NADH dehydrogenase biquinone1 alpha subcomplex assembly factor 3, also known as 2P1, E3-3, or C3orf60, is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

that in humans is encoded by the ''NDUFAF3''

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 ba ...

. NDUFAF3 is a mitochondrial assembly protein involved in the assembly of

NADH dehydrogenase (ubiquinone) Respiratory complex I, (also known as NADH:ubiquinone oxidoreductase, Type I NADH dehydrogenase and mitochondrial complex I) is the first large protein complex of the respiratory chains of many organisms from bacteria to humans. It catalyzes the ...

also known as complex I, which is located in the

mitochondrial inner 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. ...

and is the largest of the five complexes of the

electron transport chain An electron transport chain (ETC) is a series of protein complexes and other molecules that transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples th ...

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, mi ...

s in this gene have been associated with severe complex I deficiency and Leigh syndrome.

Structure

''NDUFAF3'' is located on the

p arm In genetics, a locus (plural loci) is a specific, fixed position on a chromosome where a particular gene or genetic marker is located. Each chromosome carries many genes, with each gene occupying a different position or locus; in humans, the total ...

chromosome A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...

3 in position 21.31 and has 7

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 sequen ...

s. The ''NDUFAF3'' gene produces a 20.4 kDa protein composed of 184

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 am ...

s. ''NDUFAF3'' encodes two

isoforms A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isof ...

which have a common DUF498

domain Domain may refer to: Mathematics *Domain of a function, the set of input values for which the (total) function is defined **Domain of definition of a partial function **Natural domain of a partial function **Domain of holomorphy of a function * Do ...

. Predictions indicate that isoform A contains an additional 35 amino acid

N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...

sequence and is thus longer than isoform B. The extra sequence may be involved in mitochondrial targeting, supporting NDUFAF3's function in mitochondrial assembly.

Function

NADH:ubiquinone oxidoreductase (complex I)

catalyzes Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...

the transfer of electrons from NADH to ubiquinone (coenzyme Q) in the first step of the mitochondrial respiratory chain, resulting in the translocation of

proton A proton is a stable subatomic particle, symbol , H+, or 1H+ with a positive electric charge of +1 ''e'' elementary charge. Its mass is slightly less than that of a neutron and 1,836 times the mass of an electron (the proton–electron mass ...

s across the mitochondrial inner membrane. The ''NDUFAF3'' gene encodes a mitochondrial complex I assembly protein that localizes to the mitochondrial inner membrane and interacts with complex I subunits and is important for the correct function of the mitochondrial respiratory chain. NDUFAF3 colocalizes, comigrates to several assembly intermediates, and is codependent with

NDUFAF4 NADH:ubiquinone oxidoreductase complex assembly factor 4, (NDUFAF4) also known as Hormone-regulated proliferation-associated protein of 20 kDa, (HRPAP20) or C6orf66 is a protein that in humans is encoded by the ''NDUFAF4'' gene. NDUFAF4 is a mit ...

from the early to late stages of complex I assembly. In addition to their close interactions with each other, NDUFAF3 and NDUFAF4 interact with

NDUFS2 NADH dehydrogenase biquinoneiron-sulfur protein 2, mitochondrial (NDUFS2) also known as NADH-ubiquinone oxidoreductase 49 kDa subunit is an enzyme that in humans is encoded by the ''NDUFS2'' gene. The protein encoded by this gene is a core subuni ...

NDUFS3 NADH dehydrogenase biquinoneiron-sulfur protein 3, mitochondrial is an enzyme that in humans is encoded by the ''NDUFS3'' gene on chromosome 11. This gene encodes one of the iron-sulfur protein (IP) components of mitochondrial NADH:ubiquinone ox ...

NDUFS8 NADH dehydrogenase biquinoneiron-sulfur protein 8, mitochondrial also known as NADH-ubiquinone oxidoreductase 23 kDa subunit, Complex I-23kD (CI-23kD), or TYKY subunit is an enzyme that in humans is encoded by the ''NDUFS8'' gene. The NDUFS8 prot ...

, and

NDUFA5 NADH dehydrogenase biquinone1 alpha subcomplex subunit 5 is an enzyme that in humans is encoded by the ''NDUFA5'' gene. The NDUFA5 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and ...

in a

translation Translation is the communication of the Meaning (linguistic), meaning of a #Source and target languages, source-language text by means of an Dynamic and formal equivalence, equivalent #Source and target languages, target-language text. The ...

-dependent early assembly mechanism. It is also suggested that NDUFAF3 is involved in coupling mitochondrial translation with membrane insertion in the process of complex I assembly.

Clinical Significance

Mutations in ''NDUFAF3'' have been associated with complex I deficiency and mitochondrial diseases. These disorders are a result of the dysfunction of the mitochondrial respiratory chain and can cause a wide range of clinical manifestations from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive

leukodystrophy Leukodystrophies are a group of usually inherited disorders characterized by degeneration of the white matter in the brain. The word ''leukodystrophy'' comes from the Greek roots ''leuko'', "white", ''dys'', "abnormal" and ''troph'', "growth". Th ...

, non-specific encephalopathy,

cardiomyopathy Cardiomyopathy is a group of diseases that affect the heart muscle. Early on there may be few or no symptoms. As the disease worsens, shortness of breath, feeling tired, and swelling of the legs may occur, due to the onset of heart failure. A ...

myopathy In medicine, myopathy is a disease of the muscle in which the muscle fibers do not function properly. This results in muscular weakness. ''Myopathy'' means muscle disease (Greek : myo- ''muscle'' + patheia '' -pathy'' : ''suffering''). This meani ...

, liver disease, Leigh syndrome,

Leber hereditary optic neuropathy Leber's hereditary optic neuropathy (LHON) is a Human mitochondrial genetics, mitochondrially inherited (transmitted from mother to offspring) degeneration of retinal ganglion cells (RGCs) and their axons that leads to an acute or subacute loss o ...

, and some forms of

Parkinson disease Parkinson may refer to: *Parkinson (surname) * ''Parkinson'' (TV series), British chat show, presented by Sir Michael Parkinson *Parkinson, Queensland, suburb of Brisbane, Australia *The Parkinsons (fl. early 20th century), American father-and-son ...

. Mutations have included the

homozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mo ...

variants c.494C > T; p.(Ala165Val), c.365 G→C resulting in R122P, and c.2 T→C resulting in M1T. Clinically, ''NDUFAF3'' mutations have been associated with Leigh syndrome and severe complex I deficiency. Some common signs and symptoms include lactic acidosis, nystagmus,

hypotonia Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases a ...

, and cerebral lesions.

Interactions

In addition to co-complexes, NDUFAF3 has protein-protein interactions with

and SNRPA.

References

External links