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13  structures 669  species 2  interactions 1788  sequences 21  architectures

Family: CHCH (PF06747)

Summary: CHCH domain

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This is the Wikipedia entry entitled "Cytochrome c oxidase". More...

Cytochrome c oxidase Edit Wikipedia article

Cytochrome C Oxidase
Cytochrome C Oxidase 1OCC in Membrane 2.png
The crystal structure of bovine cytochrome c oxidase in a phospholipid bilayer. The intermembrane space lies to top of the image. Adapted from PDB: 1OCC​ (It is a homo dimer in this structure)
EC number
CAS number 9001-16-5
IntEnz IntEnz view
ExPASy NiceZyme view
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / QuickGO

The enzyme cytochrome c oxidase or Complex IV, EC is a large transmembrane protein complex found in bacteria and the mitochondrion of eukaryotes.

It is the last enzyme in the respiratory electron transport chain of mitochondria (or bacteria) located in the mitochondrial (or bacterial) membrane. It receives an electron from each of four cytochrome c molecules, and transfers them to one oxygen molecule, converting molecular oxygen to two molecules of water. In the process, it binds four protons from the inner aqueous phase to make water and in addition translocates four protons across the membrane, in the process, helping to establish a transmembrane difference of proton electrochemical potential that the ATP synthase then uses to synthesize ATP.


Subunit I and II of Complex IV excluding all other subunits, PDB: 2EIK

The complex is a large integral membrane protein composed of several metal prosthetic sites and 14 [1] protein subunits in mammals. In mammals, eleven subunits are nuclear in origin, and three are synthesized in the mitochondria. The complex contains two hemes, a cytochrome a and cytochrome a3, and two copper centers, the CuA and CuB centers.[2] In fact, the cytochrome a3 and CuB form a binuclear center that is the site of oxygen reduction. Cytochrome c, which is reduced by the preceding component of the respiratory chain (cytochrome bc1 complex, complex III), docks near the CuA binuclear center and passes an electron to it, being oxidized back to cytochrome c containing Fe3+. The reduced CuA binuclear center now passes an electron on to cytochrome a, which in turn passes an electron on to the cytochrome a3-CuB binuclear center. The two metal ions in this binuclear center are 4.5 Å apart and coordinate a hydroxide ion in the fully oxidized state.

Crystallographic studies of cytochrome c oxidase show an unusual post-translational modification, linking C6 of Tyr(244) and the ε-N of His(240) (bovine enzyme numbering). It plays a vital role in enabling the cytochrome a3- CuB binuclear center to accept four electrons in reducing molecular oxygen to water. The mechanism of reduction was formerly thought to involve a peroxide intermediate, which was believed to lead to superoxide production. However, the currently accepted mechanism involves a rapid four-electron reduction involving immediate oxygen-oxygen bond cleavage, avoiding any intermediate likely to form superoxide.[3]


COX assembly in yeast is a complex process that is not entirely understood due to the rapid and irreversible aggregation of hydrophobic subunits that form the holoenzyme complex, as well as aggregation of mutant subunits with exposed hydrophobic patches.[4] COX subunits are encoded in both the nuclear and mitochondrial genomes. The three subunits that form the COX catalytic core are encoded in the mitochondrial genome.

Hemes and cofactors are inserted into subunits I & II. Subunits I and IV initiate assembly. Different subunits may associate to form sub-complex intermediates that later bind to other subunits to form the COX complex.[4] In post-assembly modifications, COX will form a homodimer. This is required for activity. Both dimers are connected by a cardiolipin molecule,[4][5][6] which has been found to play a key role in stabilization of the holoenzyme complex. The dissociation of subunits VIIa and III in conjunction with the removal of cardiolipin results in total loss of enzyme activity.[6] Subunits encoded in the nuclear genome are known to play a role in enzyme dimerization and stability. Mutations to these subunits eliminate COX function.[4]

Assembly is known to occur in at least three distinct rate-determining steps. The products of these steps have been found, though specific subunit compositions have not been determined.[4]

Synthesis and assembly of COX subunits I, II, and III are facilitated by translational activators, which interact with the 5’ untranslated regions of mitochondrial mRNA transcripts. Translational activators are encoded in the nucleus. They can operate through either direct or indirect interaction with other components of translation machinery, but exact molecular mechanisms are unclear due to difficulties associated with synthesizing translation machinery in-vitro.[7][8] Though the interactions between subunits I, II, and III encoded within the mitochondrial genome make a lesser contribution to enzyme stability than interactions between bigenomic subunits, these subunits are more conserved, indicating potential unexplored roles for enzyme activity.[9]

Table of conserved subunits of cytochrome c oxidase complex[10][11]

No. Subunit name Human protein Protein description from UniProt Pfam family with Human protein
1 Cox1 COX1_HUMAN Cytochrome c oxidase subunit 1 Pfam PF00115
2 Cox2 COX2_HUMAN Cytochrome c oxidase subunit 2 Pfam PF02790, Pfam PF00116
3 Cox3 COX3_HUMAN Cytochrome c oxidase subunit 3 Pfam PF00510
4 Cox4i1 COX41_HUMAN Cytochrome c oxidase subunit 4 isoform 1, mitochondrial Pfam PF02936
5 Cox4a2 COX42_HUMAN Cytochrome c oxidase subunit 4 isoform 2, mitochondrial Pfam PF02936
6 Cox5a COX5A_HUMAN Cytochrome c oxidase subunit 5A, mitochondrial Pfam PF02284
7 Cox5b COX5B_HUMAN Cytochrome c oxidase subunit 5B, mitochondrial Pfam PF01215
8 Cox6a1 CX6A1_HUMAN Cytochrome c oxidase subunit 6A1, mitochondrial Pfam PF02046
9 Cox6a2 CX6A2_HUMAN Cytochrome c oxidase subunit 6A2, mitochondrial Pfam PF02046
10 Cox6b1 CX6B1_HUMAN Cytochrome c oxidase subunit 6B1 Pfam PF02297
11 Cox6b2 CX6B2_HUMAN Cytochrome c oxidase subunit 6B2 Pfam PF02297
12 Cox6c COX6C_HUMAN Cytochrome c oxidase subunit 6C Pfam PF02937
13 Cox7a1 CX7A1_HUMAN Cytochrome c oxidase subunit 7A1, mitochondrial Pfam PF02238
14 Cox7a2 CX7A2_HUMAN Cytochrome c oxidase subunit 7A2, mitochondrial Pfam PF02238
15 Cox7a3 COX7S_HUMAN Putative cytochrome c oxidase subunit 7A3, mitochondrial Pfam PF02238
16 Cox7b COX7B_HUMAN Cytochrome c oxidase subunit 7B, mitochondrial Pfam PF05392
17 Cox7c COX7C_HUMAN Cytochrome c oxidase subunit 7C, mitochondrial Pfam PF02935
18 Cox7r COX7R_HUMAN Cytochrome c oxidase subunit 7A-related protein, mitochondrial Pfam PF02238
19 Cox8a COX8A_HUMAN Cytochrome c oxidase subunit 8A, mitochondrial P Pfam PF02285
20 Cox8c COX8C_HUMAN Cytochrome c oxidase subunit 8C, mitochondrial Pfam PF02285
Assembly subunits[12][13][14]
1 Coa1 COA1_HUMAN Cytochrome c oxidase assembly factor 1 homolog Pfam PF08695
2 Coa3 COA3_HUMAN Cytochrome c oxidase assembly factor 3 homolog, mitochondrial Pfam PF09813
3 Coa4 COA4_HUMAN Cytochrome c oxidase assembly factor 4 homolog, mitochondrial Pfam PF06747
4 Coa5 COA5_HUMAN Cytochrome c oxidase assembly factor 5 Pfam PF10203
5 Coa6 COA6_HUMAN Cytochrome c oxidase assembly factor 6 homolog Pfam PF02297
6 Coa7 COA7_HUMAN Cytochrome c oxidase assembly factor 7, Pfam PF08238
7 Cox11 COX11_HUMAN Cytochrome c oxidase assembly protein COX11 mitochondrial Pfam PF04442
8 Cox14 COX14_HUMAN Cytochrome c oxidase assembly protein Pfam PF14880
9 Cox15 COX15_HUMAN Cytochrome c oxidase assembly protein COX15 homolog Pfam PF02628
10 Cox16 COX16_HUMAN Cytochrome c oxidase assembly protein COX16 homolog mitochondrial Pfam PF14138
11 Cox17 COX17_HUMAN Cytochrome c oxidase copper chaperone Pfam PF05051
12 Cox18[15] COX18_HUMAN Mitochondrial inner membrane protein (Cytochrome c oxidase assembly protein 18) Pfam PF02096
13 Cox19 COX19_HUMAN Cytochrome c oxidase assembly protein Pfam PF06747
14 Cox20 COX20_HUMAN Cytochrome c oxidase protein 20 homolog Pfam PF12597


Summary reaction:

4 Fe2+-cytochrome c + 8 H+in + O2 → 4 Fe3+-cytochrome c + 2 H2O + 4 H+out

Two electrons are passed from two cytochrome c's, through the CuA and cytochrome a sites to the cytochrome a3- CuB binuclear center, reducing the metals to the Fe2+ form and Cu+. The hydroxide ligand is protonated and lost as water, creating a void between the metals that is filled by O2. The oxygen is rapidly reduced, with two electrons coming from the Fe2+cytochrome a3, which is converted to the ferryl oxo form (Fe4+=O). The oxygen atom close to CuB picks up one electron from Cu+, and a second electron and a proton from the hydroxyl of Tyr(244), which becomes a tyrosyl radical: The second oxygen is converted to a hydroxide ion by picking up two electrons and a proton. A third electron arising from another cytochrome c is passed through the first two electron carriers to the cytochrome a3- CuB binuclear center, and this electron and two protons convert the tyrosyl radical back to Tyr, and the hydroxide bound to CuB2+ to a water molecule. The fourth electron from another cytochrome c flows through CuA and cytochrome a to the cytochrome a3- CuB binuclear center, reducing the Fe4+=O to Fe3+, with the oxygen atom picking up a proton simultaneously, regenerating this oxygen as a hydroxide ion coordinated in the middle of the cytochrome a3- CuB center as it was at the start of this cycle. The net process is that four reduced cytochrome c's are used, along with 4 protons, to reduce O2 to two water molecules.[16]


COX exists in three conformational states: fully oxidized (pulsed), partially reduced, and fully reduced. Each inhibitor has a high affinity to a different state. In the pulsed state, both the heme a3 and the CuB nuclear centers are oxidized; this is the conformation of the enzyme that has the highest activity. A two-electron reduction initiates a conformational change that allows oxygen to bind at the active site to the partially-reduced enzyme. Four electrons bind to COX to fully reduce the enzyme. Its fully reduced state, which consists of a reduced Fe2+ at the cytochrome a3 heme group and a reduced CuB+ binuclear center, is considered the inactive or resting state of the enzyme.[17]

Cyanide, azide, and carbon monoxide[18] all bind to cytochrome c oxidase, thus competitively inhibiting the protein from functioning by preventing the binding of oxygen at the active site, which results in the chemical asphyxiation of cells. Higher concentrations of molecular oxygen are needed to compensate for increasing inhibitor concentrations, leading to an overall reduction in metabolic activity in the cell in the presence of an inhibitor. Other ligands, such as nitric oxide and hydrogen sulfide, can also inhibit COX by binding to regulatory sites on the enzyme, reducing the rate of cellular respiration.[19]

Cyanide is a competitive inhibitor for COX, binding with high affinity to the partially-reduced state of the enzyme and hindering further reduction of the enzyme. In the pulsed state, cyanide binds slowly, but with high affinity. The ligand is posited to electrostatically stabilize both metals at once by positioning itself between them. A high nitric oxide concentration, such as one added exogenously to the enzyme, reverses cyanide inhibition of COX.[20]

Nitric oxide can reversibly[21] bind to either metal ion in the binuclear center to be oxidized to nitrite. NO and CN will compete with oxygen to bind at the site, reducing the rate of cellular respiration. Endogenous NO, however, which is produced at lower levels, augments CN inhibition. Higher levels of NO, which correlate with the existence of more enzyme in the reduced state, lead to a greater inhibition of cyanide.[17] At these basal concentrations, NO inhibition of Complex IV is known to have beneficial effects, such as increasing oxygen levels in blood vessel tissues. The inability of the enzyme to reduce oxygen to water results in a buildup of oxygen, which can diffuse deeper into surrounding tissues.[21] NO inhibition of Complex IV has a larger effect at lower oxygen concentrations, increasing its utility as a vasodilator in tissues of need.[21]

Hydrogen sulfide will bind COX in a noncompetitive fashion at a regulatory site on the enzyme, similar to carbon monoxide. Sulfide has the highest affinity to either the pulsed or partially reduced states of the enzyme, and is capable of partially reducing the enzyme at the heme a3 center. It is unclear whether endogenous H2S levels are sufficient to inhibit the enzyme. There is no interaction between hydrogen sulfide and the fully reduced conformation of COX.[19]

Methanol in methylated spirits is converted into formic acid, which also inhibits the same oxidase system. High levels of ATP can allosterically inhibit cytochrome c oxidase, binding from within the mitochondrial matrix.[22]

Subcellular localization and presence at extramitochondrial sites

Cytochrome c oxidase has 3 subunits which are encoded by mitochondrial DNA. Of these 3 subunits encoded by mitochondrial DNA, two have been identified in extramitochondrial locations. In pancreatic acinar tissue, these subunits were found in zymogen granules. Additionally, in the anterior pituitary, relatively high amounts of these subunits were found in growth hormone secretory granules.[23] The extramitochondrial function of these cytochrome c oxidase subunits has not yet been characterized. Besides cytochrome c oxidase subunits, extramitochondrial localization has also been observed for large numbers of other mitochondrial proteins.[24][25] This raises the possibility about existence of yet unidentified specific mechanisms for protein translocation from mitochondria to other cellular destinations.[23][25][26]

Genetic defects and disorders

Defects involving genetic mutations altering cytochrome c oxidase (COX) functionality or structure can result in severe, often fatal metabolic disorders. Such disorders usually manifest in early childhood and affect predominantly tissues with high energy demands (brain, heart, muscle). Among the many classified mitochondrial diseases, those involving dysfunctional COX assembly are thought to be the most severe.[27]

The vast majority of COX disorders are linked to mutations in nuclear-encoded proteins referred to as assembly factors, or assembly proteins. These assembly factors contribute to COX structure and functionality, and are involved in several essential processes, including transcription and translation of mitochondrion-encoded subunits, processing of preproteins and membrane insertion, and cofactor biosynthesis and incorporation.[28]

Currently, mutations have been identified in seven COX assembly factors: SURF1, SCO1, SCO2, COX10, COX15, COX20, COA5 and LRPPRC. Mutations in these proteins can result in altered functionality of sub-complex assembly, copper transport, or translational regulation. Each gene mutation is associated with the etiology of a specific disease, with some having implications in multiple disorders. Disorders involving dysfunctional COX assembly via gene mutations include Leigh syndrome, cardiomyopathy, leukodystrophy, anemia, and sensorineural deafness.


The increased reliance of neurons on oxidative phosphorylation for energy[29] facilitates the use of COX histochemistry in mapping regional brain metabolism in animals, since it establishes a direct and positive correlation between enzyme activity and neuronal activity.[30] This can be seen in the correlation between COX enzyme amount and activity, which indicates the regulation of COX at the level of gene expression. COX distribution is inconsistent across different regions of the animal brain, but its pattern of its distribution is consistent across animals. This pattern has been observed in the monkey, mouse, and calf brain. One isozyme of COX has been consistently detected in histochemical analysis of the brain.[31]

Such brain mapping has been accomplished in spontaneous mutant mice with cerebellar disease such as reeler[32] and a transgenic model of Alzheimer's disease.[33] This technique has also been used to map learning activity in animal brain.[34]

Additional images

See also


  1. ^ Balsa E, Marco R, Perales-Clemente E, Szklarczyk R, Calvo E, Landázuri MO, Enríquez JA (September 2012). "NDUFA4 is a subunit of complex IV of the mammalian electron transport chain". Cell Metab. 16 (3): 378–86. doi:10.1016/j.cmet.2012.07.015. PMID 22902835. 
  2. ^ Tsukihara T, Aoyama H, Yamashita E, Tomizaki T, Yamaguchi H, Shinzawa-Itoh K, Nakashima R, Yaono R, Yoshikawa S (August 1995). "Structures of metal sites of oxidized bovine heart cytochrome c oxidase at 2.8 A". Science. 269 (5227): 1069–74. Bibcode:1995Sci...269.1069T. doi:10.1126/science.7652554. PMID 7652554. 
  3. ^ Voet, Donald (2010). Biochemistry. New York: J. Wiley & Sons. pp. 865–866. ISBN 0-470-57095-4. 
  4. ^ a b c d e Fontanesi F, Soto IC, Horn D, Barrientos A (December 2006). "Assembly of mitochondrial cytochrome c-oxidase, a complicated and highly regulated cellular process". Am. J. Physiol., Cell Physiol. 291 (6): C1129–47. doi:10.1152/ajpcell.00233.2006. PMID 16760263. 
  5. ^ Khalimonchuk O, Rödel G (December 2005). "Biogenesis of cytochrome c oxidase". Mitochondrion. 5 (6): 363–88. doi:10.1016/j.mito.2005.08.002. PMID 16199211. 
  6. ^ a b Sedlák E, Robinson NC (September 15, 2015). "Destabilization of the Quaternary structure of Bovine Heart Cytochrome c Oxidase upon Removal of Tightly Bound Cardiolipin". Biochemistry. 54 (36): 5569–77. doi:10.1021/acs.biochem.5b00540. PMID 26284624. 
  7. ^ Herrmann JM, Woellhaf MW, Bonnefoy N (February 2013). "Control of protein synthesis in yeast mitochondria: the concept of translational activators". Biochimica et Biophysica Acta. 1833 (2): 286–294. doi:10.1016/j.bbamcr.2012.03.007. PMID 22450032. 
  8. ^ Soto IC, Fontanesi F, Liu J, Barrientos A (June 2012). "Biogenesis and assembly of eukaryotic cytochrome c oxidase catalytic core". Biochimica et Biophysica Acta. 1817 (6): 883–97. doi:10.1016/j.bbabio.2011.09.005. PMC 3262112Freely accessible. PMID 21958598. 
  9. ^ Aledo JC, Valverde H, Ruiz-Camacho M, Morilla L, López FD (2014). "Protein-Protein Interfaces from Cytochrome c Oxidase I Evolve Faster than Nonbonding Surfaces, yet Negative Selection Is the Driving Force". Genome Biology and Evolution. 6 (11): 3064–76. doi:10.1093/gbe/evu240. PMC 4255772Freely accessible. PMID 25359921. 
  10. ^ Zhang Z; Huang L; Shulmeister VM; Chi YI; Kim KK; Hung LW; et al. (1998). "Electron transfer by domain movement in cytochrome bc1". Nature. 392 (6677): 677–84. Bibcode:1998Natur.392..677Z. doi:10.1038/33612. PMID 9565029. 
  11. ^ Kaila VR; Oksanen E; Goldman A; Bloch DA; Verkhovsky MI; Sundholm D; et al. (2011). "A combined quantum chemical and crystallographic study on the oxidized binuclear center of cytochrome c oxidase". Biochim Biophys Acta. 1807 (7): 769–78. doi:10.1016/j.bbabio.2010.12.016. PMID 21211513. 
  12. ^ Szklarczyk R, Wanschers BF, Cuypers TD, Esseling JJ, Riemersma M, van den Brand MA, et al. (2012). "Iterative orthology prediction uncovers new mitochondrial proteins and identifies C12orf62 as the human ortholog of COX14, a protein involved in the assembly of cytochrome c oxidase". Genome Biol. 13 (2): R12. doi:10.1186/gb-2012-13-2-r12. PMC 3334569Freely accessible. PMID 22356826. 
  13. ^ Mick DU; Dennerlein S; Wiese H; Reinhold R; Pacheu-Grau D; Lorenzi I; et al. (2012). "MITRAC links mitochondrial protein translocation to respiratory-chain assembly and translational regulation". Cell. 151 (7): 1528–41. doi:10.1016/j.cell.2012.11.053. PMID 23260140. 
  14. ^ Kozjak-Pavlovic V; Prell F; Thiede B; Götz M; Wosiek D; Ott C; et al. (2014). "C1orf163/RESA1 is a novel mitochondrial intermembrane space protein connected to respiratory chain assembly". J Mol Biol. 426 (4): 908–20. doi:10.1016/j.jmb.2013.12.001. PMID 24333015. 
  15. ^ Gaisne M, Bonnefoy N (2006). "The COX18 gene, involved in mitochondrial biogenesis, is functionally conserved and tightly regulated in humans and fission yeast". FEMS Yeast Res. 6 (6): 869–82. doi:10.1111/j.1567-1364.2006.00083.x. PMID 16911509. 
  16. ^ Voet and Voet, Biochemistry (2011) pp.841–45
  17. ^ a b Leavesley H, Li L, Prabhakaran K, Malmström BG (January 2008). "Interaction of cyanide and nitric oxide with cytochrome c oxidase: Implications for acute cyanide toxicity". Toxicological Sciences. 101 (1): 101–11. doi:10.1093/toxsci/kfm254. PMID 17906319. 
  18. ^ Alonso JR, Cardellach F, López S, Casademont J, Miró O (September 2003). "Carbon monoxide specifically inhibits cytochrome c oxidase of human mitochondrial respiratory chain". Pharmacol. Toxicol. 93 (3): 142–6. doi:10.1034/j.1600-0773.2003.930306.x. PMID 12969439. 
  19. ^ a b Nicholls P, Marshall D, Cooper C, Wilson M (October 2013). "Sulfide inhibition of and metabolism by cytochrome c oxidase". Biochm. Soc. Trans. 41 (5): 1312–16. doi:10.1042/BST20130070. PMID 24059525. 
  20. ^ Jensen P, Wilson MT, Aasa R, Malmström BG (December 1984). "Cyanide inhibition of cytochrome c oxidase. A rapid-freeze e.p.r. investigation". Biochem. J. 224 (3): 829–837. doi:10.1042/bj2240829. PMC 1144519Freely accessible. PMID 6098268. 
  21. ^ a b c Gladwin MT, Shiva S (May 22, 2009). "The ligand binding battle at cytochrome c oxidase: how NO regulates oxygen gradients in tissue". Circ. Res. 104 (10): 1136–8. doi:10.1161/CIRCRESAHA.109.198911. PMID 19461104. 
  22. ^ Arnold S, Kadenbach B (October 1997). "Cell respiration s controlled by ATP, an allosteric inhibitor of cytochrome-c oxidase". Eur J Biochem. 249: 350–354. doi:10.1111/j.1432-1033.1997.t01-1-00350.x. 
  23. ^ a b Sadacharan SK, Singh B, Bowes T, Gupta RS (2005). "Localization of mitochondrial DNA encoded cytochrome c oxidase subunits I and II in rat pancreatic zymogen granules and pituitary growth hormone granules". Histochem Cell Biol. 124: 409–421. doi:10.1007/s00418-005-0056-2. PMID 16133117. 
  24. ^ Gupta, R. S., Ramachandra, N. B., Bowes, T. and Singh, B. (2008) Unusual cellular disposition of the mitochondrial molecular chaperones Hsp60, Hsp70 and Hsp10. Novartis Found Symp. 291: 59-68.
  25. ^ a b Soltys BJ, Gupta RS (1999). "Mitochondrial proteins at unexpected cellular locations: export of proteins from mitochondria from an evolutionary perspective". International Review of Cytology. 94: 133–196. 
  26. ^ Soltys BJ, Gupta RS (1999). "Mitochondrial proteins at unexpected locations: Are they exported?". Trends Biochem. Sci. 24: 174–177. doi:10.1016/s0968-0004(99)01390-0. PMID 10322429. 
  27. ^ Pecina P, Houstková H, Hansíková H, Zeman J, Houstek J (2004). "Genetic defects of cytochrome c oxidase assembly" (PDF). Physiol Res. 53 Suppl 1: S213–23. PMID 15119951. 
  28. ^ Zee JM, Glerum DM (December 2006). "Defects in cytochrome oxidase assembly in humans: lessons from yeast". Biochem. Cell Biol. 84 (6): 859–69. doi:10.1139/o06-201. PMID 17215873. 
  29. ^ Johar K, Priya A, Dhar S, Liu Q, Wong-Riley MT (November 2013). "Neuron-specific specificity protein 4 bigenomically regulates the transcription of all mitochondria and nucleus-encoded cytochrome c oxidase subunit genes in neurons". Journal of Neurochemistry. 127 (4): 496–508. doi:10.1111/jnc.12433. PMC 3820366Freely accessible. PMID 24032355. 
  30. ^ Wong-Riley MT. (1989). "Cytochrome oxidase: an endogenous metabolic marker for neuronal activity". Trends Neurosci. 12 (3): 94–111. doi:10.1016/0166-2236(89)90165-3. PMID 2469224. 
  31. ^ Hevner RF, Wong-Riley MT (November 1989). "Brain cytochrome c oxidase: purification, antibody production, and immunohistochemical/histochemical correlations in the CNS". J. Neurosci. 9 (11): 3884–98. PMID 2555458. 
  32. ^ Strazielle C, Hayzoun K, Derer M, Mariani J, Lalonde R (April 2006). "Regional brain variations of cytochrome oxidase activity in Relnrl-orl mutant mice". J. Neurosci. Res. 83 (5): 821–31. doi:10.1002/jnr.20772. PMID 16511878. 
  33. ^ Strazielle C, Sturchler-Pierrat C, Staufenbiel M, Lalonde R (2003). "Regional brain cytochrome oxidase activity in beta-amyloid precursor protein transgenic mice with the Swedish mutation". Neuroscience. 118 (4): 1151–63. doi:10.1016/S0306-4522(03)00037-X. PMID 12732258. 
  34. ^ Conejo NM, González-Pardo H, Gonzalez-Lima F, Arias JL (2010). "Spatial learning of the water maze: progression of brain circuits mapped with cytochrome oxidase histochemistry". Neurobiol. Learn. Mem. 93 (3): 362–71. doi:10.1016/j.nlm.2009.12.002. PMID 19969098. 

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This is the Wikipedia entry entitled "NADH dehydrogenase (ubiquinone)". More...

NADH dehydrogenase (ubiquinone) Edit Wikipedia article

Complex I (EC (also referred to as NADH:ubiquinone oxidoreductase or, especially in the context of the human protein, NADH dehydrogenase) is an enzyme of the respiratory chains of myriad organisms from bacteria to humans that falls under the H+ or Na+-translocating NADH Dehydrogenase (NDH) Family (TC# 3.D.1), a member of the Na+ transporting Mrp superfamily. It catalyzes the transfer of electrons from NADH to coenzyme Q10 (CoQ10) and, in eukaryotes, it is located in the inner mitochondrial membrane. NADH:ubiquinone oxidoreductases type I of bacteria and of eukaryotic mitochondria and chloroplasts couple electron transfer to the electrogenic transport of protons or Na+.[1][2] It is one of the "entry enzymes" of cellular respiration or oxidative phosphorylation in the mitochondria.[3][4]

NADH:ubiquinone reductase (H+-translocating).
EC number
IntEnz IntEnz view
ExPASy NiceZyme view
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / QuickGO
Structure of the complex I hydrophilic domain from Thermus thermophilus PDB: 2FUG​. The large transmembrane domain lies to the bottom of the image and extends to the right; this section of the complex lies in the mitochondrial matrix.


CoQ to CoQH2.
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 (CoQH2). 3. The energy from the redox reaction results in conformational change allowing hydrogen ions to pass through four transmembrane helix channels.

Complex I is the first enzyme of the 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).[5] Complex I is the largest and most complicated enzyme of the electron transport chain.[6]

The reaction catalyzed by complex I is:

NADH + H+ + CoQ + 4H+in→ NAD+ + CoQH2 + 4H+out

In this process, the complex translocates four protons across the inner membrane per molecule of oxidized NADH, helping to build the electrochemical potential difference used to produce ATP. Escherichia coli complex I (NADH dehydrogenase) is capable of proton translocation in the same direction to the established Δψ, showing that in the tested conditions, the coupling ion is H+.[7] Na+ transport in the opposite direction was observed, and although Na+ was not necessary for the catalytic or proton transport activities, its presence increased the latter. H+ was translocated by the Paracoccus denitrificans complex I, but in this case, H+ transport was not influenced by Na+, and Na+ transport was not observed. Possibly, the E. coli complex I has two energy coupling sites (one Na+ independent and the other Na+dependent), as observed for the Rhodothermus marinus complex I, whereas the coupling mechanism of the P. denitrificans enzyme is completely Na+ independent. It is also possible that another transporter catalyzes the uptake of Na+. Complex I energy transduction by proton pumping may not be exclusive to the R. marinus enzyme. The Na+/H+ antiport activity seems not to be a general property of complex I.[7] However, the existence of Na+-translocating activity of the complex I is still in question.

The reaction can be reversed – referred to as aerobic succinate-supported NAD+ 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.[8]

Complex I may have a role in triggering apoptosis.[9] In fact, there has been shown to be a correlation between mitochondrial activities and programmed cell death (PCD) during somatic embryo development.[10]


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 FMNH2. The electron acceptor – the isoalloxazine ring – of FMN is identical to that of FAD. The electrons are then transferred through the FMN via a series of iron-sulfur (Fe-S) clusters[how many?], 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 pK values of ionizable side chain, and causes four hydrogen ions to be pumped out of the mitochondrial matrix.[11] Ubiquinone (CoQ) accepts two electrons to be reduced to ubiquinol (CoQH2).[5]

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.[12] 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).[13][14]

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.[15]

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 III and IV).[12] 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.[16]

The N2 cluster's proximity to a nearby cysteine residue results in a conformational change upon reduction in the nearby helicases, leading to small but important changes in the overall protein conformation.[17] 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+ translocation mechanism (i.e. all four protons move across the membrane at the same time).[15][18] 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.[19][20]

The resulting ubiquinol localized to the membrane domain interacts with negatively charged residues in the membrane arm, stabilizing conformational changes.[12] An antiporter mechanism (Na+/H+ swap) has been proposed using evidence of conserved Asp residues in the membrane arm.[21] The presence of Lys, Glu, and His residues enable for proton gating (a protonation followed by deprotonation event across the membrane) driven by the pKa of the residues.[12]

Composition and structure

NADH:ubiquinone oxidoreductase is the largest of the respiratory complexes. In mammals, 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 prosthetic group (FMN) and eight iron-sulfur clusters (FeS). Of the 44 subunits, seven are encoded by the mitochondrial genome.[22][23][24]

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. The structure of the eukaryotic complex is not well characterised. However, the Sazanov group succeeded in solving the structures of the complex I hydrophilic domain from the bacterium Thermus thermophilus (PDB: 2FUG​) [25] and complex I membrane domains from both the E. coli (PDB: 3rko​) and T. thermophilus (PDB: 4HE8​) enzymes. In February 2013 the structure of an entire, intact complex I (from T. thermophilus) was published for the first time, again by the Sazanov group (PDB: 4HEA​). 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+/ H+ antiporters of 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.[26]

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.[27] All 45 subunits of the bovine NDHI have been sequenced.[28][29] 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 by Roessler et al. (2010) 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.[30]

A simulational study by Hayashi and Stuchebrukhov further identified the electron tunneling pathways in atomic resolution based on the tunneling current theory. The distinct pathways between neighboring Fe/S clusters primarily consist of two cysteine ligands and one additional key residue, which was supported by sensitivity of simulated electron transfer rates to their mutations and their conservation among various complex I homologues from simple bacteria to human beings. This result shows that the crucial part of complex I developed for optimal efficiency with specific key residues during early stages of the biological evolution and has been conserved since then. Internal water between protein subunits was identified as an essential mediator enhancing the overall electron transfer rate to achieve physiologically significant value.[31][32]

Conserved subunits of Complex I[33]
# Human/Bovine subunit Human protein Protein description (UniProt) Pfam family with Human protein
Core Subunitsa
1 NDUFS7 / PSST / NUKM NDUS7_HUMAN NADH dehydrogenase [ubiquinone] iron-sulfur protein 7, mitochondrial EC EC Pfam PF01058
2 NDUFS8 / TYKY / NUIM NDUS8_HUMAN NADH dehydrogenase [ubiquinone] iron-sulfur protein 8, mitochondrial EC EC Pfam PF12838
3 NDUFV2 / 24kD / NUHMc NDUV2_HUMAN NADH dehydrogenase [ubiquinone] flavoprotein 2, mitochondrial EC EC Pfam PF01257
4 NDUFS3 / 30kD / NUGM NDUS3_HUMAN NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrial EC EC Pfam PF00329
5 NDUFS2 / 49kD / NUCM NDUS2_HUMAN NADH dehydrogenase [ubiquinone] iron-sulfur protein 2, mitochondrial EC EC Pfam PF00346
6 NDUFV1 / 51kD / NUBM NDUV1_HUMAN NADH dehydrogenase [ubiquinone] flavoprotein 1, mitochondrial EC EC Pfam PF01512
7 NDUFS1 / 75kD / NUAM NDUS1_HUMAN NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial EC EC Pfam PF00384
8 ND1 / NU1M NU1M_HUMAN NADH-ubiquinone oxidoreductase chain 1 EC Pfam PF00146
9 ND2 / NU2M NU2M_HUMAN NADH-ubiquinone oxidoreductase chain 2 EC Pfam PF00361, Pfam PF06444
10 ND3 / NU3M NU3M_HUMAN NADH-ubiquinone oxidoreductase chain 3 EC Pfam PF00507
11 ND4 / NU4M NU4M_HUMAN NADH-ubiquinone oxidoreductase chain 4 EC Pfam PF01059, Pfam PF00361
12 ND4L / NULM NU4LM_HUMAN NADH-ubiquinone oxidoreductase chain 4L EC Pfam PF00420
13 ND5 / NU5M NU5M_HUMAN NADH-ubiquinone oxidoreductase chain 5 EC Pfam PF00361, Pfam PF06455, Pfam PF00662
14 ND6 / NU6M NU6M_HUMAN NADH-ubiquinone oxidoreductase chain 6 EC Pfam PF00499
Core accessory subunitsb
15 NDUFS6 / 13A NDUS6_HUMAN NADH dehydrogenase [ubiquinone] iron-sulfur protein 6, mitochondrial Pfam PF10276
16 NDUFA12 / B17.2 NDUAC_HUMAN NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 12 Pfam PF05071
17 NDUFS4 / AQDQ NDUS4_HUMAN NADH dehydrogenase [ubiquinone] iron-sulfur protein 4, mitochondrial Pfam PF04800
18 NDUFA9 / 39kDa NDUA9_HUMAN NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 9, mitochondrial Pfam PF01370
19 NDUFAB1 / ACPM ACPM_HUMAN Acyl carrier protein, mitochondrial Pfam PF00550
20 NDUFA2 / B8 NDUA2_HUMAN NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 2 Pfam PF05047
21 NDUFA1 / MFWE NDUA1_HUMAN NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 1 Pfam PF15879
22 NDUFB3 / B12 NDUB3_HUMAN NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 3 Pfam PF08122
23 NDUFA5 / AB13 NDUA5_HUMAN NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 5 Pfam PF04716
24 NDUFA6 / B14 NDUA6_HUMAN NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 6 Pfam PF05347
25 NDUFA11 / B14.7 NDUAB_HUMAN NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 11 Pfam PF02466
26 NDUFB11 / ESSS NDUBB_HUMAN NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 11, mitochondrial Pfam PF10183
27 NDUFS5 / PFFD NDUS5_HUMAN NADH dehydrogenase [ubiquinone] iron-sulfur protein 5 Pfam PF10200
28 NDUFB4 / B15 NDUB4_HUMAN NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 4 Pfam PF07225
29 NDUFA13 /A13 NDUAD_HUMAN NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 13 Pfam PF06212
30 NDUFB7 / B18 NDUB7_HUMAN NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 7 Pfam PF05676
31 NDUFA8 / PGIV NDUA8_HUMAN NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 8 Pfam PF06747
32 NDUFB9 / B22 NDUB9_HUMAN NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 9 Pfam PF05347
33 NDUFB10 / PDSW NDUBA_HUMAN NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 10 Pfam PF10249
34 NDUFB8 / ASHI NDUB8_HUMAN NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 8, mitochondrial Pfam PF05821
35 NDUFC2 / B14.5B NDUC2_HUMAN NADH dehydrogenase [ubiquinone] 1 subunit C2 Pfam PF06374
36 NDUFB2 / AGGG NDUB2_HUMAN NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 2, mitochondrial Pfam PF14813
37 NDUFA7 / B14.5A NDUA7_HUMAN NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 7 Pfam PF07347
38 NDUFA3 / B9 NDUA3_HUMAN NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 3 Pfam PF14987
39 NDUFA4 / MLRQc NDUA4_HUMAN NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 4 Pfam PF06522
40 NDUFB5 / SGDH NDUB5_HUMAN NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 5, mitochondrial Pfam PF09781
41 NDUFB1 / MNLL NDUB1_HUMAN NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 1 Pfam PF08040
42 NDUFC1 / KFYI NDUC1_HUMAN NADH dehydrogenase [ubiquinone] 1 subunit C1, mitochondrial Pfam PF15088
43 NDUFA10 / 42kD NDUAA_HUMAN NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 10, mitochondrial Pfam PF01712
44 NDUFA4L2 NUA4L_HUMAN NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 4-like 2 Pfam PF15880
45 NDUFV3 NDUV3_HUMAN NADH dehydrogenase [ubiquinone] flavoprotein 3, 10kDa -
46 NDUFB6 NDUB6_HUMAN NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 6 Pfam PF09782
Assembly factor proteins[34]
47 NDUFAF1c 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


  • a Found in all species except fungi
  • b May or may not be present in any species
  • c Found in fungal species such as Schizosaccharomyces pombe


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).[37] The best-known inhibitor of complex I is rotenone (commonly used as an organic pesticide). Rotenone and rotenoids 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.[38] 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.

Acetogenins 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.[3] Interestingly, Rolliniastatin-2, an acetogenin, is the first complex I inhibitor found that does not share the same binding site as rotenone.[39]

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.[40]

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.[41] 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.[42]

Inhibition of complex I has been implicated in hepatotoxicity associated with a variety of drugs, for instance flutamide and nefazodone.[43]

Active/deactive 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, “deactive”, D-form. After exposure of idle enzyme to elevated, but physiological temperatures (>30 °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−1) 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~104 min−1). In the presence of divalent cations (Mg2+, Ca2+), 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 residue(s), 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.

It was found that these conformational changes may have a very important physiological significance. The deactive, but not the active form of complex I was susceptible to inhibition by nitrosothiols and peroxynitrite.[44] 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, or when the tissue nitric oxide:oxygen ratio increases (i.e. metabolic hypoxia).[45]

Production of superoxide

Recent investigations suggest that complex I is a potent source of reactive oxygen species.[46] 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).[46][47]

During reverse electron transfer, complex I might be the most important site of superoxide production within mitochondria, with up to 5% of electrons being diverted to superoxide formation. Reverse electron transfer, the process by which electrons from the reduced ubiquinol pool (supplied by succinate dehydrogenase, glycerol-3-phosphate dehydrogenase, or dihydro-oorotate dehydrogenase in mammalian mitochondria) pass through complex I to reduce NAD+ 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 it can be a very potent source of superoxide when succinate concentrations are high and oxaloacetate or malate concentrations are low.[48]

Superoxide is a reactive oxygen species that contributes to cellular oxidative stress and is linked to neuromuscular diseases and aging.[49] NADH dehdyrogenase produces superoxide by transferring one electron from FMNH2 to oxygen (O2). The radical flavin leftover is unstable, and transfers the remaining electron to the iron-sulfur centers. Interestingly, it is the ratio of NADH to NAD+ that determines the rate of superoxide formation.[50]


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.[51] 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.[52]

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.[53] 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.[54]

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.[55]


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
    • 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


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External links

As of this edit, this article uses content from "3.D.1 The H+ or Na+-translocating NADH Dehydrogenase (NDH) Family", which is licensed in a way that permits reuse under the Creative Commons Attribution-ShareAlike 3.0 Unported License, but not under the GFDL. All relevant terms must be followed.

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This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

CHCH domain Provide feedback

we have identified a conserved motif in the LOC118487 protein that we have called the CHCH motif. Alignment of this protein with related members showed the presence of three subgroups of proteins, which are called the S (Small), N (N-terminal extended) and C (C-terminal extended) subgroups. All three sub-groups of proteins have in common that they contain a predicted conserved [coiled coil 1]-[helix 1]-[coiled coil 2]-[helix 2] domain (CHCH domain). Within each helix of the CHCH domain, there are two cysteines present in a C-X9-C motif. The N-group contains an additional double helix domain, and each helix contains the C-X9-C motif. This family contains a number of characterised proteins: Cox19 protein - a nuclear gene of Saccharomyces cerevisiae, codes for an 11-kDa protein (Cox19p) required for expression of cytochrome oxidase. Because cox19 mutants are able to synthesise the mitochondrial and nuclear gene products of cytochrome oxidase, Cox19p probably functions post-translationally during assembly of the enzyme. Cox19p is present in the cytoplasm and mitochondria, where it exists as a soluble intermembrane protein. This dual location is similar to what was previously reported for Cox17p, a low molecular weight copper protein thought to be required for maturation of the CuA centre of subunit 2 of cytochrome oxidase. Cox19p have four conserved potential metal ligands, these are three cysteines and one histidine. Mrp10 - belongs to the class of yeast mitochondrial ribosomal proteins that are essential for translation [2]. Eukaryotic NADH-ubiquinone oxidoreductase 19 kDa (NDUFA8) subunit [3]. The CHCH domain was previously called DUF657 [4].

Literature references

  1. Nobrega MP, Bandeira SC, Beers J, Tzagoloff A; , J Biol Chem 2002;277:40206-40211.: Characterization of COX19, a widely distributed gene required for expression of mitochondrial cytochrome oxidase. PUBMED:12171940 EPMC:12171940

  2. Jin C, Myers AM, Tzagoloff A; , Curr Genet 1997;31:228-234.: Cloning and characterization of MRP10, a yeast gene coding for a mitochondrial ribosomal protein. PUBMED:9065385 EPMC:9065385

  3. Triepels R, van den Heuvel L, Loeffen J, Smeets R, Trijbels F, Smeitink J; , Hum Genet 1998;103:557-563.: The nuclear-encoded human NADH:ubiquinone oxidoreductase NDUFA8 subunit: cDNA cloning, chromosomal localization, tissue distribution, and mutation detection in complex-I-deficient patients. PUBMED:9860297 EPMC:9860297

  4. Westerman BA, Poutsma A, Steegers EA, Oudejans CB; , Genomics 2004;83:1094-1104.: C2360, a nuclear protein expressed in human proliferative cytotrophoblasts, is a representative member of a novel protein family with a conserved coiled coil-helix-coiled coil-helix domain. PUBMED:15177562 EPMC:15177562

Internal database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR010625

A conserved motif was identified in the LOC118487 protein was called the CHCH motif. Alignment of this protein with related members showed the presence of three subgroups of proteins, which are called the S (Small), N (N-terminal extended) and C (C-terminal extended) subgroups. All three sub-groups of proteins have in common that they contain a predicted conserved [coiled coil 1]-[helix 1]-[coiled coil 2]-[helix 2] domain (CHCH domain). Within each helix of the CHCH domain, there are two cysteines present in a C-X9-C motif. The N-group contains an additional double helix domain, and each helix contains the C-X9-C motif. This family contains a number of characterised proteins: Cox19 protein - a nuclear gene of Saccharomyces cerevisiae, codes for an 11 kDa protein (Cox19p) required for expression of cytochrome oxidase. Because cox19 mutants are able to synthesise the mitochondrial and nuclear gene products of cytochrome oxidase, Cox19p probably functions post-translationally during assembly of the enzyme. Cox19p is present in the cytoplasm and mitochondria, where it exists as a soluble intermembrane protein. This dual location is similar to what was previously reported for Cox17p, a low molecular weight copper protein thought to be required for maturation of the CuA centre of subunit 2 of cytochrome oxidase. Cox19p have four conserved potential metal ligands, these are three cysteines and one histidine. Mrp10 - belongs to the class of yeast mitochondrial ribosomal proteins that are essential for translation [PUBMED:9065385]. Eukaryotic NADH-ubiquinone oxidoreductase 19 kDa (NDUFA8) subunit [PUBMED:9860297]. The CHCH domain was previously called DUF657 [PUBMED:15177562].

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan CHCH (CL0351), which has the following description:

The conserved [coiled coil 1]-[helix 1]-[coiled coil 2]-[helix 2] domain (CHCH domain) superfamily members include NADH-ubiquinone oxidoreductases, some cytochrome oxidases and yeast mitochondrial ribosomal proteins. Within each helix of the CHCH domain there are two cysteines present in a C-X9-C motif.

The clan contains the following 8 members:



We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...

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We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

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We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

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You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...


This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Westerman BA, Poutsma A, Steegers E, Oudejans CBM
Previous IDs: none
Type: Domain
Author: Westerman BA, Poutsma A, Steegers E, Oudejans CBM, Bateman A
Number in seed: 50
Number in full: 1788
Average length of the domain: 35.50 aa
Average identity of full alignment: 27 %
Average coverage of the sequence by the domain: 23.10 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 26740544 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 26.9 26.9
Trusted cut-off 26.9 26.9
Noise cut-off 26.8 26.8
Model length: 35
Family (HMM) version: 12
Download: download the raw HMM for this family

Species distribution

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Colour assignments

Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence


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There are 2 interactions for this family. More...

COX17 SBP_bac_1


For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the CHCH domain has been found. There are 13 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.

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