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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 severe complex I deficiency and Leigh syndrome.[5][9][10]

AliasesNDUFAF3, 2P1, C3orf60, E3-3, NADH:ubiquinone oxidoreductase complex assembly factor 3, MC1DN18
External IDsMGI: 1913956 HomoloGene: 32460 GeneCards: NDUFAF3
Gene location (Human)
Chromosome 3 (human)
Chr.Chromosome 3 (human)[1]
Chromosome 3 (human)
Genomic location for NDUFAF3
Genomic location for NDUFAF3
Band3p21.31Start49,020,459 bp[1]
End49,023,495 bp[1]
RNA expression pattern
PBB GE C3orf60 209177 at fs.png
More reference expression data
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC)Chr 3: 49.02 – 49.02 MbChr 9: 108.57 – 108.57 Mb
PubMed search[3][4]
View/Edit HumanView/Edit Mouse



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]


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 SignificanceEdit

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]


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


  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000178057 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000070283 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:".
  4. ^ "Mouse PubMed Reference:".
  5. ^ a b c d "NDUFAF3 NADH:ubiquinone oxidoreductase complex assembly factor 3 [Homo sapiens (human)] - Gene - NCBI". Retrieved 2018-07-25.
  6. ^ a b "NDUFAF3 - NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 3 - Homo sapiens (Human) - NDUFAF3 gene & protein". Retrieved 2018-07-25.
  7. ^ a b "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. ^ a b c d e f g h 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. ^ a b c d 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". 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 readingEdit

External linksEdit

This article incorporates text from the United States National Library of Medicine, which is in the public domain.