Abstract

The electron-transfer flavoprotein dehydrogenase gene (ETFDH) that encodes the ETF-ubiquinone oxidoreductase (ETF-QO) has been reported to be the major cause of multiple acyl-CoA dehydrogenase deficiency (MADD). ETF-QO is an electron carrier that mainly functions in mitochondrial fatty acid β-oxidation and the delivery of electrons to the ubiquinone pool in the mitochondrial respiratory chain. A high frequency of c.250G>A has been found in Taiwanese patients with late-onset MADD. We postulated that the ETFDH c.250G>A mutation may concomitantly impair fatty acid β-oxidation and mitochondrial function. Using MADD patient-derived lymphoblastoid cells and specifically overexpressed ETFDH c.92C>T, c.250G>A, or coexisted c.92C>T and c.250G>A (c.92C>T + c.250G>A) mutated lymphoblastoid cells, we addressed the genotype-phenotype relationship of ETFDH variation in the pathogenesis of MADD. The decreased adenosine triphosphate synthesis, dissipated mitochondrial membrane potentials, reduced mitochondrial bioenergetics, and increased neutral lipid droplets and lipid peroxides were found in the MADD patient-derived lymphoblastoid cells. Riboflavin and/or coenzyme Q10 supplementation rescued cells from lipid droplet accumulation. All three mutant types, c.92C>T, c.250G>A, or c.92C>T + c.250G>A, had increased lipid droplet accumulation after treatment with palmitic acid. These results help to clarify the molecular pathogenesis of MADD as a result of the high frequency of the ETFDH c.250G>A and c.92C>T mutations. View Full-Text
Keywords: multiple acyl-CoA dehydrogenase deficiency; electron-transfer flavoprotein dehydrogenase; electron-transfer flavoprotein-ubiquinone oxidoreductase; mitochondrial dysfunction; lipid droplet accumulation multiple acyl-CoA dehydrogenase deficiency; electron-transfer flavoprotein dehydrogenase; electron-transfer flavoprotein-ubiquinone oxidoreductase; mitochondrial dysfunction; lipid droplet accumulation
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Chokchaiwong, S.; Kuo, Y.-T.; Hsu, S.-P.; Hsu, Y.-C.; Lin, S.-H.; Zhong, W.-B.; Lin, Y.-F.; Kao, S.-H. ETF-QO Mutants Uncoupled Fatty Acid β-Oxidation and Mitochondrial Bioenergetics Leading to Lipid Pathology. Cells 2019, 8, 106.

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