ETFDH
Identifiers
Aliases	ETFDH, electron-transferring-flavoprotein dehydrogenase, ETFQO, MADD, electron transfer flavoprotein dehydrogenase
External IDs	OMIM: 231675 MGI: 106100 HomoloGene: 3275 GeneCards: ETFDH
Gene location (Human) Chr. Chromosome 4 (human)[1] Band 4q32.1 Start 158,671,968 bp[1] End 158,710,742 bp[1]
Gene location (Mouse) Chr. Chromosome 3 (mouse)[2] Band 3 E3|3 34.91 cM Start 79,511,095 bp[2] End 79,536,807 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in left ventricle right lobe of liver jejunal mucosa right ventricle gastrocnemius muscle right adrenal gland left adrenal gland Achilles tendon biceps brachii duodenum Top expressed in right ventricle myocardium of ventricle cardiac muscles interventricular septum intercostal muscle digastric muscle soleus muscle thoracic diaphragm brown adipose tissue sternocleidomastoid muscle More reference expression data BioGPS More reference expression data
Gene ontology Molecular function 4 iron, 4 sulfur cluster binding ubiquinone binding quinone binding flavin adenine dinucleotide binding iron-sulfur cluster binding metal ion binding electron transfer activity oxidoreductase activity electron-transferring-flavoprotein dehydrogenase activity oxidoreductase activity, acting on metal ions, flavin as acceptor Cellular component membrane integral component of mitochondrial inner membrane mitochondrial matrix mitochondrion mitochondrial inner membrane mitochondrial membrane mitochondrial electron transfer flavoprotein complex Biological process fatty acid beta-oxidation using acyl-CoA dehydrogenase response to oxidative stress electron transport chain respiratory electron transport chain Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 2110 66841 Ensembl ENSG00000171503 ENSMUSG00000027809 UniProt Q16134 Q921G7 RefSeq (mRNA) NM_004453 NM_001281737 NM_001281738 NM_025794 RefSeq (protein) NP_001268666 NP_001268667 NP_004444 NP_080070 Location (UCSC) Chr 4: 158.67 – 158.71 Mb Chr 3: 79.51 – 79.54 Mb PubMed search [3] [4]
Wikidata
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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.^[5]

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.^[5]

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.^[6][7] 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.^[5] This 64-kDA mature form is a monomer integrated into the mitochondrial inner membrane, containing a 4Fe-4S cluster and 1 molecule of FAD.^[7]

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.^[7] It accepts electrons from ETF and reduces ubiquinone.^[8][9]

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.^[8][9]

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.^[10]

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.^[11]