MT-ND4

Last updated
ND4
Identifiers
Aliases ND4 , MTMT-NADH dehydrogenase, subunit 4 (complex I), NADH dehydrogenase subunit 4
External IDs OMIM: 516003 MGI: 102498 HomoloGene: 38240 GeneCards: ND4
Orthologs
SpeciesHumanMouse
Entrez

4538

17719

Ensembl

ENSG00000198886

ENSMUSG00000064363

UniProt

P03905

P03911

RefSeq (mRNA)

n/a

n/a

RefSeq (protein)

n/a

NP_904337

Location (UCSC) Chr M: 0.01 – 0.01 Mb Chr M: 0.01 – 0.01 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse
Location of the MT-ND4 gene in the human mitochondrial genome. MT-ND4 is one of the seven NADH dehydrogenase mitochondrial genes (yellow boxes). Map of the human mitochondrial genome.svg
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. [5] 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. [6] 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. [7] [8] [9] [10]

Contents

Structure

The MT-ND4 gene is located in human mitochondrial DNA from base pair 10,760 to 12,137. [5] [11] The MT-ND4 gene produces a 52 kDa protein composed of 459 amino acids. [12] [13] 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. [6]

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). [11] 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). [14] 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. [6]

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. [7]

Clinical significance

MT-ND4 contains one of five mitochondrial single-nucleotide polymorphisms (SNPs) associated with age-related macular degeneration (AMD) in Mexican Americans, mt12007. [10]

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. [9]

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. [8]

MT-ND4 is downregulated in cystic fibrosis, a disease that results from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) channel. [7]

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. [15]

Related Research Articles

<span class="mw-page-title-main">Homoplasmy</span> Identity of organellar DNA sequences in a cell

Homoplasmy is a term used in genetics to describe a eukaryotic cell whose copies of mitochondrial DNA are all identical. In normal and healthy tissues, all cells are homoplasmic. Homoplasmic mitochondrial DNA copies may be normal or mutated; however, most mutations are heteroplasmic. It has been discovered, though, that homoplasmic mitochondrial DNA mutations may be found in human tumors.

<span class="mw-page-title-main">Leber's hereditary optic neuropathy</span> Mitochondrially inherited degeneration of retinal cells in human

Leber's hereditary optic neuropathy (LHON) is a mitochondrially inherited degeneration of retinal ganglion cells (RGCs) and their axons that leads to an acute or subacute loss of central vision; it predominantly affects young adult males. LHON is transmitted only through the mother, as it is primarily due to mutations in the mitochondrial genome, and only the egg contributes mitochondria to the embryo. Men cannot pass on the disease to their offspring. LHON is usually due to one of three pathogenic mitochondrial DNA (mtDNA) point mutations. These mutations are at nucleotide positions 11778 G to A, 3460 G to A and 14484 T to C, respectively in the ND4, ND1 and ND6 subunit genes of complex I of the oxidative phosphorylation chain in mitochondria.

<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-ND2</span> Mitochondrial gene coding for a protein involved in the respiratory chain

MT-ND2 is a gene of the mitochondrial genome coding for the NADH dehydrogenase 2 (ND2) protein. The ND2 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. Variants of human MT-ND2 are associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), Leigh's syndrome (LS), Leber's hereditary optic neuropathy (LHON) and increases in adult BMI.

<span class="mw-page-title-main">MT-ND4L</span> Mitochondrial gene coding for a protein involved in the respiratory chain

MT-ND4L is a gene of the mitochondrial genome coding for the NADH-ubiquinone oxidoreductase chain 4L (ND4L) protein. The ND4L 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. Variants of human MT-ND4L are associated with increased BMI in adults and Leber's Hereditary Optic Neuropathy (LHON).

<span class="mw-page-title-main">MT-ND3</span> Mitochondrial protein-coding gene whose product is involved in the respiratory chain

MT-ND3 is a gene of the mitochondrial genome coding for the NADH dehydrogenase 3 (ND3) protein. The ND3 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. Variants of MT-ND3 are associated with Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), Leigh's syndrome (LS) and Leber's hereditary optic neuropathy (LHON).

<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">MT-ND1</span> Mitochondrial gene coding for a protein involved in the respiratory chain

MT-ND1 is a gene of the mitochondrial genome coding for the NADH-ubiquinone oxidoreductase chain 1 (ND1) protein. The ND1 protein is a subunit of NADH dehydrogenase, which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Variants of the human MT-ND1 gene are associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), Leigh's syndrome (LS), Leber's hereditary optic neuropathy (LHON) and increases in adult BMI.

<span class="mw-page-title-main">Cytochrome c oxidase subunit III</span> Enzyme of the respiratory chain encoded by the mitochondrial genome

Cytochrome c oxidase subunit III (COX3) is an enzyme that in humans is encoded by the MT-CO3 gene. It is one of main transmembrane subunits of cytochrome c oxidase. It is also one of the three mitochondrial DNA (mtDNA) encoded subunits of respiratory complex IV. Variants of it have been associated with isolated myopathy, severe encephalomyopathy, Leber hereditary optic neuropathy, mitochondrial complex IV deficiency, and recurrent myoglobinuria.

<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">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">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">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">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">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">NDUFA11</span> Protein and coding gene in humans

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.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000198886 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000064363 - 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 "Entrez Gene: MT-ND4 mitochondrially encoded NADH dehydrogenase 4".
  6. 1 2 3 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.{{cite book}}: CS1 maint: multiple names: authors list (link)
  7. 1 2 3 Valdivieso AG, Marcucci F, Taminelli G, Guerrico AG, Alvarez S, Teiber ML, Dankert MA, Santa-Coloma TA (May 2007). "The expression of the mitochondrial gene MT-ND4 is downregulated in cystic fibrosis". Biochemical and Biophysical Research Communications. 356 (3): 805–9. doi:10.1016/j.bbrc.2007.03.057. PMID   17382898.
  8. 1 2 Gurses C, Azakli H, Alptekin A, Cakiris A, Abaci N, Arikan M, Kursun O, Gokyigit A, Ustek D (April 2014). "Mitochondrial DNA profiling via genomic analysis in mesial temporal lobe epilepsy patients with hippocampal sclerosis". Gene. 538 (2): 323–7. doi: 10.1016/j.gene.2014.01.030 . PMID   24440288.
  9. 1 2 Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AM, Elsas LJ, Nikoskelainen EK (December 1988). "Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy". Science. 242 (4884): 1427–30. Bibcode:1988Sci...242.1427W. doi:10.1126/science.3201231. PMID   3201231.
  10. 1 2 Restrepo NA, Mitchell SL, Goodloe RJ, Murdock DG, Haines JL, Crawford DC (2015). "Mitochondrial variation and the risk of age-related macular degeneration across diverse populations". Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing: 243–54. PMC   4299880 . PMID   25592585.
  11. 1 2 Homo sapiens mitochondrion, complete genome. "Revised Cambridge Reference Sequence (rCRS): accession NC_012920", National Center for Biotechnology Information . Retrieved on 30 January 2016.
  12. ↑ 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.
  13. ↑ "NADH-ubiquinone oxidoreductase chain 4". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB).
  14. ↑ "MT-ND4 - NADH-ubiquinone oxidoreductase chain 4 - Homo sapiens (Human)". UniProt.org: a hub for protein information. The UniProt Consortium.
  15. ↑ "21 binary interactions found for search term MT-ND4". IntAct Molecular Interaction Database. EMBL-EBI. Retrieved 2018-08-25.

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