Editing Respiratory complex I (section)

== Composition and structure ==

NADH:ubiquinone oxidoreductase is the largest of the respiratory complexes. In [[mammal]]s, the enzyme contains 44 separate water-soluble peripheral membrane proteins, which are anchored to the integral membrane constituents. Of particular functional importance are the [[Flavin group|flavin]] [[prosthetic group]] (FMN) and eight [[iron-sulfur cluster]]s (FeS). Of the 44 subunits, seven are encoded by the [[mitochondrial genome]].<ref name="isbn0-471-19350-X">{{cite book | vauthors = Voet JG, Voet D | title = Biochemistry | edition = 3rd | publisher = J. Wiley & Sons | location = New York | year = 2004 | pages = [https://archive.org/details/biochemistry00voet_1/page/813 813]–826 | isbn = 0-471-19350-X | url =https://archive.org/details/biochemistry00voet_1|url-access=registration }}</ref><ref name="pmid16950771">{{cite journal | vauthors = Carroll J, Fearnley IM, Skehel JM, Shannon RJ, Hirst J, Walker JE | title = Bovine complex I is a complex of 45 different subunits | journal = The Journal of Biological Chemistry | volume = 281 | issue = 43 | pages = 32724–7 | date = October 2006 | pmid = 16950771 | doi = 10.1074/jbc.M607135200 | doi-access = free }}</ref><ref name="pmid22902835">{{cite journal | vauthors = Balsa E, Marco R, Perales-Clemente E, Szklarczyk R, Calvo E, Landázuri MO, Enríquez JA | title = NDUFA4 is a subunit of complex IV of the mammalian electron transport chain | journal = Cell Metabolism | volume = 16 | issue = 3 | pages = 378–86 | date = September 2012 | pmid = 22902835 | doi = 10.1016/j.cmet.2012.07.015 | doi-access = free }}</ref>

The structure is an "L" shape with a long membrane domain (with around 60 trans-membrane helices) and a hydrophilic (or peripheral) domain, which includes all the known redox centres and the NADH binding site.<ref name="pmid16469879">{{cite journal | vauthors = [[Leonid Sazanov|Sazanov LA]], Hinchliffe P | title = Structure of the hydrophilic domain of respiratory complex I from Thermus thermophilus | journal = Science | volume = 311 | issue = 5766 | pages = 1430–6 | date = March 2006 | pmid = 16469879 | doi = 10.1126/science.1123809 | bibcode = 2006Sci...311.1430S | s2cid = 1892332 | doi-access = free }}</ref> All thirteen of the ''E. coli'' proteins, which comprise NADH dehydrogenase I, are encoded within the ''nuo'' operon, and are homologous to mitochondrial complex I subunits. The antiporter-like subunits NuoL/M/N each contains 14 conserved transmembrane (TM) helices. Two of them are discontinuous, but subunit NuoL contains a 110 Å long amphipathic α-helix, spanning the entire length of the domain. The subunit, NuoL, is related to Na<sup>+</sup>/ H<sup>+</sup> antiporters of [http://tcdb.org/search/result.php?tc=2.A.63.1.1 TC# 2.A.63.1.1] (PhaA and PhaD).

Three of the conserved, membrane-bound subunits in NADH dehydrogenase are related to each other, and to Mrp sodium-proton antiporters. Structural analysis of two prokaryotic complexes I revealed that the three subunits each contain fourteen transmembrane helices that overlay in structural alignments: the translocation of three protons may be coordinated by a lateral helix connecting them.<ref>{{cite journal | vauthors = Efremov RG, Baradaran R, [[Leonid Sazanov|Sazanov LA]] | title = The architecture of respiratory complex I | journal = Nature | volume = 465 | issue = 7297 | pages = 441–5 | date = May 2010 | pmid = 20505720 | doi = 10.1038/nature09066 | bibcode = 2010Natur.465..441E | s2cid = 4372778 }}</ref>

Complex I contains a ubiquinone binding pocket at the interface of the 49-kDa and PSST subunits. Close to iron-sulfur cluster N2, the proposed immediate electron donor for ubiquinone, a highly conserved tyrosine constitutes a critical element of the quinone reduction site. A possible quinone exchange path leads from cluster N2 to the N-terminal beta-sheet of the 49-kDa subunit.<ref>{{cite journal | vauthors = Tocilescu MA, Zickermann V, Zwicker K, Brandt U | title = Quinone binding and reduction by respiratory complex I | journal = Biochimica et Biophysica Acta (BBA) - Bioenergetics | volume = 1797 | issue = 12 | pages = 1883–90 | date = December 2010 | pmid = 20493164 | doi = 10.1016/j.bbabio.2010.05.009 | doi-access = free }}</ref> All 45 subunits of the bovine NDHI have been sequenced.<ref>{{cite journal | vauthors = Cardol P, Vanrobaeys F, Devreese B, Van Beeumen J, Matagne RF, Remacle C | title = Higher plant-like subunit composition of mitochondrial complex I from Chlamydomonas reinhardtii: 31 conserved components among eukaryotes | journal = Biochimica et Biophysica Acta (BBA) - Bioenergetics | volume = 1658 | issue = 3 | pages = 212–24 | date = October 2004 | pmid = 15450959 | doi = 10.1016/j.bbabio.2004.06.001 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Gabaldón T, Rainey D, Huynen MA | title = Tracing the evolution of a large protein complex in the eukaryotes, NADH:ubiquinone oxidoreductase (Complex I) | journal = Journal of Molecular Biology | volume = 348 | issue = 4 | pages = 857–70 | date = May 2005 | pmid = 15843018 | doi = 10.1016/j.jmb.2005.02.067 }}</ref> Each complex contains noncovalently bound FMN, coenzyme Q and several iron-sulfur centers. The bacterial NDHs have 8-9 iron-sulfur centers.

A recent study used [[electron paramagnetic resonance]] (EPR) spectra and double electron-electron resonance (DEER) to determine the path of electron transfer through the iron-sulfur complexes, which are located in the hydrophilic domain. Seven of these clusters form a chain from the flavin to the quinone binding sites; the eighth cluster is located on the other side of the flavin, and its function is unknown. The EPR and DEER results suggest an alternating or “roller-coaster” potential energy profile for the electron transfer between the active sites and along the iron-sulfur clusters, which can optimize the rate of electron travel and allow efficient energy conversion in complex I.<ref name="pmid20133838">{{cite journal | vauthors = Roessler MM, King MS, Robinson AJ, Armstrong FA, Harmer J, Hirst J | title = Direct assignment of EPR spectra to structurally defined iron-sulfur clusters in complex I by double electron-electron resonance | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 5 | pages = 1930–5 | date = February 2010 | pmid = 20133838 | pmc = 2808219 | doi = 10.1073/pnas.0908050107 | bibcode = 2010PNAS..107.1930R | doi-access = free }}</ref>

{| class=wikitable
|+Conserved subunits of Complex I<ref name="pmid21749854">{{cite journal | vauthors = Cardol P | title = Mitochondrial NADH:ubiquinone oxidoreductase (complex I) in eukaryotes: a highly conserved subunit composition highlighted by mining of protein databases | journal = Biochimica et Biophysica Acta (BBA) - Bioenergetics | volume = 1807 | issue = 11 | pages = 1390–7 | date = November 2011 | pmid = 21749854 | doi = 10.1016/j.bbabio.2011.06.015 | doi-access = free }}</ref>
!#
![[Human]]/[[Bovine]] subunit
! Human protein
! Protein description ([[UniProt]])
! [[Pfam]] family with Human protein

|-
!colspan=6 |Core Subunits<sup>a</sup>
|-

| 1 || NDUFS7 / PSST / NUKM || [[NDUFS7|NDUS7_HUMAN]] || NADH dehydrogenase [ubiquinone] iron-sulfur protein 7, mitochondrial {{EC number|1.6.5.3}} {{EC number|1.6.99.3}} || {{Pfam|PF01058}}
|-

| 2 || NDUFS8 / TYKY / NUIM || [[NDUFS8|NDUS8_HUMAN]] || NADH dehydrogenase [ubiquinone] iron-sulfur protein 8, mitochondrial {{EC number|1.6.5.3}} {{EC number|1.6.99.3}} || {{Pfam|PF12838}}
|-

| 3 || NDUFV2 / 24kD / NUHM<sup>c</sup> || [[NDUFV2|NDUV2_HUMAN]] || NADH dehydrogenase [ubiquinone] flavoprotein 2, mitochondrial {{EC number|1.6.5.3}} {{EC number|1.6.99.3}} || {{Pfam|PF01257}} 
|-

| 4 || NDUFS3 / 30kD / NUGM || [[NDUFS3|NDUS3_HUMAN]] || NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrial {{EC number|1.6.5.3}} {{EC number|1.6.99.3}}|| {{Pfam|PF00329}}
|-

| 5 || NDUFS2 / 49kD / NUCM || [[NDUFS2|NDUS2_HUMAN]] || NADH dehydrogenase [ubiquinone] iron-sulfur protein 2, mitochondrial {{EC number|1.6.5.3}} {{EC number|1.6.99.3}}  ||  {{Pfam|PF00346}}
|-

| 6 || NDUFV1 / 51kD / NUBM || [[NDUFV1|NDUV1_HUMAN]] || NADH dehydrogenase [ubiquinone] flavoprotein 1, mitochondrial {{EC number|1.6.5.3}} {{EC number|1.6.99.3}}       ||  {{Pfam|PF01512}}
|-

| 7 || NDUFS1 / 75kD / NUAM || [[NDUFS1|NDUS1_HUMAN]] || NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial {{EC number|1.6.5.3}} {{EC number|1.6.99.3}} ||  {{Pfam|PF00384}}
|-

| 8 || ND1 / NU1M || [[MT-ND1|NU1M_HUMAN]] || NADH-ubiquinone oxidoreductase chain 1 {{EC number|1.6.5.3}} || {{Pfam|PF00146}}
|-

| 9 || ND2 / NU2M || [[MT-ND2|NU2M_HUMAN]] || NADH-ubiquinone oxidoreductase chain 2 {{EC number|1.6.5.3}} ||  {{Pfam|PF00361}}, {{Pfam|PF06444}}
|-

| 10 || ND3 / NU3M || [[MT-ND3|NU3M_HUMAN]] || NADH-ubiquinone oxidoreductase chain 3 {{EC number|1.6.5.3}} ||  {{Pfam|PF00507}}
|-

| 11 || ND4 / NU4M || [[MT-ND4|NU4M_HUMAN]] || NADH-ubiquinone oxidoreductase chain 4 {{EC number|1.6.5.3}} ||  {{Pfam|PF01059}}, {{Pfam|PF00361}}
|-

| 12 || ND4L / NULM || [[MT-ND4L|NU4LM_HUMAN]] || NADH-ubiquinone oxidoreductase chain 4L {{EC number|1.6.5.3}}||  {{Pfam|PF00420}}
|-

| 13 || ND5 / NU5M || [[MT-ND5|NU5M_HUMAN]] || NADH-ubiquinone oxidoreductase chain 5 {{EC number|1.6.5.3}} || {{Pfam|PF00361}}, {{Pfam|PF06455}}, {{Pfam|PF00662 }}
|-

| 14 || ND6 / NU6M || [[MT-ND6|NU6M_HUMAN]] || NADH-ubiquinone oxidoreductase chain 6 {{EC number|1.6.5.3}} ||  {{Pfam|PF00499 }}
|-

|-
!colspan=6 |Core accessory subunits<sup>b</sup>
|-

| 15 || NDUFS6 / 13A || [[NDUFS6|NDUS6_HUMAN]] || NADH dehydrogenase [ubiquinone] iron-sulfur protein 6, mitochondrial || {{Pfam|PF10276 }}
|-

| 16 || NDUFA12 / B17.2 || [[NDUFA12|NDUAC_HUMAN]] || NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 12 ||  {{Pfam|PF05071}}
|-

| 17 || NDUFS4 / AQDQ || [[NDUFS4|NDUS4_HUMAN]] || NADH dehydrogenase [ubiquinone] iron-sulfur protein 4, mitochondrial ||  {{Pfam|PF04800}}
|-

| 18 || NDUFA9 / 39kDa || [[NDUFA9|NDUA9_HUMAN]] || NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 9, mitochondrial||  {{Pfam|PF01370 }}
|-

| 19 || NDUFAB1 / ACPM || [[NDUFAB1|ACPM_HUMAN]] || Acyl carrier protein, mitochondrial         ||  {{Pfam|PF00550}}
|-

| 20 || NDUFA2 / B8 || [[NDUFA2|NDUA2_HUMAN]] || NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 2 || {{Pfam|PF05047}}
|-

| 21 || NDUFA1 / MFWE || [[NDUFA1|NDUA1_HUMAN]] || NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 1      || {{Pfam|PF15879 }}
|-

| 22 || NDUFB3 / B12 || [[NDUFB3|NDUB3_HUMAN]] || NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 3 ||  {{Pfam|PF08122 }}
|-

| 23 || NDUFA5 / AB13 || [[NDUFA5|NDUA5_HUMAN]] || NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 5 ||  {{Pfam|PF04716}}
|-

| 24 || NDUFA6 / B14 || [[NDUFA6|NDUA6_HUMAN]] || NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 6 ||  {{Pfam|PF05347 }}
|-

| 25 || NDUFA11 / B14.7 || [[NDUFA11|NDUAB_HUMAN]] || NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 11             ||  {{Pfam|PF02466}}
|-

| 26 || NDUFB11 / ESSS || [[NDUFB11|NDUBB_HUMAN]] || NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 11, mitochondrial||   {{Pfam|PF10183}}
|-

| 27 || NDUFS5 / PFFD || [[NDUFS5|NDUS5_HUMAN]] || NADH dehydrogenase [ubiquinone] iron-sulfur protein 5  ||  {{Pfam|PF10200 }}
|-

| 28 || NDUFB4 / B15 || [[NDUFB4|NDUB4_HUMAN]] || NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 4 ||   {{Pfam|PF07225}}
|-

| 29 || NDUFA13 /A13  || [[NDUFA13|NDUAD_HUMAN]] || NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 13 ||   {{Pfam|PF06212}}
|-

| 30 || NDUFB7 / B18 || [[NDUFB7|NDUB7_HUMAN]] || NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 7 ||  {{Pfam|PF05676 }}
|-

| 31 || NDUFA8 / PGIV || [[NDUFA8|NDUA8_HUMAN]] || NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 8|| {{Pfam|PF06747 }}
|-

| 32 || NDUFB9 / B22 || [[NDUFB9|NDUB9_HUMAN]] || NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 9 ||  {{Pfam|PF05347 }}
|-

| 33 || NDUFB10 / PDSW || [[NDUFB10|NDUBA_HUMAN]] || NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 10||   {{Pfam|PF10249}}
|-

| 34 || NDUFB8 / ASHI || [[NDUFB8|NDUB8_HUMAN]] || NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 8, mitochondrial|| {{Pfam|PF05821  }}
|-

| 35 || NDUFC2 / B14.5B || [[NDUFC2|NDUC2_HUMAN]] || NADH dehydrogenase [ubiquinone] 1 subunit C2           ||  {{Pfam|PF06374}}
|-

| 36 || NDUFB2 / AGGG || [[NDUFB2|NDUB2_HUMAN]] || NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 2, mitochondrial||  {{Pfam|PF14813 }}
|-

| 37 || NDUFA7 / B14.5A || [[NDUFA7|NDUA7_HUMAN]] || NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 7||  {{Pfam|PF07347 }}
|-

| 38 || NDUFA3 / B9 || [[NDUFA3|NDUA3_HUMAN]] || NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 3||  {{Pfam|PF14987}}
|-

| 39 || NDUFA4 / MLRQ<sup>c,d</sup> || [[NDUFA4|NDUA4_HUMAN]] || NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 4|| {{Pfam|PF06522 }}
|-

| 40 || NDUFB5 / SGDH || [[NDUFB5|NDUB5_HUMAN]] || NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 5, mitochondrial||  {{Pfam|PF09781}}
|-

| 41 || NDUFB1 / MNLL || [[NDUFB1|NDUB1_HUMAN]] || NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 1 || {{Pfam|PF08040 }}
|-

| 42 || NDUFC1 / KFYI || [[NDUFC1|NDUC1_HUMAN]] || NADH dehydrogenase [ubiquinone] 1 subunit C1, mitochondrial ||  {{Pfam|PF15088 }}
|-

| 43 || NDUFA10 / 42kD || [[NDUFA10|NDUAA_HUMAN]] || NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 10, mitochondrial || {{Pfam|PF01712 }}
|-

| 44 || NDUFA4L2 || [[NDUFA4L2|NUA4L_HUMAN]] || NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 4-like 2  || {{Pfam|PF15880 }}
|-

| 45 || NDUFV3   || [[NDUFV3|NDUV3_HUMAN]] || NADH dehydrogenase [ubiquinone] flavoprotein 3, 10kDa || -
|-
     
| 46 || NDUFB6   || [[NDUFB6|NDUB6_HUMAN]] || NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 6 ||  {{Pfam|PF09782 }}
|-

|-
!colspan=6 |Assembly factor proteins<ref name="pmid16200211">{{cite journal | vauthors = Ogilvie I, Kennaway NG, Shoubridge EA | title = A molecular chaperone for mitochondrial complex I assembly is mutated in a progressive encephalopathy | journal = The Journal of Clinical Investigation | volume = 115 | issue = 10 | pages = 2784–92 | date = October 2005 | pmid = 16200211 | pmc = 1236688 | doi = 10.1172/JCI26020 }}</ref>
|-<ref name="pmid17557076">{{cite journal | vauthors = Dunning CJ, McKenzie M, Sugiana C, Lazarou M, Silke J, Connelly A, Fletcher JM, Kirby DM, Thorburn DR, Ryan MT | title = Human CIA30 is involved in the early assembly of mitochondrial complex I and mutations in its gene cause disease | journal = The EMBO Journal | volume = 26 | issue = 13 | pages = 3227–37 | date = July 2007 | pmid = 17557076 | pmc = 1914096 | doi = 10.1038/sj.emboj.7601748 }}</ref><ref name="pmid19463981">{{cite journal | vauthors = 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 | title = Mutations in NDUFAF3 (C3ORF60), encoding an NDUFAF4 (C6ORF66)-interacting complex I assembly protein, cause fatal neonatal mitochondrial disease | journal = American Journal of Human Genetics | volume = 84 | issue = 6 | pages = 718–27 | date = June 2009 | pmid = 19463981 | pmc = 2694978 | doi = 10.1016/j.ajhg.2009.04.020 }}</ref>

| 47 || NDUFAF1<sup>c</sup> || CIA30_HUMAN ||  NADH dehydrogenase [ubiquinone] 1 alpha subcomplex, assembly factor 1 ||   {{Pfam|PF08547 }}
|-
 
| 48 || NDUFAF2 || MIMIT_HUMAN || NADH dehydrogenase [ubiquinone] 1 alpha subcomplex, assembly factor 2 ||   {{Pfam|PF05071 }}
|-

| 49 || NDUFAF3 || NDUF3_HUMAN ||   NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 3 ||   {{Pfam|PF05071 }}
|-

| 50 || NDUFAF4 ||  NDUF4_HUMAN ||  NADH dehydrogenase [ubiquinone] 1 alpha subcomplex, assembly factor 4 ||  {{Pfam|PF06784 }}
|-

|}

Notes:
*<sup>a</sup> Found in all species except fungi
*<sup>b</sup> May or may not be present in any species
*<sup>c</sup> Found in fungal species such as ''[[Schizosaccharomyces pombe]]''
*<sup>d</sup> Recent research has described [[NDUFA4]] to be a subunit of [[Cytochrome c oxidase|complex IV]], and not of complex I<ref name="pubmed.ncbi.nlm.nih.gov">{{Cite journal|last1=Balsa|first1=Eduardo|last2=Marco|first2=Ricardo|last3=Perales-Clemente|first3=Ester|last4=Szklarczyk|first4=Radek|last5=Calvo|first5=Enrique|last6=Landázuri|first6=Manuel O.|last7=Enríquez|first7=José Antonio|date=2012-09-05|title=NDUFA4 is a subunit of complex IV of the mammalian electron transport chain|journal=Cell Metabolism|volume=16|issue=3|pages=378–386|doi=10.1016/j.cmet.2012.07.015|issn=1932-7420|pmid=22902835|doi-access=free}}</ref>