Editing Respiratory complex I

{{Short description|Protein complex involved in cellular respiration}}
[[File:NADH Dehydrogenase Mechanism (Fixed).png|thumb|500px|NADH Dehydrogenase Mechanism: 
1. The seven primary iron sulfur centers serve to carry electrons from the site of NADH dehydration to ubiquinone. Note that N7 is not found in eukaryotes.

2. There is a reduction of ubiquinone (CoQ) to ubiquinol (CoQH<sub>2</sub>).

3. The energy from the redox reaction results in conformational change allowing hydrogen ions to pass through four transmembrane helix channels.
]]

'''Respiratory complex I''', {{EC number|7.1.1.2}} (also known as '''NADH:ubiquinone oxidoreductase''', '''Type I NADH dehydrogenase''' and '''mitochondrial complex I''') is the first large [[protein complex]] of the [[Electron transport chain|respiratory chain]]s of many organisms from bacteria to humans. It catalyzes the transfer of [[electron]]s from [[NADH]] to [[coenzyme Q10]] (CoQ10) and translocates protons across the inner [[mitochondria]]l membrane in eukaryotes or the plasma membrane of bacteria.

{{Infobox protein family
| Symbol = Respiratory complex I
| Name = Respiratory complex I
| image = 
| width =
| caption = 
| InterPro= 
| PROSITE = 
| SCOP = 
| TCDB =
| OPM family= 246
| OPM protein= 6g72
| Pfam= 
| PDB=
| Membranome superfamily= 255
}}

{{infobox enzyme
| Name      = NADH:ubiquinone reductase (H<sup>+</sup>-translocating).
| EC_number = 7.1.1.2
| GO_code   = 0008137
|name=|CAS_number=}}

This enzyme is essential for the normal functioning of cells, and mutations in its subunits lead to a wide range of inherited neuromuscular and metabolic disorders. Defects in this enzyme are responsible for the development of several pathological processes such as [[Reperfusion injury|ischemia/reperfusion]] damage ([[stroke]] and [[Myocardial infarction|cardiac infarction]]), Parkinson's disease and others.{{Citation needed|date=May 2023}}

== Function ==

[[Image:NAD+toNADH.png|thumb|274x274px|NAD<sup>+</sup> to NADH.]]
[[Image:FMN to FMNH2.svg|thumb|274x274px|FMN to FMNH<sub>2</sub>.]]
[[Image:QtoQH2.png|thumb|276x276px|CoQ to CoQH<sub>2</sub>.]]

Complex I is the first enzyme of the [[Electron transport chain#Mitochondrial electron transport chains|mitochondrial electron transport chain]]. There are three energy-transducing enzymes in the electron transport chain - NADH:ubiquinone oxidoreductase (complex I), [[Coenzyme Q – cytochrome c reductase]] (complex III), and [[cytochrome c oxidase]] (complex IV).<ref name="Berg">{{cite book | vauthors = Berg J, Tymoczko J, Stryer L | title = Biochemistry | edition = 6th | publisher = WH Freeman & Company | location = New York | year = 2006  | pages = 509–513 }}</ref> Complex I is the largest and most complicated enzyme of the electron transport chain.<ref name = "pmid16756485">{{cite journal | vauthors = Brandt U | title = Energy converting NADH:quinone oxidoreductase (complex I) | journal = Annual Review of Biochemistry | volume = 75 | pages = 69–92 | year = 2006 | pmid = 16756485 | doi = 10.1146/annurev.biochem.75.103004.142539 }}</ref>

The reaction catalyzed by complex I is:

:NADH + H<sup>+</sup> + CoQ + 4H<sup>+</sup><sub>in</sub>→ NAD<sup>+</sup> + CoQH<sub>2</sub> + 4H<sup>+</sup><sub>out</sub>

In this process, the complex translocates four [[proton pump|protons]] across the inner membrane per molecule of oxidized [[NADH]],<ref>{{cite journal | vauthors = Wikström M | title = Two protons are pumped from the mitochondrial matrix per electron transferred between NADH and ubiquinone | journal = FEBS Letters | volume = 169 | issue = 2 | pages = 300–4 | date = April 1984 | pmid = 6325245 | doi = 10.1016/0014-5793(84)80338-5 | doi-access = free }}</ref><ref name="pmid17094937">{{cite journal | vauthors = Galkin A, Dröse S, Brandt U | title = The proton pumping stoichiometry of purified mitochondrial complex I reconstituted into proteoliposomes | journal = Biochimica et Biophysica Acta (BBA) - Bioenergetics | volume = 1757 | issue = 12 | pages = 1575–81 | date = December 2006 | pmid = 17094937 | doi = 10.1016/j.bbabio.2006.10.001 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Galkin AS, Grivennikova VG, Vinogradov AD | title = -->H+/2e- stoichiometry in NADH-quinone reductase reactions catalyzed by bovine heart submitochondrial particles | journal = FEBS Letters | volume = 451 | issue = 2 | pages = 157–61 | date = May 1999 | pmid = 10371157 | doi = 10.1016/s0014-5793(99)00575-x | s2cid = 2337382 | doi-access = free }}</ref> helping to build the [[electrochemical potential]] difference used to produce [[Adenosine triphosphate|ATP]]. ''[[Escherichia coli]]'' complex I (NADH dehydrogenase) is capable of proton translocation in the same direction to the established [[Water potential|Δψ]], showing that in the tested conditions, the coupling ion is H<sup>+</sup>.<ref name="Batista 286–292">{{cite journal | vauthors = Batista AP, Pereira MM | title = Sodium influence on energy transduction by complexes I from Escherichia coli and Paracoccus denitrificans | journal = Biochimica et Biophysica Acta (BBA) - Bioenergetics | volume = 1807 | issue = 3 | pages = 286–92 | date = March 2011 | pmid = 21172303 | doi = 10.1016/j.bbabio.2010.12.008 | doi-access = free }}</ref> Na<sup>+</sup> transport in the opposite direction was observed, and although Na<sup>+</sup> was not necessary for the catalytic or proton transport activities, its presence increased the latter. H<sup>+</sup> was translocated by the ''[[Paracoccus denitrificans]]'' complex I, but in this case, H<sup>+</sup> transport was not influenced by Na<sup>+</sup>, and Na<sup>+</sup> transport was not observed. Possibly, the ''E. coli'' complex I has two energy coupling sites (one Na<sup>+</sup> independent and the other Na<sup>+</sup>dependent), as observed for the ''[[Rhodothermus marinus]]'' complex I, whereas the coupling mechanism of the ''P. denitrificans'' enzyme is completely Na<sup>+</sup> independent. It is also possible that another transporter catalyzes the uptake of Na<sup>+</sup>. Complex I energy transduction by proton pumping may not be exclusive to the ''R. marinus'' enzyme. The Na<sup>+</sup>/H<sup>+</sup> antiport activity seems not to be a general property of complex I.<ref name="Batista 286–292"/> However, the existence of Na<sup>+</sup>-translocating activity of the complex I is still in question.

The reaction can be reversed – referred to as aerobic succinate-supported NAD<sup>+</sup> reduction by ubiquinol – in the presence of a high membrane potential, but the exact catalytic mechanism remains unknown. Driving force of this reaction is a potential across the membrane which can be maintained either by ATP-hydrolysis or by complexes III and IV during succinate oxidation.<ref name="pmid17760425">{{cite journal | vauthors = Grivennikova VG, Kotlyar AB, Karliner JS, Cecchini G, Vinogradov AD | title = Redox-dependent change of nucleotide affinity to the active site of the mammalian complex I | journal = Biochemistry | volume = 46 | issue = 38 | pages = 10971–8 | date = September 2007 | pmid = 17760425 | pmc = 2258335 | doi = 10.1021/bi7009822 }}</ref>

Complex I may have a role in triggering [[apoptosis]].<ref name="pmid20371875">{{cite journal | vauthors = Chomova M, Racay P | title = Mitochondrial complex I in the network of known and unknown facts | journal = General Physiology and Biophysics | volume = 29 | issue = 1 | pages = 3–11 | date = March 2010 | pmid = 20371875 | doi = 10.4149/gpb_2010_01_3 | doi-access = free }}</ref> In fact, there has been shown to be a correlation between mitochondrial activities and [[programmed cell death]] (PCD) during somatic embryo development.<ref name="pmid 19834734">{{cite journal | vauthors = Petrussa E, Bertolini A, Casolo V, Krajnáková J, Macrì F, Vianello A | title = Mitochondrial bioenergetics linked to the manifestation of programmed cell death during somatic embryogenesis of Abies alba | journal = Planta | volume = 231 | issue = 1 | pages = 93–107 | date = December 2009 | pmid = 19834734 | doi = 10.1007/s00425-009-1028-x | s2cid = 25828432 }}</ref>

Complex I is not homologous to '''Na<sup>+</sup>-translocating NADH Dehydrogenase (NDH) Family''' ([http://tcdb.org/search/result.php?tc=3.D.1 TC# 3.D.1]), a member of the [[Mrp superfamily|Na<sup>+</sup> transporting Mrp superfamily]].

As a result of a two NADH molecule being oxidized to NAD+, three molecules of ATP can be produced by Complex V ([[ATP synthase]]) downstream in the respiratory chain.

==Mechanism==

=== Overall mechanism ===
All redox reactions take place in the hydrophilic domain of complex I. NADH initially binds to complex I, and transfers two electrons to the [[flavin mononucleotide]] (FMN) prosthetic group of the enzyme, creating FMNH<sub>2</sub>. The electron acceptor – the isoalloxazine ring – of FMN is identical to that of [[Flavin adenine dinucleotide|FAD]]. The electrons are then transferred through the FMN via a series of [[Iron–sulfur protein|iron-sulfur (Fe-S) clusters]],<ref name=":0" /> and finally to [[coenzyme Q10]] (ubiquinone). This electron flow changes the redox state of the protein, inducing conformational changes of the protein which alters the p''K'' values of ionizable side chain, and causes four hydrogen ions to be pumped out of the mitochondrial matrix.<ref name="BioChem">{{cite book | title = Principles of Biochemistry, 3rd Edition | chapter = Chapter 18, Mitochondrial ATP synthesis | vauthors = Voet DJ, Voet GJ, Pratt CW | publisher = Wiley | year = 2008 | isbn = 978-0-470-23396-2 | page = 608 }}</ref> [[Ubiquinone]] (CoQ) accepts two electrons to be reduced to [[ubiquinol]] (CoQH<sub>2</sub>).<ref name="Berg"/>

=== Electron transfer mechanism ===
The proposed pathway for electron transport prior to ubiquinone reduction is as follows: NADH – FMN – N3 – N1b – N4 – N5 – N6a – N6b – N2 – Q, where Nx is a labelling convention for iron sulfur clusters.<ref name=":0">{{cite journal | vauthors = Sazanov LA | title = A giant molecular proton pump: structure and mechanism of respiratory complex I | journal = Nature Reviews. Molecular Cell Biology | volume = 16 | issue = 6 | pages = 375–88 | date = June 2015 | pmid = 25991374 | doi = 10.1038/nrm3997 | s2cid = 31633494 }}</ref> The high reduction potential of the N2 cluster and the relative proximity of the other clusters in the chain enable efficient electron transfer over long distance in the protein (with transfer rates from NADH to N2 iron-sulfur cluster of about 100 μs).<ref>{{cite journal | vauthors = Ohnishi T | title = Iron-sulfur clusters/semiquinones in complex I | journal = Biochimica et Biophysica Acta (BBA) - Bioenergetics | volume = 1364 | issue = 2 | pages = 186–206 | date = May 1998 | pmid = 9593887 | doi = 10.1016/s0005-2728(98)00027-9 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Bridges HR, Bill E, Hirst J | title = Mössbauer spectroscopy on respiratory complex I: the iron-sulfur cluster ensemble in the NADH-reduced enzyme is partially oxidized | journal = Biochemistry | volume = 51 | issue = 1 | pages = 149–58 | date = January 2012 | pmid = 22122402 | pmc = 3254188 | doi = 10.1021/bi201644x }}</ref>

The equilibrium dynamics of Complex I are primarily driven by the quinone redox cycle. In conditions of high proton motive force (and accordingly, a ubiquinol-concentrated pool), the enzyme runs in the reverse direction. Ubiquinol is oxidized to ubiquinone, and the resulting released protons reduce the proton motive force.<ref name="Efremov 1785–1795">{{cite journal | vauthors = Efremov RG, [[Leonid Sazanov|Sazanov LA]] | title = The coupling mechanism of respiratory complex I - a structural and evolutionary perspective | journal = Biochimica et Biophysica Acta (BBA) - Bioenergetics | volume = 1817 | issue = 10 | pages = 1785–95 | date = October 2012 | pmid = 22386882 | doi = 10.1016/j.bbabio.2012.02.015 | doi-access = free }}</ref>

=== Proton translocation mechanism ===
The coupling of proton translocation and electron transport in Complex I is currently proposed as being indirect (long range conformational changes) as opposed to direct (redox intermediates in the hydrogen pumps as in [[heme]] groups of Complexes [[Coenzyme Q – cytochrome c reductase|III]] and [[Cytochrome c oxidase|IV]]).<ref name=":0" /> The architecture of the hydrophobic region of complex I shows multiple proton transporters that are mechanically interlinked. The three central components believed to contribute to this long-range conformational change event are the pH-coupled N2 iron-sulfur cluster, the quinone reduction, and the transmembrane helix subunits of the membrane arm. Transduction of conformational changes to drive the transmembrane transporters linked by a 'connecting rod' during the reduction of ubiquinone can account for two or three of the four protons pumped per NADH oxidized. The remaining proton must be pumped by direct coupling at the ubiquinone-binding site. It is proposed that direct and indirect coupling mechanisms account for the pumping of the four protons.<ref>{{cite journal | vauthors = Treberg JR, Quinlan CL, Brand MD | title = Evidence for two sites of superoxide production by mitochondrial NADH-ubiquinone oxidoreductase (complex I) | journal = The Journal of Biological Chemistry | volume = 286 | issue = 31 | pages = 27103–10 | date = August 2011 | pmid = 21659507 | pmc = 3149303 | doi = 10.1074/jbc.M111.252502 | doi-access = free }}</ref>

The N2 cluster's proximity to a nearby cysteine residue results in a conformational change upon reduction in the nearby helices, leading to small but important changes in the overall protein conformation.<ref>{{cite journal | vauthors = Berrisford JM, [[Leonid Sazanov|Sazanov LA]] | title = Structural basis for the mechanism of respiratory complex I | journal = The Journal of Biological Chemistry | volume = 284 | issue = 43 | pages = 29773–83 | date = October 2009 | pmid = 19635800 | pmc = 2785608 | doi = 10.1074/jbc.m109.032144 | doi-access = free }}</ref> Further [[electron paramagnetic resonance]] studies of the electron transfer have demonstrated that most of the energy that is released during the subsequent CoQ reduction is on the final [[ubiquinol]] formation step from [[semiquinone]], providing evidence for the "single stroke" H<sup>+</sup> translocation mechanism (i.e. all four protons move across the membrane at the same time).<ref name="Efremov 1785–1795" /><ref>{{cite journal | vauthors = Baranova EA, Morgan DJ, [[Leonid Sazanov|Sazanov LA]] | title = Single particle analysis confirms distal location of subunits NuoL and NuoM in Escherichia coli complex I | journal = Journal of Structural Biology | volume = 159 | issue = 2 | pages = 238–42 | date = August 2007 | pmid = 17360196 | doi = 10.1016/j.jsb.2007.01.009 }}</ref> Alternative theories suggest a "two stroke mechanism" where each reduction step ([[semiquinone]] and [[ubiquinol]]) results in a stroke of two protons entering the intermembrane space.<ref>{{cite journal | vauthors = Brandt U | title = A two-state stabilization-change mechanism for proton-pumping complex I | journal = Biochimica et Biophysica Acta (BBA) - Bioenergetics | volume = 1807 | issue = 10 | pages = 1364–9 | date = October 2011 | pmid = 21565159 | doi = 10.1016/j.bbabio.2011.04.006 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Zickermann V, Wirth C, Nasiri H, Siegmund K, Schwalbe H, Hunte C, Brandt U | title = Structural biology. Mechanistic insight from the crystal structure of mitochondrial complex I | journal = Science | volume = 347 | issue = 6217 | pages = 44–9 | date = January 2015 | pmid = 25554780 | doi = 10.1126/science.1259859 | s2cid = 23582849 | url = http://publikationen.ub.uni-frankfurt.de/files/44770/Zickermann_et_al_Zweitveroeffentlichung.pdf }}</ref>

The resulting [[ubiquinol]] localized to the membrane domain interacts with negatively charged residues in the membrane arm, stabilizing conformational changes.<ref name=":0" /> An [[antiporter]] mechanism (Na<sup>+</sup>/H<sup>+</sup> swap) has been proposed using evidence of conserved Asp residues in the membrane arm.<ref>{{cite journal | vauthors = Hunte C, Screpanti E, Venturi M, Rimon A, Padan E, Michel H | title = Structure of a Na+/H+ antiporter and insights into mechanism of action and regulation by pH | journal = Nature | volume = 435 | issue = 7046 | pages = 1197–202 | date = June 2005 | pmid = 15988517 | doi = 10.1038/nature03692 | bibcode = 2005Natur.435.1197H | s2cid = 4372674 }}</ref> The presence of Lys, Glu, and His residues enable for proton gating (a protonation followed by deprotonation event across the membrane) driven by the pK<sub>a</sub> of the residues.<ref name=":0" />

== 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>

==Inhibitors==
Inhibition of complex I is the mode of action of the METI acaricides and insecticides: fenazaquin, fenpyroximate, pyrimidifen, pyridaben, [[tebufenpyrad]], and tolfenpyrad.<ref name=":02">{{Cite book |last=Jeschke |first=Peter |url=https://onlinelibrary.wiley.com/doi/book/10.1002/9783527699261 |title=Modern Crop Protection Compounds |last2=Witschel |first2=Matthias |last3=Krämer |first3=Wolfgang |last4=Schirmer |first4=Ulrich |date=25 January 2019 |publisher=Wiley‐VCH |isbn=9783527699261 |edition=3rd |pages=1156-1201 |chapter=32.3 Inhibitors of Mitochondrial Electron Transport: Acaricides and Insecticides}}</ref><ref>{{Cite journal |last=Bajda |first=Sabina |last2=Dermauw |first2=Wannes |last3=Panteleri |first3=Rafaela |last4=Sugimoto |first4=Naoya |date=January 2017 |title=A mutation in the PSST homologue of complex I (NADH:ubiquinone oxidoreductase) from Tetranychus urticae is associated with resistance to METI acaricides |url=https://doi.org/10.1016/j.ibmb.2016.11.010 |journal=Insect Biochemistry and Molecular Biology |volume=80 |pages=79-90 |issn=0965-1748}}</ref><ref>{{Cite journal |last=De Rouck |first=Sander |last2=İnak |first2=Emre |last3=Dermauw |first3=Wannes |last4=Van Leeuwen |first4=Thomas |date=August 2023 |title=A review of the molecular mechanisms of acaricide resistance in mites and ticks |url=https://doi.org/10.1016/j.ibmb.2023.103981 |journal=Insect Biochemistry and Molecular Biology |volume=159 |pages=103981 |issn=0965-1748}}</ref> They are assigned to [[Insecticide Resistance Action Committee#Table of modes of action and classes of insecticide|IRAC]] group 21A. Perhaps the best-known inhibitor of complex I is [[rotenone]], which is used as a piscicide and previously commonly used as an organic pesticide, but now banned in many countries. It is in IRAC group 21B. Rotenone and [[rotenoid]]s are [[isoflavonoids]] occurring in several genera of tropical plants such as Antonia (''[[Loganiaceae]]''), [[Derris]] and [[Lonchocarpus]] (''[[Faboideae]]'', ''[[Fabaceae]]''). There have been reports of the indigenous people of French Guiana using rotenone-containing plants to fish - due to its ichthyotoxic effect - as early as the 17th century.<ref name="pmid7132401">{{cite journal | vauthors = Moretti C, Grenand P | title = [The "nivrées", or ichthyotoxic plants of French Guyana] | language = fr | journal = Journal of Ethnopharmacology | volume = 6 | issue = 2 | pages = 139–60 | date = September 1982 | pmid = 7132401 | doi = 10.1016/0378-8741(82)90002-2 }}</ref> Rotenone binds to the [[ubiquinone]] binding site of complex I as well as [[piericidin A]], another potent inhibitor with a close structural homologue to ubiquinone.

[[Acetogenin]]s from [[Annonaceae]] are even more potent inhibitors of complex I. They cross-link to the ND2 subunit, which suggests that ND2 is essential for quinone-binding.<ref name="pmid20074573">{{cite journal|vauthors=Nakamaru-Ogiso E, Han H, Matsuno-Yagi A, Keinan E, Sinha SC, Yagi T, Ohnishi T|date=March 2010|title=The ND2 subunit is labeled by a photoaffinity analogue of asimicin, a potent complex I inhibitor|journal=FEBS Letters|volume=584|issue=5|pages=883–8|doi=10.1016/j.febslet.2010.01.004|pmc=2836797|pmid=20074573}}</ref> Rolliniastatin-2, an acetogenin, is the first complex I inhibitor found that does not share the same binding site as rotenone.<ref name="pmid 8037664">{{cite journal | vauthors = Degli Esposti M, Ghelli A, Ratta M, Cortes D, Estornell E | title = Natural substances (acetogenins) from the family Annonaceae are powerful inhibitors of mitochondrial NADH dehydrogenase (Complex I) | journal = The Biochemical Journal | volume = 301 | pages = 161–7 | date = July 1994 | issue = Pt 1 | pmid = 8037664 | pmc = 1137156 | doi =  10.1042/bj3010161}}</ref> [[Bullatacin]] (an [[acetogenin]] found in ''[[Asimina triloba]]'' fruit) is the most potent known inhibitor of NADH dehydrogenase (ubiquinone) ({{IC50}}=1.2 nM, stronger than rotenone).<ref name="pmid9711297">{{cite journal |vauthors=Miyoshi H, Ohshima M, Shimada H, Akagi T, Iwamura H, McLaughlin JL |date=July 1998 |title=Essential structural factors of annonaceous acetogenins as potent inhibitors of mitochondrial complex I |journal=Biochimica et Biophysica Acta (BBA) - Bioenergetics |volume=1365 |issue=3 |pages=443–52 |doi=10.1016/s0005-2728(98)00097-8 |pmid=9711297 |doi-access=free}}</ref> 

Despite more than 50 years of study of complex I, no inhibitors blocking the electron flow inside the enzyme have been found. Hydrophobic inhibitors like rotenone or piericidin most likely disrupt the electron transfer between the terminal FeS cluster N2 and ubiquinone. It has been shown that long-term systemic inhibition of complex I by rotenone can induce selective degeneration of dopaminergic neurons.<ref name="pmid18599602 ">{{cite journal | vauthors = Watabe M, Nakaki T | title = Mitochondrial complex I inhibitor rotenone inhibits and redistributes vesicular monoamine transporter 2 via nitration in human dopaminergic SH-SY5Y cells | journal = Molecular Pharmacology | volume = 74 | issue = 4 | pages = 933–40 | date = October 2008 | pmid = 18599602 | doi = 10.1124/mol.108.048546 | s2cid = 1844073 }}</ref>

Complex I is also blocked by [[adenosine diphosphate ribose]] – a reversible [[competitive inhibitor]] of NADH oxidation – by binding to the enzyme at the nucleotide binding site.<ref name="pmid 9230920">{{cite journal | vauthors = Zharova TV, Vinogradov AD | title = A competitive inhibition of the mitochondrial NADH-ubiquinone oxidoreductase (complex I) by ADP-ribose | journal = Biochimica et Biophysica Acta (BBA) - Bioenergetics | volume = 1320 | issue = 3 | pages = 256–64 | date = July 1997 | pmid = 9230920 | doi = 10.1016/S0005-2728(97)00029-7 | doi-access = free }}</ref> Both hydrophilic NADH and hydrophobic ubiquinone analogs act at the beginning and the end of the internal electron-transport pathway, respectively.

The antidiabetic drug [[Metformin]] has been shown to induce a mild and transient inhibition of the mitochondrial respiratory chain complex I, and this inhibition appears to play a key role in its mechanism of action.<ref name="pmid 22117616">{{cite journal | vauthors = Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F | title = Cellular and molecular mechanisms of metformin: an overview | journal = Clinical Science | volume = 122 | issue = 6 | pages = 253–70 | date = March 2012 | pmid = 22117616 | pmc = 3398862 | doi = 10.1042/CS20110386 | url = http://www.hal.inserm.fr/inserm-00658070/document }}</ref>

Inhibition of complex I has been implicated in [[hepatotoxicity]] associated with a variety of drugs, for instance [[flutamide]] and [[nefazodone]].<ref name="NadanacivaWill2011">{{cite journal | vauthors = Nadanaciva S, Will Y | title = New insights in drug-induced mitochondrial toxicity | journal = Current Pharmaceutical Design | volume = 17 | issue = 20 | pages = 2100–12 | year = 2011 | pmid = 21718246 | doi = 10.2174/138161211796904795 }}</ref> Further, complex I inhibition was shown to trigger NAD<sup>+</sup>-independent [[glucose]] catabolism.<ref>{{Cite journal |last=Abrosimov |first=Roman |last2=Baeken |first2=Marius W. |last3=Hauf |first3=Samuel |last4=Wittig |first4=Ilka |last5=Hajieva |first5=Parvana |last6=Perrone |first6=Carmen E. |last7=Moosmann |first7=Bernd |date=2024-01-25 |title=Mitochondrial complex I inhibition triggers NAD+-independent glucose oxidation via successive NADPH formation, “futile” fatty acid cycling, and FADH2 oxidation |url=https://doi.org/10.1007/s11357-023-01059-y |journal=GeroScience |language=en |doi=10.1007/s11357-023-01059-y |issn=2509-2723|doi-access=free |pmc=11226580 }}</ref>

==Active/inactive transition==

The catalytic properties of eukaryotic complex I are not simple. Two catalytically and structurally distinct forms exist in any given preparation of the enzyme: one is the fully competent, so-called “active” A-form and the other is the catalytically silent, dormant, “inactive”, D-form. After exposure of idle enzyme to elevated, but physiological temperatures (>30&nbsp;°C) in the absence of substrate, the enzyme converts to the D-form. This form is catalytically incompetent but can be activated by the slow reaction (k~4 min<sup>−1</sup>) of NADH oxidation with subsequent ubiquinone reduction. After one or several turnovers the enzyme becomes active and can catalyse physiological NADH:ubiquinone reaction at a much higher rate (k~10<sup>4</sup> min<sup>−1</sup>). In the presence of divalent cations (Mg<sup>2+</sup>, Ca<sup>2+</sup>), or at alkaline pH the activation takes much longer.

The high [[activation energy]] (270 kJ/mol) of the deactivation process indicates the occurrence of major conformational changes in the organisation of the complex I. However, until now, the only conformational difference observed between these two forms is the number of [[cysteine]] residues exposed at the surface of the enzyme. Treatment of the D-form of complex I with the sulfhydryl reagents [[N-Ethylmaleimide]] or [[DTNB]] irreversibly blocks critical cysteine residues, abolishing the ability of the enzyme to respond to activation, thus inactivating it irreversibly. The A-form of complex I is insensitive to sulfhydryl reagents.<ref>{{cite journal | vauthors = Babot M, Birch A, Labarbuta P, Galkin A | title = Characterisation of the active/de-active transition of mitochondrial complex I | journal = Biochimica et Biophysica Acta (BBA) - Bioenergetics | volume = 1837 | issue = 7 | pages = 1083–92 | date = July 2014 | pmid = 24569053 | pmc = 4331042 | doi = 10.1016/j.bbabio.2014.02.018 }}</ref><ref>{{cite journal | vauthors = Dröse S, Stepanova A, Galkin A | title = Ischemic A/D transition of mitochondrial complex I and its role in ROS generation | journal = Biochimica et Biophysica Acta (BBA) - Bioenergetics | volume = 1857 | issue = 7 | pages = 946–57 | date = July 2016 | pmid = 26777588 | pmc = 4893024 | doi = 10.1016/j.bbabio.2015.12.013 }}</ref>

It was found that these conformational changes may have a very important physiological significance. The inactive, but not the active form of complex I was susceptible to inhibition by nitrosothiols and [[peroxynitrite]].<ref name="pmid17956863">{{cite journal | vauthors = Galkin A, Moncada S | title = S-nitrosation of mitochondrial complex I depends on its structural conformation | journal = The Journal of Biological Chemistry | volume = 282 | issue = 52 | pages = 37448–53 | date = December 2007 | pmid = 17956863 | doi = 10.1074/jbc.M707543200 | doi-access = free }}</ref> It is likely that transition from the active to the inactive form of complex I takes place during pathological conditions when the turnover of the enzyme is limited at physiological temperatures, such as during [[Hypoxia (medical)|hypoxia]], ischemia <ref>{{cite journal | vauthors = Kim M, Stepanova A, Niatsetskaya Z, Sosunov S, Arndt S, Murphy MP, Galkin A, Ten VS | display-authors = 6 | title = Attenuation of oxidative damage by targeting mitochondrial complex I in neonatal hypoxic-ischemic brain injury | journal = Free Radical Biology & Medicine | volume = 124 | pages = 517–524 | date = August 2018 | pmid = 30037775 | pmc = 6389362 | doi = 10.1016/j.freeradbiomed.2018.06.040 }}</ref><ref>{{cite journal | vauthors = Stepanova A, Konrad C, Guerrero-Castillo S, Manfredi G, Vannucci S, Arnold S, Galkin A | title = Deactivation of mitochondrial complex I after hypoxia-ischemia in the immature brain | journal = Journal of Cerebral Blood Flow and Metabolism | volume = 39 | issue = 9 | pages = 1790–1802 | date = September 2019 | pmid = 29629602 | pmc = 6727140 | doi = 10.1177/0271678X18770331 }}</ref> or when the tissue [[nitric oxide]]:oxygen ratio increases (i.e. metabolic hypoxia).<ref name="pmid11994742">{{cite journal | vauthors = Moncada S, Erusalimsky JD | title = Does nitric oxide modulate mitochondrial energy generation and apoptosis? | journal = Nature Reviews. Molecular Cell Biology | volume = 3 | issue = 3 | pages = 214–20 | date = March 2002 | pmid = 11994742 | doi = 10.1038/nrm762 | s2cid = 29513174 }}</ref>

==Production of superoxide==

Recent investigations suggest that complex I is a potent source of [[reactive oxygen species]].<ref name="pmid19061483">{{cite journal | vauthors = Murphy MP | title = How mitochondria produce reactive oxygen species | journal = The Biochemical Journal | volume = 417 | issue = 1 | pages = 1–13 | date = January 2009 | pmid = 19061483 | pmc = 2605959 | doi = 10.1042/BJ20081386 }}</ref> Complex I can produce [[superoxide]] (as well as [[hydrogen peroxide]]), through at least two different pathways. During forward electron transfer, only very small amounts of superoxide are produced (probably less than 0.1% of the overall electron flow).<ref name="pmid19061483"/><ref name="pmid9067806">{{cite journal | vauthors = Hansford RG, Hogue BA, Mildaziene V | title = Dependence of H2O2 formation by rat heart mitochondria on substrate availability and donor age | journal = Journal of Bioenergetics and Biomembranes | volume = 29 | issue = 1 | pages = 89–95 | date = February 1997 | pmid = 9067806 | doi = 10.1023/A:1022420007908 | s2cid = 7501110 }}</ref><ref>{{cite journal | vauthors = Stepanova A, Konrad C, Manfredi G, Springett R, Ten V, Galkin A | title = The dependence of brain mitochondria reactive oxygen species production on oxygen level is linear, except when inhibited by antimycin A | journal = Journal of Neurochemistry | volume = 148 | issue = 6 | pages = 731–745 | date = March 2019 | pmid = 30582748 | pmc = 7086484 | doi = 10.1111/jnc.14654 }}</ref>

During reverse electron transfer, complex I might be the most important site of superoxide production within mitochondria, with around 3-4% of electrons being diverted to superoxide formation.<ref name="Reverse electron transfer results i">{{cite journal | vauthors = Stepanova A, Kahl A, Konrad C, Ten V, Starkov AS, Galkin A | title = Reverse electron transfer results in a loss of flavin from mitochondrial complex I: Potential mechanism for brain ischemia reperfusion injury | journal = Journal of Cerebral Blood Flow and Metabolism | volume = 37 | issue = 12 | pages = 3649–3658 | date = December 2017 | pmid = 28914132 | pmc = 5718331 | doi = 10.1177/0271678X17730242 }}</ref> Reverse electron transfer, the process by which electrons from the reduced ubiquinol pool (supplied by [[succinate dehydrogenase]], [[glycerol-3-phosphate dehydrogenase]], [[electron-transferring flavoprotein]] or [[dihydroorotate dehydrogenase]] in mammalian mitochondria) pass through complex I to reduce NAD<sup>+</sup> to NADH, driven by the inner mitochondrial membrane potential electric potential. Although it is not precisely known under what pathological conditions reverse-electron transfer would occur in vivo, in vitro experiments indicate that this process can be a very potent source of superoxide when [[succinate]] concentrations are high and [[oxaloacetate]] or [[malate]] concentrations are low.<ref name="pmid17916065">{{cite journal | vauthors = Muller FL, Liu Y, Abdul-Ghani MA, Lustgarten MS, Bhattacharya A, Jang YC, Van Remmen H | title = High rates of superoxide production in skeletal-muscle mitochondria respiring on both complex I- and complex II-linked substrates | journal = The Biochemical Journal | volume = 409 | issue = 2 | pages = 491–9 | date = January 2008 | pmid = 17916065 | doi = 10.1042/BJ20071162 }}</ref> This can take place during tissue ischaemia, when oxygen delivery is blocked.<ref>{{cite journal | vauthors = Sahni PV, Zhang J, Sosunov S, Galkin A, Niatsetskaya Z, Starkov A, Brookes PS, Ten VS | display-authors = 6 | title = Krebs cycle metabolites and preferential succinate oxidation following neonatal hypoxic-ischemic brain injury in mice | journal = Pediatric Research | volume = 83 | issue = 2 | pages = 491–497 | date = February 2018 | pmid = 29211056 | pmc = 5866163 | doi = 10.1038/pr.2017.277 }}</ref>

Superoxide is a reactive oxygen species that contributes to cellular oxidative stress and is linked to neuromuscular diseases and aging.<ref name="pmid18307315">{{cite journal | vauthors = Esterházy D, King MS, Yakovlev G, Hirst J | title = Production of reactive oxygen species by complex I (NADH:ubiquinone oxidoreductase) from Escherichia coli and comparison to the enzyme from mitochondria | journal = Biochemistry | volume = 47 | issue = 12 | pages = 3964–71 | date = March 2008 | pmid = 18307315 | doi = 10.1021/bi702243b | doi-access = free }}</ref> NADH dehydrogenase produces superoxide by transferring one electron from FMNH<sub>2</sub> (or semireduced flavin) to oxygen (O<sub>2</sub>). The radical flavin leftover is unstable, and transfers the remaining electron to the iron-sulfur centers. It is the ratio of NADH to NAD<sup>+</sup> that determines the rate of superoxide formation.<ref name="pmid16682634">{{cite journal | vauthors = Kussmaul L, Hirst J | title = The mechanism of superoxide production by NADH:ubiquinone oxidoreductase (complex I) from bovine heart mitochondria | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 20 | pages = 7607–12 | date = May 2006 | pmid = 16682634 | pmc = 1472492 | doi = 10.1073/pnas.0510977103 | bibcode = 2006PNAS..103.7607K | doi-access = free }}</ref><ref>{{cite journal | vauthors = Galkin A, Brandt U | title = Superoxide radical formation by pure complex I (NADH:ubiquinone oxidoreductase) from Yarrowia lipolytica | journal = The Journal of Biological Chemistry | volume = 280 | issue = 34 | pages = 30129–35 | date = August 2005 | pmid = 15985426 | doi = 10.1074/jbc.M504709200 | doi-access = free }}</ref>

==Pathology==
Mutations in the subunits of complex I can cause [[mitochondrial diseases]], including [[Leigh syndrome]]. Point mutations in various complex I subunits derived from mitochondrial DNA ([[mtDNA]]) can also result in [[Leber's Hereditary Optic Neuropathy]].There is some evidence that complex I defects may play a role in the etiology of [[Parkinson's disease]], perhaps because of reactive oxygen species (complex I can, like [[complex III]], leak electrons to oxygen, forming highly toxic [[superoxide]]).

Although the exact etiology of Parkinson's disease is unclear, it is likely that mitochondrial dysfunction, along with proteasome inhibition and environmental toxins, may play a large role. In fact, the inhibition of complex I has been shown to cause the production of peroxides and a decrease in [[proteasome]] activity, which may lead to Parkinson's disease.<ref name="pmid20417232">{{cite journal | vauthors = Chou AP, Li S, Fitzmaurice AG, Bronstein JM | title = Mechanisms of rotenone-induced proteasome inhibition | journal = Neurotoxicology | volume = 31 | issue = 4 | pages = 367–72 | date = August 2010 | pmid = 20417232 | pmc = 2885979 | doi = 10.1016/j.neuro.2010.04.006 }}</ref> Additionally, Esteves et al. (2010) found that cell lines with Parkinson's disease show increased proton leakage in complex I, which causes decreased maximum respiratory capacity.<ref name="pmid20132468">{{cite journal | vauthors = Esteves AR, Lu J, Rodova M, Onyango I, Lezi E, Dubinsky R, Lyons KE, Pahwa R, Burns JM, Cardoso SM, Swerdlow RH | title = Mitochondrial respiration and respiration-associated proteins in cell lines created through Parkinson's subject mitochondrial transfer | journal = Journal of Neurochemistry | volume = 113 | issue = 3 | pages = 674–82 | date = May 2010 | pmid = 20132468 | doi = 10.1111/j.1471-4159.2010.06631.x | doi-access = free }}</ref>

Brain ischemia/reperfusion injury is mediated via complex I impairment.<ref>{{cite journal | vauthors = Galkin A | title = Brain Ischemia/Reperfusion Injury and Mitochondrial Complex I Damage | journal = Biochemistry. Biokhimiia | volume = 84 | issue = 11 | pages = 1411–1423 | date = November 2019 | pmid = 31760927 | doi = 10.1134/S0006297919110154 | s2cid = 207990089 }}</ref> Recently it was found that oxygen deprivation leads to conditions in which mitochondrial complex I lose its natural cofactor, flavin mononucleotide (FMN) and become inactive.<ref>{{cite journal | vauthors = Kahl A, Stepanova A, Konrad C, Anderson C, Manfredi G, Zhou P, Iadecola C, Galkin A | display-authors = 6 | title = Critical Role of Flavin and Glutathione in Complex I-Mediated Bioenergetic Failure in Brain Ischemia/Reperfusion Injury | journal = Stroke | volume = 49 | issue = 5 | pages = 1223–1231 | date = May 2018 | pmid = 29643256 | pmc = 5916474 | doi = 10.1161/STROKEAHA.117.019687 }}</ref><ref name=":1">{{cite journal | vauthors = Stepanova A, Sosunov S, Niatsetskaya Z, Konrad C, Starkov AA, Manfredi G, Wittig I, Ten V, Galkin A | display-authors = 6 | title = Redox-Dependent Loss of Flavin by Mitochondrial Complex I in Brain Ischemia/Reperfusion Injury | journal = Antioxidants & Redox Signaling | volume = 31 | issue = 9 | pages = 608–622 | date = September 2019 | pmid = 31037949 | pmc = 6657304 | doi = 10.1089/ars.2018.7693 }}</ref> When oxygen is present the enzyme catalyzes a physiological reaction of NADH oxidation by ubiquinone, supplying electrons downstream of the respiratory chain (complexes III and IV). Ischemia leads to dramatic increase of [[Succinic acid|succinate]] level. In the presence of succinate mitochondria catalyze reverse electron [[Reverse electron flow|transfer]] so that fraction of electrons from succinate is directed upstream to FMN of complex I. Reverse electron transfer results in a reduction of complex I FMN,<ref name="Reverse electron transfer results i"/> increased generation of ROS, followed by a loss of the reduced cofactor (FMNH<sub>2</sub>) and impairment of mitochondria energy production. The FMN loss by complex I and I/R injury can be alleviated by the administration of FMN precursor, riboflavin.<ref name=":1" />

Recent studies have examined other roles of complex I activity in the brain. Andreazza et al. (2010) found that the level of complex I activity was significantly decreased in patients with bipolar disorder, but not in patients with depression or schizophrenia. They found that patients with bipolar disorder showed increased protein oxidation and nitration in their prefrontal cortex. These results suggest that future studies should target complex I for potential therapeutic studies for bipolar disorder.<ref name="pmid20368511">{{cite journal | vauthors = Andreazza AC, Shao L, Wang JF, Young LT | title = Mitochondrial complex I activity and oxidative damage to mitochondrial proteins in the prefrontal cortex of patients with bipolar disorder | journal = Archives of General Psychiatry | volume = 67 | issue = 4 | pages = 360–8 | date = April 2010 | pmid = 20368511 | doi = 10.1001/archgenpsychiatry.2010.22 | doi-access = free }}</ref> Similarly, Moran et al. (2010) found that patients with severe complex I deficiency showed decreased oxygen consumption rates and slower growth rates. However, they found that mutations in different genes in complex I lead to different phenotypes, thereby explaining the variations of pathophysiological manifestations of complex I deficiency.<ref name="pmid20153825">{{cite journal | vauthors = Morán M, Rivera H, Sánchez-Aragó M, Blázquez A, Merinero B, Ugalde C, Arenas J, Cuezva JM, Martín MA | title = Mitochondrial bioenergetics and dynamics interplay in complex I-deficient fibroblasts | journal = Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | volume = 1802 | issue = 5 | pages = 443–53 | date = May 2010 | pmid = 20153825 | doi = 10.1016/j.bbadis.2010.02.001 | doi-access = free }}</ref>

Exposure to pesticides can also inhibit complex I and cause disease symptoms. For example, chronic exposure to low levels of dichlorvos, an organophosphate used as a pesticide, has been shown to cause liver dysfunction. This occurs because dichlorvos alters complex I and II activity levels, which leads to decreased mitochondrial electron transfer activities and decreased ATP synthesis.<ref name="pmid 20132858">{{cite journal | vauthors = Binukumar BK, Bal A, Kandimalla R, Sunkaria A, Gill KD | title = Mitochondrial energy metabolism impairment and liver dysfunction following chronic exposure to dichlorvos | journal = Toxicology | volume = 270 | issue = 2–3 | pages = 77–84 | date = April 2010 | pmid = 20132858 | doi = 10.1016/j.tox.2010.01.017 }}</ref>

== In chloroplasts ==
A proton-pumping, ubiquinone-using NADH dehydrogenase complex, homologous to complex I, is found in the chloroplast genomes of most [[land plant]]s under the name ''ndh''. This complex is inherited from the original symbiosis from cyanobacteria, but has been lost in most eukaryotic algae, some [[gymnosperm]]s (''Pinus'' and [[gnetophytes]]), and some very young lineages of [[angiosperm]]s. The purpose of this complex is originally cryptic as chloroplasts do not participate in respiration, but now it is known that ''ndh'' serves to maintain photosynthesis in stressful situations. This makes it at least partially dispensable in favorable conditions. It is evident that angiosperm lineages without ''ndh'' do not last long from their young ages, but how gymnosperms survive on land without ''ndh'' for so long is unknown.<ref>{{cite journal |last1=Sabater |first1=B |title=On the Edge of Dispensability, the Chloroplast ''ndh'' Genes. |journal=International Journal of Molecular Sciences |date=19 November 2021 |volume=22 |issue=22 |page=12505 |doi=10.3390/ijms222212505 |pmid=34830386 |pmc=8621559 |doi-access=free}}</ref>

==Genes==

The following is a list of humans genes that encode components of complex I:
* NADH dehydrogenase (ubiquinone) 1 alpha subcomplex
** [[NDUFA1]] – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 1, 7.5kDa
** [[NDUFA2]] – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 2, 8kDa
** NDUFA3 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 3, 9kDa
** [[NDUFA4]] – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 4, 9kDa - recently described to be part of complex IV<ref name="pubmed.ncbi.nlm.nih.gov"/>
** NDUFA4L – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 4-like
** NDUFA4L2 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 4-like 2
** [[NDUFA5]] – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 5, 13kDa
** [[NDUFA6]] – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 6, 14kDa
** NDUFA7 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 7, 14.5kDa
** [[NDUFA8]] – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 8, 19kDa
** [[NDUFA9]] – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 9, 39kDa
** [[NDUFA10]] – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 10, 42kDa
** NDUFA11 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 11, 14.7kDa
** [[NDUFA12]] – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 12
** [[NDUFA13]] – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 13
** NDUFAB1 – NADH dehydrogenase (ubiquinone) 1, alpha/beta subcomplex, 1, 8kDa
** [[NDUFAF1]] – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, assembly factor 1
** NDUFAF2 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, assembly factor 2
** NDUFAF3 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, assembly factor 3
** NDUFAF4 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, assembly factor 4
* NADH dehydrogenase (ubiquinone) 1 beta subcomplex
** [[NDUFB1]] – NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 1, 7kDa
** [[NDUFB2]] – NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 2, 8kDa
** NDUFB3 – NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 3, 12kDa
** NDUFB4 – NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 4, 15kDa
** NDUFB5 – NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 5, 16kDa
** [[NDUFB6]] – NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 6, 17kDa
** [[NDUFB7]] – NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 7, 18kDa
** [[NDUFB8]] – NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 8, 19kDa
** [[NDUFB9]] – NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 9, 22kDa
** [[NDUFB10]] – NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 10, 22kDa
** [[NDUFB11]] – NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 11, 17.3kDa
*  NADH dehydrogenase (ubiquinone) 1, subcomplex unknown
** [[NDUFC1]] – NADH dehydrogenase (ubiquinone) 1, subcomplex unknown, 1, 6kDa
** [[NDUFC2]] – NADH dehydrogenase (ubiquinone) 1, subcomplex unknown, 2, 14.5kDa
* NADH dehydrogenase (ubiquinone) Fe-S protein
** [[NDUFS1]] – NADH dehydrogenase (ubiquinone) Fe-S protein 1, 75kDa (NADH-coenzyme Q reductase)
** [[NDUFS2]] – NADH dehydrogenase (ubiquinone) Fe-S protein 2, 49kDa (NADH-coenzyme Q reductase)
** [[NDUFS3]] – NADH dehydrogenase (ubiquinone) Fe-S protein 3, 30kDa (NADH-coenzyme Q reductase)
** [[NDUFS4]] – NADH dehydrogenase (ubiquinone) Fe-S protein 4, 18kDa (NADH-coenzyme Q reductase)
** [[NDUFS5]] – NADH dehydrogenase (ubiquinone) Fe-S protein 5, 15kDa (NADH-coenzyme Q reductase)
** [[NDUFS6]] – NADH dehydrogenase (ubiquinone) Fe-S protein 6, 13kDa (NADH-coenzyme Q reductase)
** [[NDUFS7]] – NADH dehydrogenase (ubiquinone) Fe-S protein 7, 20kDa (NADH-coenzyme Q reductase)
** [[NDUFS8]] – NADH dehydrogenase (ubiquinone) Fe-S protein 8, 23kDa (NADH-coenzyme Q reductase)
* NADH dehydrogenase (ubiquinone) flavoprotein 1
** [[NDUFV1]] – NADH dehydrogenase (ubiquinone) flavoprotein 1, 51kDa
** [[NDUFV2]] – NADH dehydrogenase (ubiquinone) flavoprotein 2, 24kDa
** [[NDUFV3]] – NADH dehydrogenase (ubiquinone) flavoprotein 3, 10kDa
* mitochondrially encoded NADH dehydrogenase subunit
** [[MT-ND1]] - mitochondrially encoded NADH dehydrogenase subunit 1
** [[MT-ND2]] - mitochondrially encoded NADH dehydrogenase subunit 2
** [[MT-ND3]] - mitochondrially encoded NADH dehydrogenase subunit 3
** [[MT-ND4]] - mitochondrially encoded NADH dehydrogenase subunit 4
** [[MT-ND4L]] - mitochondrially encoded NADH dehydrogenase subunit 4L
** [[MT-ND5]] - mitochondrially encoded NADH dehydrogenase subunit 5
** [[MT-ND6]] - mitochondrially encoded NADH dehydrogenase subunit 6

== References ==
{{Reflist|2}}

== External links ==
*[https://ist.ac.at/research/research-groups/sazanov-group/ Institute of Science and Technology Austria (ISTA): Sazanov Group MRC MBU Sazanov group]
* [https://web.archive.org/web/20090112031333/http://www2.ufp.pt/~pedros/anim/2frame-ien.htm Interactive Molecular model of NADH dehydrogenase] (Requires [https://web.archive.org/web/20060320002451/http://www.mdl.com/products/framework/chime/ MDL Chime])
*[http://www.complexi.org Complex I homepage]
*[https://www.facebook.com/mitochondrialcomplexi Complex I news facebook page]
* {{MeshName|Electron+Transport+Complex+I}}

{{Flavoproteins}}
{{Electron transport chain}}
{{Proton pumps}}
{{Mitochondrial DNA}}
{{Enzymes}}
{{Portal bar|Biology|border=no}}

{{CCBYSASource|sourcepath=http://www.tcdb.org/search/result.php?tc=3.D.1|sourcearticle=3.D.1 The H+ or Na+-translocating NADH Dehydrogenase (NDH) Family|revision=699838558}}

{{DEFAULTSORT:Nadh Dehydrogenase}}
[[Category:Cellular respiration]]
[[Category:Glycolysis]]
[[Category:EC 7.1.1]]
[[Category:Integral membrane proteins]]