Biology:MT-ND4

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Short description: Mitochondrial gene coding for a protein involved in the respiratory chain


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example
Location of the MT-ND4 gene in the human mitochondrial genome. MT-ND4 is one of the seven NADH dehydrogenase mitochondrial genes (yellow boxes).

MT-ND4 is a gene of the mitochondrial genome coding for the NADH-ubiquinone oxidoreductase chain 4 (ND4) protein.[1] The ND4 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.[2] Variations in the MT-ND4 gene are associated with age-related macular degeneration (AMD), Leber's hereditary optic neuropathy (LHON), mesial temporal lobe epilepsy (MTLE) and cystic fibrosis.[3][4][5][6]

Structure

The MT-ND4 gene is located in human mitochondrial DNA from base pair 10,760 to 12,137.[1][7] The MT-ND4 gene produces a 52 kDa protein composed of 459 amino acids.[8][9] MT-ND4 is one of seven mitochondrial genes encoding subunits of the enzyme NADH dehydrogenase (ubiquinone), together with MT-ND1, MT-ND2, MT-ND3, MT-ND4L, MT-ND5, and MT-ND6. Also known as Complex I, this enzyme is the largest of the respiratory complexes. The structure is L-shaped with a long, hydrophobic transmembrane domain and a hydrophilic domain for the peripheral arm that includes all the known redox centres and the NADH binding site. MT-ND4 and the rest of the mitochondrially encoded subunits are the most hydrophobic of the subunits of Complex I and form the core of the transmembrane region.[2]

An unusual feature of the human MT-ND4 gene is the 7-nucleotide gene overlap of its first three codons (5'-ATG CTA AAA-3' coding for amino acids Met-Leu-Lys) with the last three codons of the MT-ND4L gene (5'-CAA TGC TAA-3' coding for Gln, Cys and Stop).[7] With respect to the MT-ND4L reading frame (+1), the MT-ND4 gene starts in the +3 reading frame: [CAA][TGC][TAA]AA versus CA[ATG][CTA][AAA].

Function

MT-ND4 is a subunit of the respiratory chain Complex I that is believed to belong to the minimal assembly of core proteins required to catalyze NADH dehydrogenation and electron transfer to ubiquinone (coenzyme Q10).[10] Initially, NADH binds to Complex I and transfers two electrons to the isoalloxazine ring of the flavin mononucleotide (FMN) prosthetic arm to form FMNH2. The electrons are transferred through a series of iron-sulfur (Fe-S) clusters in the prosthetic arm and finally to coenzyme Q10 (CoQ), which is reduced to ubiquinol (CoQH2). The flow of electrons changes the redox state of the protein, resulting in a conformational change and pK shift of the ionizable side chain, which pumps four hydrogen ions out of the mitochondrial matrix.[2]

Studies in cystic fibrosis cases suggest that MT-ND4 expression is indirectly upregulated by the cystic fibrosis transmembrane conductance regulator (CFTR) channel chloride transport activity. Channel flow double-electrode (CFDE) cells ectopically expressing wild-type CFTR channels were used to test the effect of CFTR chloride transport inhibitors glibenclamide and CFTR(inh)172 and demonstrated a reduction in MT-ND4 expression.[3]

Clinical significance

MT-ND4 contains one of five mitochondrial single-nucleotide polymorphisms (SNPs) associated with age-related macular degeneration (AMD) in Mexican Americans, mt12007.[6]

Leber's hereditary optic neuropathy (LHON) correlates with a mutation in the MT-ND4 gene in multiple families. The mutation at codon 340 results in the elimination of an Sfa NI site by the conversion of a highly conserved arginine to a histidine. This provides a simple diagnostic test by which to identify LHON, a maternally inherited disease that results in optic nerve degeneration and cardiac dysrythmia.[5]

Amino acid changes in MT-ND4, MT-ND5 and MT-ATP8 resulting from mutations at the 11994, 8502 and 13,231 bp of mtDNA are significantly correlated in mesial temporal lobe epilepsy (MTLE) patients with hippocampal sclerosis. The 11994 C>T mutation to the MT-ND4 gene results in a Thr to Ile shift at the 412 position. Genome analysis has never been used in MTLE cases and could provide another diagnostic method in the disease.[4]

MT-ND4 is downregulated in cystic fibrosis, a disease that results from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) channel.[3]

Interactions

MT-ND4 has been shown to have 21 binary protein-protein interactions including 15 co-complex interactions. MT-ND4 appears to interact with SP1, ZNF16, CTCF, GRB2, and ATM.[11]

References

  1. ↑ 1.0 1.1 "Entrez Gene: MT-ND4 mitochondrially encoded NADH dehydrogenase 4". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4538. 
  2. ↑ 2.0 2.1 2.2 Pratt, Donald Voet, Judith G. Voet, Charlotte W. (2013). "18". Fundamentals of biochemistry : life at the molecular level (4th ed.). Hoboken, NJ: Wiley. pp. 581–620. ISBN 9780470547847. 
  3. ↑ 3.0 3.1 3.2 "The expression of the mitochondrial gene MT-ND4 is downregulated in cystic fibrosis". Biochemical and Biophysical Research Communications 356 (3): 805–9. May 2007. doi:10.1016/j.bbrc.2007.03.057. PMID 17382898. https://repositorio.uca.edu.ar/handle/123456789/1456. 
  4. ↑ 4.0 4.1 "Mitochondrial DNA profiling via genomic analysis in mesial temporal lobe epilepsy patients with hippocampal sclerosis". Gene 538 (2): 323–7. April 2014. doi:10.1016/j.gene.2014.01.030. PMID 24440288. 
  5. ↑ 5.0 5.1 "Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy". Science 242 (4884): 1427–30. December 1988. doi:10.1126/science.3201231. PMID 3201231. Bibcode: 1988Sci...242.1427W. 
  6. ↑ 6.0 6.1 "Mitochondrial variation and the risk of age-related macular degeneration across diverse populations". Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing: 243–54. 2015. PMID 25592585. 
  7. ↑ 7.0 7.1 Homo sapiens mitochondrion, complete genome. "Revised Cambridge Reference Sequence (rCRS): accession NC_012920", National Center for Biotechnology Information. Retrieved on 30 January 2016.
  8. ↑ "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research 113 (9): 1043–53. October 2013. doi:10.1161/CIRCRESAHA.113.301151. PMID 23965338. 
  9. ↑ "NADH-ubiquinone oxidoreductase chain 4". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). https://amino.heartproteome.org/web/protein/P03905. 
  10. ↑ "MT-ND4 - NADH-ubiquinone oxidoreductase chain 4 - Homo sapiens (Human)". The UniProt Consortium. https://www.uniprot.org/uniprot/P03905. 
  11. ↑ "21 binary interactions found for search term MT-ND4". IntAct Molecular Interaction Database. EMBL-EBI. https://www.ebi.ac.uk/intact/interactions?conversationContext=3&query=MT-ND4. 

Further reading

External links



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