Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial is an
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
that in humans is encoded by the ''ETFDH''
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
. This gene encodes a component of the
electron-transfer system in
mitochondria and is essential for
electron transfer
Electron transfer (ET) occurs when an electron relocates from an atom or molecule to another such chemical entity. ET is a mechanistic description of certain kinds of redox reactions involving transfer of electrons.
Electrochemical processes ar ...
from a number of mitochondrial
flavin-containing
dehydrogenase
A dehydrogenase is an enzyme belonging to the group of oxidoreductases that oxidizes a substrate by reducing an electron acceptor, usually NAD+/NADP+ or a flavin coenzyme such as FAD or FMN. Like all catalysts, they catalyze reverse as well as ...
s to the main respiratory chain.
Function
Electron-transferring-flavoprotein dehydrogenase in the
inner mitochondrial membrane
The inner mitochondrial membrane (IMM) is the mitochondrial membrane which separates the mitochondrial matrix from the intermembrane space.
Structure
The structure of the inner mitochondrial membrane is extensively folded and compartmentalized. ...
accepts electrons from
electron-transfer flavoprotein
An electron transfer flavoprotein (ETF) or electron transfer flavoprotein complex (CETF) is a flavoprotein located on the matrix face of the inner mitochondrial membrane and functions as a specific electron acceptor for primary dehydrogenases, tra ...
which is located in the
mitochondrial matrix
In the mitochondrion, the matrix is the space within the inner membrane. The word "matrix" stems from the fact that this space is viscous, compared to the relatively aqueous cytoplasm. The mitochondrial matrix contains the mitochondrial DNA, ri ...
and
reduces ubiquinone
Coenzyme Q, also known as ubiquinone and marketed as CoQ10, is a coenzyme family that is ubiquitous in animals and most bacteria (hence the name ubiquinone). In humans, the most common form is coenzyme Q10 or ubiquinone-10.
It is a 1,4-benzoq ...
in the mitochondrial membrane. Deficiency in electron-transferring-flavoprotein dehydrogenase have been demonstrated in some patients with
type II glutaric aciduria.
Structure
The ''ETFDH'' gene is located on the q arm of
chromosome 4
Chromosome 4 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 4 spans more than 186 million base pairs (the building material of DNA) and represents between 6 and 6.5 percent of the to ...
in position 32.1 and has 13
exon
An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequenc ...
s spanning 36,613 base pairs.
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.
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
Mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...
s in the ''ETFDH'' can cause glutaric aciduria 2C (GA2C), an
autosomal recessively inherited disorder of
fatty acid
In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, ...
,
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
, and
choline Choline is an essential nutrient for humans and many other animals. Choline occurs as a cation that forms various salts (X− in the depicted formula is an undefined counteranion). Humans are capable of some ''de novo synthesis'' of choline but ...
metabolism. It is characterized by multiple
acyl-CoA dehydrogenase deficiencies resulting in large excretion not only of
glutaric acid
Glutaric acid is the organic compound with the formula C3H6(COOH)2 . Although the related "linear" dicarboxylic acids adipic and succinic acids are water-soluble only to a few percent at room temperature, the water-solubility of glutaric acid ...
, but also of
lactic,
ethylmalonic,
butyric
Butyric acid (; from grc, βούτῡρον, meaning "butter"), also known under the systematic name butanoic acid, is a straight-chain alkyl carboxylic acid with the chemical formula CH3CH2CH2CO2H. It is an oily, colorless liquid with an unpl ...
,
isobutyric,
2-methyl-butyric, and
isovaleric acids.
A c.250G>A (p.Ala84Thr) mutation, the most common mutation in the ''ETFDH'' gene, causes increased production of
reactive oxygen species
In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen.
The reduction of molecular oxygen ...
(ROS) and shortened
neurite
A neurite or neuronal process refers to any projection from the cell body of a neuron. This projection can be either an axon or a dendrite. The term is frequently used when speaking of immature or developing neurons, especially of cells in cultur ...
s in cells
expressing
Expression may refer to:
Linguistics
* Expression (linguistics), a word, phrase, or sentence
* Fixed expression, a form of words with a specific meaning
* Idiom, a type of fixed expression
* Metaphorical expression, a particular word, phrase, ...
this mutant compared to
wild type
The wild type (WT) is the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard "normal" allele at a locus, in contrast to that produced by a non-standard, "m ...
cells.
Suberic acid, an accumulated
intermediate metabolite
In biochemistry, a metabolite is an intermediate or end product of metabolism.
The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, ...
in dehydrogenase deficiency, can significantly impair neurite outgrowth in
NSC34 cells. This shortening of neurites can be restored by
riboflavin
Riboflavin, also known as vitamin B2, is a vitamin found in food and sold as a dietary supplement. It is essential to the formation of two major coenzymes, flavin mononucleotide and flavin adenine dinucleotide. These coenzymes are involved in e ...
,
carnitine
Carnitine is a quaternary ammonium compound involved in metabolism in most mammals, plants, and some bacteria. In support of energy metabolism, carnitine transports long-chain fatty acids into mitochondria to be oxidized for energy production, ...
, or
Coenzyme Q10
Coenzyme Q, also known as ubiquinone and marketed as CoQ10, is a coenzyme family that is ubiquitous in animals and most bacteria (hence the name ubiquinone). In humans, the most common form is coenzyme Q10 or ubiquinone-10.
It is a 1,4-ben ...
supplements.
Interactions
The encoded protein
interacts with
MYH7B,
LINC00174
The LINC (Laboratory INstrument Computer) is a 12-bit, 2048-word transistorized computer. The LINC is considered by some the first minicomputer and a forerunner to the personal computer. Originally named the "Linc", suggesting the project's ori ...
,
LINC00574,
Homeobox protein goosecoid-2,
AIRE,
OTX1,
Keratin-associated protein 13-2,
Keratin-associated protein 11-1,
TRIM69,
Zinc finger protein 581, and
COX6B1.
References
Further reading
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