NDUFAF3

Last updated
NDUFAF3
Identifiers
Aliases NDUFAF3 , 2P1, C3orf60, E3-3, NADH:ubiquinone oxidoreductase complex assembly factor 3, MC1DN18
External IDs OMIM: 612911 MGI: 1913956 HomoloGene: 32460 GeneCards: NDUFAF3
Orthologs
SpeciesHumanMouse
Entrez

25915

66706

Ensembl

ENSG00000178057

ENSMUSG00000070283

UniProt

Q9BU61

Q9JKL4

RefSeq (mRNA)

NM_199417
NM_199069
NM_199070
NM_199073
NM_199074

NM_023247

RefSeq (protein)

NP_951032
NP_951033
NP_951047
NP_951056

NP_075736

Location (UCSC) Chr 3: 49.02 – 49.02 Mb Chr 9: 108.44 – 108.44 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 3, also known as 2P1, E3-3, or C3orf60, is a protein that in humans is encoded by the NDUFAF3 gene. [5] [6] [7] NDUFAF3 is a mitochondrial assembly protein involved in the assembly of NADH dehydrogenase (ubiquinone) also known as complex I, which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. [8] [9] Mutations in this gene have been associated with severe complex I deficiency and Leigh syndrome. [5] [9] [10]

Contents

Structure

NDUFAF3 is located on the p arm of chromosome 3 in position 21.31 and has 7 exons. [5] The NDUFAF3 gene produces a 20.4 kDa protein composed of 184 amino acids. [11] [12] NDUFAF3 encodes two isoforms which have a common DUF498 domain. Predictions indicate that isoform A contains an additional 35 amino acid N-terminal sequence and is thus longer than isoform B. The extra sequence may be involved in mitochondrial targeting, supporting NDUFAF3's function in mitochondrial assembly. [9]

Function

NADH:ubiquinone oxidoreductase (complex I) catalyzes the transfer of electrons from NADH to ubiquinone (coenzyme Q) in the first step of the mitochondrial respiratory chain, resulting in the translocation of protons across the mitochondrial inner membrane. [13] 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. [5] [9]

NDUFAF3 colocalizes, comigrates to several assembly intermediates, and is codependent with NDUFAF4 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, NDUFS3, NDUFS8, and NDUFA5 in a translation-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. [9]

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, non-specific encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease. [6] [7] Mutations have included the homozygous variants c.494C > T; p.(Ala165Val), [10] c.365 G→C resulting in R122P, and c.2 T→C resulting in M1T. [9] Clinically, NDUFAF3 mutations have been associated with Leigh syndrome [10] and severe complex I deficiency. [9] Some common signs and symptoms include lactic acidosis, nystagmus, hypotonia, and cerebral lesions. [9] [10]

Interactions

In addition to co-complexes, NDUFAF3 has protein-protein interactions with NDUFAF4 [14] and SNRPA. [15]

Related Research Articles

<span class="mw-page-title-main">MT-ND6</span> Mitochondrial gene coding for a protein involved in the respiratory chain

MT-ND6 is a gene of the mitochondrial genome coding for the NADH-ubiquinone oxidoreductase chain 6 protein (ND6). The ND6 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Variations in the human MT-ND6 gene are associated with Leigh's syndrome, Leber's hereditary optic neuropathy (LHON) and dystonia.

<span class="mw-page-title-main">MT-ND5</span> Mitochondrial gene coding for a protein involved in the respiratory chain

MT-ND5 is a gene of the mitochondrial genome coding for the NADH-ubiquinone oxidoreductase chain 5 protein (ND5). The ND5 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Variations in human MT-ND5 are associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) as well as some symptoms of Leigh's syndrome and Leber's hereditary optic neuropathy (LHON).

<span class="mw-page-title-main">NDUFS4</span> Protein-coding gene in the species Homo sapiens

NADH dehydrogenase [ubiquinone] iron-sulfur protein 4, mitochondrial (NDUFS4) also known as NADH-ubiquinone oxidoreductase 18 kDa subunit is an enzyme that in humans is encoded by the NDUFS4 gene. This gene encodes a nuclear-encoded accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase. Complex I removes electrons from NADH and passes them to the electron acceptor ubiquinone. Mutations in this gene can cause mitochondrial complex I deficiencies such as Leigh syndrome.

<span class="mw-page-title-main">NDUFS3</span> Protein-coding gene in the species Homo sapiens

NADH dehydrogenase [ubiquinone] iron-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 oxidoreductase. Mutations in this gene are associated with Leigh syndrome resulting from mitochondrial complex I deficiency.

<span class="mw-page-title-main">NDUFV1</span> Protein-coding gene in the species Homo sapiens

NADH dehydrogenase [ubiquinone] flavoprotein 1, mitochondrial (NDUFV1) is an enzyme that in humans is encoded by the NDUFV1 gene. The NDUFV1 gene encodes the 51-kD subunit of complex I of the mitochondrial respiratory chain. Defects in complex I are a common cause of mitochondrial dysfunction. Mitochondrial complex I deficiency is linked to myopathies, encephalomyopathies, and neurodegenerative disorders such as Parkinson's disease and Leigh syndrome.

<span class="mw-page-title-main">NDUFS8</span> Protein-coding gene in the species Homo sapiens

NADH dehydrogenase [ubiquinone] iron-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 protein is a subunit of NADH dehydrogenase (ubiquinone) also known as Complex I, which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Mutations in this gene have been associated with Leigh syndrome.

<span class="mw-page-title-main">NDUFS2</span> Protein-coding gene in the species Homo sapiens

NADH dehydrogenase [ubiquinone] iron-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 subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase. Mutations in this gene are associated with mitochondrial complex I deficiency.

<span class="mw-page-title-main">NDUFS1</span> Protein-coding gene in the species Homo sapiens

NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial (NDUFS1) is an enzyme that in humans is encoded by the NDUFS1 gene. The encoded protein, NDUFS1, is the largest subunit of complex I, located on the inner mitochondrial membrane, and is important for mitochondrial oxidative phosphorylation. Mutations in this gene are associated with complex I deficiency.

<span class="mw-page-title-main">NDUFS7</span> Protein-coding gene in the species Homo sapiens

NADH dehydrogenase [ubiquinone] iron-sulfur protein 7, mitochondrial, also knowns as NADH-ubiquinone oxidoreductase 20 kDa subunit, Complex I-20kD (CI-20kD), or PSST subunit is an enzyme that in humans is encoded by the NDUFS7 gene. The NDUFS7 protein is a subunit of NADH dehydrogenase (ubiquinone) also known as Complex I, which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain.

<span class="mw-page-title-main">NDUFB6</span> Protein-coding gene in the species Homo sapiens

NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 6, also known as complex I-B17, is a protein that in humans is encoded by the NDUFB6 gene. NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 6, is an accessory subunit of the NADH dehydrogenase (ubiquinone) complex, located in the mitochondrial inner membrane. It is also known as Complex I and is the largest of the five complexes of the electron transport chain.

<span class="mw-page-title-main">NDUFA2</span> Protein-coding gene in the species Homo sapiens

NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 2 is a protein that in humans is encoded by the NDUFA2 gene. The NDUFA2 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Mutations in the NDUFA2 gene are associated with Leigh's syndrome.

<span class="mw-page-title-main">NDUFA9</span> Protein-coding gene in the species Homo sapiens

NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 9 is an enzyme that in humans is encoded by the NDUFA9 gene. The NDUFA9 protein is a subunit of NADH:ubiquinone oxidoreductase, which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Mutations in NADH dehydrogenase (ubiquinone), also known as Complex I, frequently lead to complex neurodegenerative diseases such as Leigh's syndrome. In the case of NDUFA9, a mutation to the MT-ND3 gene might interrupt their interaction and formation of subcomplexes, compromising Complex I function and leading to disease.

<span class="mw-page-title-main">FOXRED1</span> Protein-coding gene in the species Homo sapiens

FAD-dependent oxidoreductase domain-containing protein 1 (FOXRED1), also known as H17, or FP634 is an enzyme that in humans is encoded by the FOXRED1 gene. FOXRED1 is an oxidoreductase and complex I-specific molecular chaperone involved in the assembly and stabilization of NADH dehydrogenase (ubiquinone) also known as complex I, which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Mutations in FOXRED1 have been associated with Leigh syndrome and infantile-onset mitochondrial encephalopathy.

<span class="mw-page-title-main">NDUFAF1</span> Protein-coding gene in the species Homo sapiens

Complex I intermediate-associated protein 30, mitochondrial (CIA30), or NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 1 (NDUFAF1), is a protein that in humans is encoded by the NDUFAF1 or CIA30 gene. The NDUFAF1 gene encodes a human homolog of a Neurospora crassa protein involved in the assembly of complex I. The NDUFAF1 protein is an assembly factor of NADH dehydrogenase (ubiquinone) also known as complex I, which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Variants of the NDUFAF1 gene are associated with hypertrophic cardiomyopathy, leukodystrophy, and cardioencephalomyopathy.

<span class="mw-page-title-main">NDUFB7</span> Protein-coding gene in the species Homo sapiens

NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 7, also known as complex I-B18, is an enzyme that in humans is encoded by the NDUFB7 gene. NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 7 is an accessory subunit of the NADH dehydrogenase (ubiquinone) complex, located in the mitochondrial inner membrane. It is also known as Complex I and is the largest of the five complexes of the electron transport chain.

<span class="mw-page-title-main">NDUFB11</span> Protein-coding gene in the species Homo sapiens

NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 11, mitochondrial is an enzyme that in humans is encoded by the NDUFB11 gene. NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 11 is an accessory subunit of the NADH dehydrogenase (ubiquinone) complex, located in the mitochondrial inner membrane. It is also known as Complex I and is the largest of the five complexes of the electron transport chain. NDUFB11 mutations have been associated with linear skin defects with multiple congenital anomalies 3 and mitochondrial complex I deficiency.

<span class="mw-page-title-main">NDUFAF4</span> Protein-coding gene in the species Homo sapiens

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 mitochondrial assembly protein involved in the assembly of NADH dehydrogenase (ubiquinone) also known as complex I, which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Mutations in this gene have been associated with complex I deficiency and infantile mitochondrial encephalomyopathy. Elevations in HRPAP20 have also been implicated in breast cancer.

<span class="mw-page-title-main">NDUFAF2</span> Protein-coding gene in the species Homo sapiens

NADH:ubiquinone oxidoreductase complex assembly factor 2 (NDUFAF2), also known as B17.2L or NDUFA12L is a protein that in humans is encoded by the NDUFAF2, or B17.2L, gene. The NDUFAF2 protein is a chaperone involved in the assembly of NADH dehydrogenase (ubiquinone) also known as complex I, which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Mutations in this gene have been associated with progressive encephalopathy and Leigh disease resulting from mitochondrial complex I deficiency.

NADH:ubiquinone oxidoreductase complex assembly factor 5, also known as Arginine-hydroxylase NDUFAF5, or Putative methyltransferase NDUFAF5, is a protein that in humans is encoded by the NDUFAF5 gene. The NADH-ubiquinone oxidoreductase complex of the mitochondrial respiratory chain catalyzes the transfer of electrons from NADH to ubiquinone, and consists of at least 43 subunits. The complex is located in the inner mitochondrial membrane. This gene encodes a mitochondrial protein that is associated with the matrix face of the mitochondrial inner membrane and is required for complex I assembly. A mutation in this gene results in mitochondrial complex I deficiency. Multiple transcript variants encoding different isoforms have been found for this gene.

<span class="mw-page-title-main">NDUFAF7</span> Gene of the species Homo sapiens

Protein arginine methyltransferase NDUFAF7, mitochondrial, also known as NADH:ubiquinone oxidoreductase complex assembly factor 7 (NDUFAF7),MidA, C2orf56, or PRO1853, is a protein that in humans is encoded by the NDUFAF7 gene. NDUFAF7 is a methyltransferase mitochondrial assembly enzyme involved in the assembly and stabilization of NADH dehydrogenase (ubiquinone) also known as complex I, which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Mutations in NDUFAF7 have been associated with pathologic myopia and complex I deficiency.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000178057 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000070283 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 3 4 "NDUFAF3 NADH:ubiquinone oxidoreductase complex assembly factor 3 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2018-07-25.
  6. 1 2 "NDUFAF3 - NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 3 - Homo sapiens (Human) - NDUFAF3 gene & protein". www.uniprot.org. Retrieved 2018-07-25.
  7. 1 2 "UniProt: the universal protein knowledgebase". Nucleic Acids Research. 45 (D1): D158–D169. January 2017. doi:10.1093/nar/gkw1099. PMC   5210571 . PMID   27899622.
  8. ↑ Donald Voet; Judith G. Voet; Charlotte W. Pratt (2013). "18". Fundamentals of biochemistry : life at the molecular level (4th ed.). Hoboken, NJ: Wiley. pp. 581–620. ISBN   9780470547847.
  9. 1 2 3 4 5 6 7 8 Saada A, Vogel RO, Hoefs SJ, van den Brand MA, Wessels HJ, Willems PH, Venselaar H, Shaag A, Barghuti F, Reish O, Shohat M, Huynen MA, Smeitink JA, van den Heuvel LP, Nijtmans LG (June 2009). "Mutations in NDUFAF3 (C3ORF60), encoding an NDUFAF4 (C6ORF66)-interacting complex I assembly protein, cause fatal neonatal mitochondrial disease". American Journal of Human Genetics. 84 (6): 718–27. doi:10.1016/j.ajhg.2009.04.020. PMC   2694978 . PMID   19463981.
  10. 1 2 3 4 Baertling F, Sánchez-Caballero L, Timal S, van den Brand MA, Ngu LH, Distelmaier F, Rodenburg RJ, Nijtmans LG (March 2017). "Mutations in mitochondrial complex I assembly factor NDUFAF3 cause Leigh syndrome". Molecular Genetics and Metabolism. 120 (3): 243–246. doi:10.1016/j.ymgme.2016.12.005. PMID   27986404.
  11. ↑ Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P (October 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research. 113 (9): 1043–53. doi:10.1161/CIRCRESAHA.113.301151. PMC   4076475 . PMID   23965338.
  12. ↑ Yao, Daniel. "Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) —— Protein Information". amino.heartproteome.org. Retrieved 2018-07-25.
  13. ↑ Reference, Genetics Home. "NDUFAF1 gene". Genetics Home Reference. Retrieved 2018-07-25.
  14. ↑ "ndufaf3-ndufaf4". IntAct. EMBL-EBI.
  15. ↑ "ndufaf3-snrpa-1". IntAct. EMBL-EBI.

Further reading

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