ETFDH explained

Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial is an enzyme that in humans is encoded by the ETFDH gene. This gene encodes a component of the electron-transfer system in mitochondria and is essential for electron transfer from a number of mitochondrial flavin-containing dehydrogenases to the main respiratory chain.^[1]

Function

Electron-transferring-flavoprotein dehydrogenase in the inner mitochondrial membrane accepts electrons from electron-transfer flavoprotein which is located in the mitochondrial matrix and reduces ubiquinone in the mitochondrial membrane. Deficiency in electron-transferring-flavoprotein dehydrogenase have been demonstrated in some patients with type II glutaric aciduria.^[1]

Structure

The ETFDH gene is located on the q arm of chromosome 4 in position 32.1 and has 13 exons spanning 36,613 base pairs.^[2] The protein is synthesized as a 67-kDa precursor which is targeted to mitochondria and processed in a single step to a 64-kDa mature form located in the mitochondrial membrane.^[1] This 64-kDA mature form is a monomer integrated into the mitochondrial inner membrane, containing a 4Fe-4S cluster and 1 molecule of FAD.

Function

This enzyme, along with electron transfer flavoprotein (ETF), is required for electron transfer from more than 9 mitochondrial flavin-containing dehydrogenases to the main respiratory chains. It accepts electrons from ETF and reduces ubiquinone.

Clinical Significance

Mutations in the ETFDH can cause glutaric aciduria 2C (GA2C), an autosomal recessively inherited disorder of fatty acid, amino acid, and choline metabolism. It is characterized by multiple acyl-CoA dehydrogenase deficiencies resulting in large excretion not only of glutaric acid, but also of lactic, ethylmalonic, butyric, isobutyric, 2-methyl-butyric, and isovaleric acids.^{[3] [4]}

A c.250G>A (p.Ala84Thr) mutation, the most common mutation in the ETFDH gene, causes increased production of reactive oxygen species (ROS) and shortened neurites in cells expressing this mutant compared to wild type cells. Suberic acid, an accumulated intermediate metabolite in dehydrogenase deficiency, can significantly impair neurite outgrowth in NSC34 cells. This shortening of neurites can be restored by riboflavin, carnitine, or Coenzyme Q10 supplements.^[5]

Interactions

The encoded protein interacts with MYH7B, LINC00174, LINC00574, Homeobox protein goosecoid-2, AIRE, OTX1, Keratin-associated protein 13-2, Keratin-associated protein 11-1, TRIM69, Zinc finger protein 581, and COX6B1.^[6]

References

Further reading

• Wolfe LA, He M, Vockley J, Payne N, Rhead W, Hoppel C, Spector E, Gernert K, Gibson KM . Novel ETF dehydrogenase mutations in a patient with mild glutaric aciduria type II and complex II-III deficiency in liver and muscle . Journal of Inherited Metabolic Disease . 33 . S481-7 . December 2010 . Suppl 3 . 21088898 . 10.1007/s10545-010-9246-8 . 3970109 .
• Wen B, Li D, Li W, Zhao Y, Yan C . Multiple acyl-CoA dehydrogenation deficiency as decreased acyl-carnitine profile in serum . Neurological Sciences . 36 . 6 . 853–9 . June 2015 . 25827849 . 10.1007/s10072-015-2197-y . 9449668 .
• Whitaker CH, Felice KJ, Silvers D, Wu Q . Fulminant lipid storage myopathy due to multiple acyl-coenzyme a dehydrogenase deficiency . Muscle & Nerve . 52 . 2 . 289–93 . August 2015 . 25556768 . 10.1002/mus.24552 . 31711349 .
• Olsen RK, Olpin SE, Andresen BS, Miedzybrodzka ZH, Pourfarzam M, Merinero B, Frerman FE, Beresford MW, Dean JC, Cornelius N, Andersen O, Oldfors A, Holme E, Gregersen N, Turnbull DM, Morris AA . ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency . Brain . 130 . Pt 8 . 2045–54 . August 2007 . 17584774 . 10.1093/brain/awm135 .
• Gempel K, Topaloglu H, Talim B, Schneiderat P, Schoser BG, Hans VH, Pálmafy B, Kale G, Tokatli A, Quinzii C, Hirano M, Naini A, DiMauro S, Prokisch H, Lochmüller H, Horvath R . The myopathic form of coenzyme Q10 deficiency is caused by mutations in the electron-transferring-flavoprotein dehydrogenase (ETFDH) gene . Brain . 130 . Pt 8 . 2037–44 . August 2007 . 17412732 . 4345103 . 10.1093/brain/awm054 .
• Olsen RK, Andresen BS, Christensen E, Bross P, Skovby F, Gregersen N . Clear relationship between ETF/ETFDH genotype and phenotype in patients with multiple acyl-CoA dehydrogenation deficiency . Human Mutation . 22 . 1 . 12–23 . July 2003 . 12815589 . 10.1002/humu.10226 . 24730356 . free .
• Goodman SI, Binard RJ, Woontner MR, Frerman FE . Glutaric acidemia type II: gene structure and mutations of the electron transfer flavoprotein:ubiquinone oxidoreductase (ETF:QO) gene . Molecular Genetics and Metabolism . 77 . 1–2 . 86–90 . 2003 . 12359134 . 10.1016/S1096-7192(02)00138-5 .
• Simkovic M, Degala GD, Eaton SS, Frerman FE . Expression of human electron transfer flavoprotein-ubiquinone oxidoreductase from a baculovirus vector: kinetic and spectral characterization of the human protein . The Biochemical Journal . 364 . Pt 3 . 659–67 . June 2002 . 12049629 . 1222614 . 10.1042/BJ20020042 .
• White RA, Dowler LL, Angeloni SV, Koeller DM . Assignment of Etfdh, Etfb, and Etfa to chromosomes 3, 7, and 13: the mouse homologs of genes responsible for glutaric acidemia type II in human . Genomics . 33 . 1 . 131–4 . April 1996 . 8617498 . 10.1006/geno.1996.0170 .
• Goodman SI, Axtell KM, Bindoff LA, Beard SE, Gill RE, Frerman FE . Molecular cloning and expression of a cDNA encoding human electron transfer flavoprotein-ubiquinone oxidoreductase . European Journal of Biochemistry . 219 . 1–2 . 277–86 . January 1994 . 8306995 . 10.1111/j.1432-1033.1994.tb19939.x . free .

Notes and References

1. Web site: Entrez Gene: ETFDH electron-transferring-flavoprotein dehydrogenase.
2. Olsen RK, Andresen BS, Christensen E, Bross P, Skovby F, Gregersen N . Clear relationship between ETF/ETFDH genotype and phenotype in patients with multiple acyl-CoA dehydrogenation deficiency . Human Mutation . 22 . 1 . 12–23 . July 2003 . 12815589 . 10.1002/humu.10226 . 24730356 . free .
3. Web site: ETFDH - Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial precursor - Homo sapiens (Human) - STXBP1 gene & protein. www.uniprot.org. en. 2018-08-29.
4. UniProt: the universal protein knowledgebase . Nucleic Acids Research . 45 . D1 . D158–D169 . January 2017 . 27899622 . 5210571 . 10.1093/nar/gkw1099 .
5. Liang WC, Lin YF, Liu TY, Chang SC, Chen BH, Nishino I, Jong YJ . Neurite growth could be impaired by ETFDH mutation but restored by mitochondrial cofactors . Muscle & Nerve . 56 . 3 . 479–485 . September 2017 . 27935074 . 10.1002/mus.25501 . 38848222 .
6. Web site: ETFDH interactions. IntAct. www.ebi.ac.uk. en. 2018-09-05.