NDUFAF1

Last updated
NDUFAF1
Identifiers
Aliases NDUFAF1 , CGI65, CIA30, CGI-65, NADH:ubiquinone oxidoreductase complex assembly factor 1, MC1DN11
External IDs OMIM: 606934 MGI: 1916952 HomoloGene: 32289 GeneCards: NDUFAF1
Orthologs
SpeciesHumanMouse
Entrez

51103

69702

Ensembl

ENSG00000137806

ENSMUSG00000027305

UniProt

Q9Y375

Q9CWX2

RefSeq (mRNA)

NM_016013

NM_027175
NM_001356467

RefSeq (protein)

NP_057097

Location (UCSC) Chr 15: 41.39 – 41.41 Mb Chr 2: 119.49 – 119.49 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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. [5] [6] [7] [8] [9] The NDUFAF1 gene encodes a human homolog of a Neurospora crassa protein involved in the assembly of complex I. [7] 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. [10] Variants of the NDUFAF1 gene are associated with hypertrophic cardiomyopathy, leukodystrophy, and cardioencephalomyopathy. [11] [12] [13]

Contents

Structure

NDUFAF1 is located on the q arm of chromosome 15 in position 15.1. [7] The NDUFAF1 gene produces a 37.8 kDa protein composed of 327 amino acids. [14] [15] NDUFAF1 is associated to complexes of 600 and 700 kDa. [8] Complex I is structured in a bipartite L-shaped configuration, which is made up of a peripheral matrix arm, consisting of flavoproteins and iron-sulfur proteins involved in electron transfer, and a membrane arm, consisting of mtDNA-encoded subunits involved in ubiquinone reduction and proton pumping. [13] NDUFAF1 has been shown to interact with assembly intermediates and may play roles in the correct assembly and combination of the peripheral arm to the complete membrane arm as well as in the stabilization and scaffolding of those intermediates through those close interactions. [8]

Function

NDUFAF1 is an assembly factor that is important for the correct assembly of NADH dehydrogenase (ubiquinone). It ensures the correct combination of complex intermediates and is necessary for the correct functioning of NADH dehydrogenase (ubiquinone). Specifically, NDUFAF1 binds to the large membrane arm intermediate and is involved in the combination of the small and large membrane arm intermediates of complex I. It has also been suggested that NDUFAF1 is involved in the stabilization and scaffolding of assembly intermediates and that this role may be more prominent than its part in intermediate combination. [8]

Clinical Significance

Mutations in NDUFAF1 can result in mitochondrial deficiencies and associated disorders. A disorder of the mitochondrial respiratory chain 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. [16]

In a patient with missense mutations in NDUFAF1, fatal infantile hypertrophic cardiomyopathy was diagnosed. In this case, complex I disassembly resulted in a mitochondrial cardiomyopathy with marked lactic acidosis. [11] Another patient, a child with a compound heterozygous mutation (c.278A > G; c.247G > A) within exon 2 in the NDUFAF1 gene, was diagnosed with leukodystrophy associated with mitochondrial complex I deficiency. Signs and symptoms included regression of mental and motor development, white matter lesions, peripheral neuropathy with high muscle tension and hyperreflexia of limbs, and high levels of lactate and creatine kinase. The parents were found to be heterozygous carriers for the mutation. [12] A third patient was found to have a mutation in both alleles of the NDUFAF1 gene and was diagnosed with cardioencephalomyopathy and reduced levels and activity of complex I. [13]

Interactions

In addition to co-complexes, NDUFAF1 has protein-protein interactions with PNLIPRP1, [17] TMEM97, [18] TMEM86B, [19] YIPF6, [20] SLC30A2, [21] ATIC, [22] and MAGEA11. [23]

Related Research Articles

<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">NADH dehydrogenase (ubiquinone), alpha 1</span> Protein-coding gene in the species Homo sapiens

NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 1 is a protein that in humans is encoded by the NDUFA1 gene. The NDUFA1 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 NDUFA1 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">NDUFV2</span> Protein-coding gene in the species Homo sapiens

NADH dehydrogenase [ubiquinone] flavoprotein 2, mitochondrial (NDUFV2) is an enzyme that in humans is encoded by the NDUFV2 gene. The encoded protein, NDUFV2, is a subunit of complex I of the mitochondrial respiratory chain, which is located on the inner mitochondrial membrane and involved in oxidative phosphorylation. Mutations in this gene are implicated in Parkinson's disease, bipolar disorder, schizophrenia, and have been found in one case of early onset hypertrophic cardiomyopathy and encephalopathy.

<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">NDUFS6</span> Protein-coding gene in the species Homo sapiens

NADH dehydrogenase [ubiquinone] iron-sulfur protein 6, mitochondrial is an enzyme that in humans is encoded by the NDUFS6 gene.

<span class="mw-page-title-main">NDUFAF3</span> Protein-coding gene in the species Homo sapiens

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

<span class="mw-page-title-main">NDUFA10</span> Protein-coding gene in the species Homo sapiens

NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 10 is an enzyme that in humans is encoded by the NDUFA10 gene. The NDUFA10 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 subunits of NADH dehydrogenase (ubiquinone), also known as Complex I, frequently lead to complex neurodegenerative diseases such as Leigh's syndrome. Furthermore, reduced NDUFA10 expression levels due to FOXM1-directed hypermethylation are associated with human squamous cell carcinoma and may be related to other forms of cancer.

<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">NDUFA11</span> Protein-coding gene in the species Homo sapiens

NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 11 is an enzyme that in humans is encoded by the NDUFA11 gene. The NDUFA11 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 subunits of NADH dehydrogenase (ubiquinone), also known as Complex I, frequently lead to complex neurodegenerative diseases such as Leigh's syndrome. Mutations in this gene are associated with severe 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.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000137806 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000027305 - 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. ↑ Janssen R, Smeitink J, Smeets R, van Den Heuvel L (March 2002). "CIA30 complex I assembly factor: a candidate for human complex I deficiency?". Human Genetics. 110 (3): 264–70. doi:10.1007/s00439-001-0673-3. PMID   11935339. S2CID   19502660.
  6. ↑ Lai CH, Chou CY, Ch'ang LY, Liu CS, Lin W (May 2000). "Identification of novel human genes evolutionarily conserved in Caenorhabditis elegans by comparative proteomics". Genome Research. 10 (5): 703–13. doi:10.1101/gr.10.5.703. PMC   310876 . PMID   10810093.
  7. 1 2 3 "Entrez Gene: NDUFAF1 NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, assembly factor 1".
  8. 1 2 3 4 Vogel RO, Janssen RJ, Ugalde C, Grovenstein M, Huijbens RJ, Visch HJ, van den Heuvel LP, Willems PH, Zeviani M, Smeitink JA, Nijtmans LG (October 2005). "Human mitochondrial complex I assembly is mediated by NDUFAF1". The FEBS Journal. 272 (20): 5317–26. doi:10.1111/j.1742-4658.2005.04928.x. PMID   16218961. S2CID   29896047.
  9. ↑ "NDUFAF1 - Complex I intermediate-associated protein 30, mitochondrial precursor - Homo sapiens (Human) - NDUFAF1 gene & protein". www.uniprot.org. Retrieved 2018-07-23.
  10. ↑ Donald., Voet (2013). Fundamentals of biochemistry : life at the molecular level. Voet, Judith G., Pratt, Charlotte W. (Fourth ed.). Hoboken, NJ: Wiley. ISBN   9780470547847. OCLC   738349533.
  11. 1 2 Fassone E, Taanman JW, Hargreaves IP, Sebire NJ, Cleary MA, Burch M, Rahman S (October 2011). "Mutations in the mitochondrial complex I assembly factor NDUFAF1 cause fatal infantile hypertrophic cardiomyopathy". Journal of Medical Genetics. 48 (10): 691–7. doi:10.1136/jmedgenet-2011-100340. PMID   21931170. S2CID   35411085.
  12. 1 2 Wu L, Peng J, Ma Y, He F, Deng X, Wang G, Lifen Y, Yin F (2016). "Leukodystrophy associated with mitochondrial complex I deficiency due to a novel mutation in the NDUFAF1 gene". Mitochondrial DNA Part A. 27 (2): 1034–7. doi:10.3109/19401736.2014.926543. PMID   24963768. S2CID   207677530.
  13. 1 2 3 Dunning CJ, McKenzie M, Sugiana C, Lazarou M, Silke J, Connelly A, Fletcher JM, Kirby DM, Thorburn DR, Ryan MT (July 2007). "Human CIA30 is involved in the early assembly of mitochondrial complex I and mutations in its gene cause disease". The EMBO Journal. 26 (13): 3227–37. doi:10.1038/sj.emboj.7601748. PMC   1914096 . PMID   17557076.
  14. ↑ 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.
  15. ↑ Yao, Daniel. "Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) —— Protein Information". amino.heartproteome.org. Retrieved 2018-07-23.
  16. ↑ "Mitochondrial complex I deficiency". www.uniprot.org. Retrieved 2018-07-23.
  17. ↑ "pnliprp1-ndufaf1-1". IntAct. Retrieved 2018-07-23.
  18. ↑ "tmem97-ndufaf1-1". IntAct. Retrieved 2018-07-23.
  19. ↑ "tmem86b-ndufaf1-1". IntAct. Retrieved 2018-07-23.
  20. ↑ "yipf6-ndufaf1-1". IntAct. Retrieved 2018-07-23.
  21. ↑ "slc30a2-ndufaf1-1". IntAct. Retrieved 2018-07-23.
  22. ↑ "atic-ndufaf1". IntAct. Retrieved 2018-07-23.
  23. ↑ "magea11-ndufaf1". IntAct. Retrieved 2018-07-23.

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