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

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

doi:10.3390/cells8020106

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.

Highlights

Multiple acyl-coenzyme A (CoA) dehydrogenase deficiency (MADD, MIM#231680), known as glutaric aciduria type II, is an inherited, autosomal recessive disorder [1]
multiple acyl-CoA dehydrogenase deficiency (MADD) primarily results from the absence and/or inactivity of either electron-transfer flavoprotein (ETF) or electron-transfer flavoprotein ubiquinone oxidoreductase (ETF-QO, called electron transfer flavoprotein dehydrogenase (ETFDH)) [1,4]
ETF and ETF-ubiquinone oxidoreductase (ETF-QO) are functionally associated; they both conduct electron transfer from flavin adenine dinucleotide (FAD)-containing acyl-CoA dehydrogenases for fatty acid β-oxidation to the ubiquinone pool for mitochondrial respiration [5]

Summary

Introduction

Multiple acyl-coenzyme A (CoA) dehydrogenase deficiency (MADD, MIM#231680), known as glutaric aciduria type II, is an inherited, autosomal recessive disorder [1]. The clinical manifestations in MADD are highly variable and related to the onset period. In the late-onset type, MADD may manifest beyond the neonatal stage as isolated muscle weakness and myofibril destruction because of intracellular lipid deposits [3]. MADD primarily results from the absence and/or inactivity of either electron-transfer flavoprotein (ETF) or electron-transfer flavoprotein ubiquinone oxidoreductase (ETF-QO, called ETFDH) [1,4]. ETF and ETF-QO are functionally associated; they both conduct electron transfer from flavin adenine dinucleotide (FAD)-containing acyl-CoA dehydrogenases for fatty acid β-oxidation to the ubiquinone pool for mitochondrial respiration [5]. ETF-QO couples electron transfer between acyl-CoA (as the electron donor) and ubiquinone (as the electron acceptor).

Methods

Results

Discussion

Conclusion