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

Suphannee Chokchaiwong, Yung-Ting Kuo, Sung-Po Hsu, Yi-Ching Hsu, Shih-Hsiang Lin, Wen-Bin Zhong, Yung-Feng Lin, Shu-Huei Kao

研究成果: 雜誌貢獻文章

摘要

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.
原文英語
頁(從 - 到)106
期刊Cells
8
發行號2
DOIs
出版狀態已發佈 - 一月 31 2019

指紋

Multiple Acyl Coenzyme A Dehydrogenase Deficiency
Acyl-CoA Dehydrogenase
Ubiquinone
Electron-Transferring Flavoproteins
Pathology
Energy Metabolism
Oxidoreductases
Fatty Acids
Lipids
Oxidation
Genes
coenzyme Q10
Electrons
Mutation
Palmitic Acid
Riboflavin
Mitochondrial Membrane Potential
Lipid Peroxides
Electron Transport
Adenosine Triphosphate

引用此文

ETF-QO Mutants Uncoupled Fatty Acid β-Oxidation and Mitochondrial Bioenergetics Leading to Lipid Pathology. / Chokchaiwong, Suphannee; Kuo, Yung-Ting; Hsu, Sung-Po; Hsu, Yi-Ching; Lin, Shih-Hsiang; Zhong, Wen-Bin; Lin, Yung-Feng; Kao, Shu-Huei.

於: Cells, 卷 8, 編號 2, 31.01.2019, p. 106.

研究成果: 雜誌貢獻文章

Chokchaiwong, Suphannee ; Kuo, Yung-Ting ; Hsu, Sung-Po ; Hsu, Yi-Ching ; Lin, Shih-Hsiang ; Zhong, Wen-Bin ; Lin, Yung-Feng ; Kao, Shu-Huei. / ETF-QO Mutants Uncoupled Fatty Acid β-Oxidation and Mitochondrial Bioenergetics Leading to Lipid Pathology. 於: Cells. 2019 ; 卷 8, 編號 2. 頁 106.
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title = "ETF-QO Mutants Uncoupled Fatty Acid β-Oxidation and Mitochondrial Bioenergetics Leading to Lipid Pathology",
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.",
keywords = "electron-transfer flavoprotein dehydrogenase, electron-transfer flavoprotein-ubiquinone oxidored, lipid droplet accumulation, mitochondrial dysfunction, multiple acyl-CoA dehydrogenase deficiency",
author = "Suphannee Chokchaiwong and Yung-Ting Kuo and Sung-Po Hsu and Yi-Ching Hsu and Shih-Hsiang Lin and Wen-Bin Zhong and Yung-Feng Lin and Shu-Huei Kao",
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T1 - ETF-QO Mutants Uncoupled Fatty Acid β-Oxidation and Mitochondrial Bioenergetics Leading to Lipid Pathology

AU - Chokchaiwong, Suphannee

AU - Kuo, Yung-Ting

AU - Hsu, Sung-Po

AU - Hsu, Yi-Ching

AU - Lin, Shih-Hsiang

AU - Zhong, Wen-Bin

AU - Lin, Yung-Feng

AU - Kao, Shu-Huei

PY - 2019/1/31

Y1 - 2019/1/31

N2 - 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.

AB - 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.

KW - electron-transfer flavoprotein dehydrogenase

KW - electron-transfer flavoprotein-ubiquinone oxidored

KW - lipid droplet accumulation

KW - mitochondrial dysfunction

KW - multiple acyl-CoA dehydrogenase deficiency

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UR - http://www.mendeley.com/research/etfqo-mutants-uncoupled-fatty-acid-%CE%B2oxidation-mitochondrial-bioenergetics-leading-lipid-pathology

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DO - 10.3390/cells8020106

M3 - Article

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JO - Cells

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SN - 2073-4409

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