NADH:Ubiquinone reductase (H+-translocating)

Complex I (EC 1.6.5.3) (also referred to as NADH:ubiquinone oxidoreductase or, especially in the context of the human protein, NADH dehydrogenase (ubiquinone)) is an enzyme of the respiratory chains of myriad organisms from bacteria to humans. It catalyzes the transfer of electrons from NADH to coenzyme Q10 (CoQ10) and, in eukaryotes, it is located in the inner mitochondrial membrane. It is one of the "entry enzymes" of cellular respiration or oxidative phosphorylation in the mitochondria.[1][2]

NADH:ubiquinone reductase (H+-translocating).
Identifiers
EC number 1.6.5.3
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO
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.

Function

NAD+ to NADH.
FMN to FMNH2.
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).[3] Complex I is the largest and most complicated enzyme of the electron transport chain.[4]

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.

The reaction can be reversed - referred to as aerobic succinate-supported NAD+ reduction - in the presence of a high membrane potential, but the exact catalytic mechanism remains unknown.[5]

Complex I may have a role in triggering apoptosis.[6] In fact, there has been shown to be a correlation between mitochondrial activities and programmed cell death (PCD) during somatic embryo development.[7]

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 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, 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.[8] Ubiquinone (CoQ) accepts two electrons to be reduced to ubiquinol (CoQH2).[3]

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.[9] 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-sulfer cluster of about 100 μs).[10][11]

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.[12]

Proton Translocation Mechanism

The coupling of proton translocation and electron transport chain 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).[9] The three central components believed to contribute to this long-range conformation change event are the pH-coupled N2 iron-sulfur cluster, the quinone reduction, and the transmembrane helix subunits of the membrane arm. The N2 cluster's proximity to a nearby cysteine residue results in a conformational change upon reduction in the nearby heliceses, leading to small but important changes in the overall protein conformation.[13] 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).[12][14] 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.[15][16]

The resulting ubiquinol localized to the membrane domain interacts with negatively charged residues in the membrane arm, stabilizing conformational changes.[9] An antiporter mechanism (Na+/H+ swap) has been proposed using evidence of conserved Asp residues in the membrane arm.[17] 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.[9]

Composition and structure

NADH:ubiquinone oxidoreductase is the largest of the respiratory complexes. In mammals, the enzyme contains 44 separate polypeptide chains. 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.[18][19][20]

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​) [21] 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​).

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.[22]

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.[23][24]

Table of Conserved subunits of Complex I[25]

No. 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 1.6.5.3 EC 1.6.99.3 Pfam PF01058
2 NDUFS8 / TYKY / NUIM NDUS8_HUMAN NADH dehydrogenase [ubiquinone] iron-sulfur protein 8, mitochondrial EC 1.6.5.3 EC 1.6.99.3 Pfam PF12838
3 NDUFV2 / 24kD / NUHMc NDUV2_HUMAN NADH dehydrogenase [ubiquinone] flavoprotein 2, mitochondrial EC 1.6.5.3 EC 1.6.99.3 Pfam PF01257
4 NDUFS3 / 30kD / NUGM NDUS3_HUMAN NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrial EC 1.6.5.3 EC 1.6.99.3 Pfam PF00329
5 NDUFS2 / 49kD / NUCM NDUS2_HUMAN NADH dehydrogenase [ubiquinone] iron-sulfur protein 2, mitochondrial EC 1.6.5.3 EC 1.6.99.3 Pfam PF00346
6 NDUFV1 / 51kD / NUBM NDUV1_HUMAN NADH dehydrogenase [ubiquinone] flavoprotein 1, mitochondrial EC 1.6.5.3 EC 1.6.99.3 Pfam PF01512
7 NDUFS1 / 75kD / NUAM NDUS1_HUMAN NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial EC 1.6.5.3 EC 1.6.99.3 Pfam PF00384
8 ND1 / NU1M NU1M_HUMAN NADH-ubiquinone oxidoreductase chain 1 EC 1.6.5.3 Pfam PF00146
9 ND2 / NU2M NU2M_HUMAN NADH-ubiquinone oxidoreductase chain 2 EC 1.6.5.3 Pfam PF00361, Pfam PF06444
10 ND3 / NU3M NU3M_HUMAN NADH-ubiquinone oxidoreductase chain 3 EC 1.6.5.3 Pfam PF00507
11 ND4 / NU4M NU4M_HUMAN NADH-ubiquinone oxidoreductase chain 4 EC 1.6.5.3 Pfam PF01059,Pfam PF00361
12 ND4L / NULM NU4LM_HUMAN NADH-ubiquinone oxidoreductase chain 4L EC 1.6.5.3 Pfam PF00420
13 ND5 / NU5M NU5M_HUMAN NADH-ubiquinone oxidoreductase chain 5 EC 1.6.5.3 Pfam PF00361, Pfam PF06455, Pfam PF00662
14 ND6 / NU6M NU6M_HUMAN NADH-ubiquinone oxidoreductase chain 6 EC 1.6.5.3 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[26]
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

Inhibitors

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.[27] 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.

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.[28]

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.[29] Both hydrophilic NADH and hydrophobic ubiquinone analogs act at the beginning and the end of the internal electron-transport pathway, respectively.

The acetogenin family are the most potent complex I inhibitors. They have been shown to cross-link to the ND2 subunit, which suggests that ND2 is essential for quinone-binding.[1] Interestingly, Rolliniastatin-2, an acetogenin, is the first complex I inhibitor found that does not share the same binding site as rotenone.[30]

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.[31]

Active/deactivated 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, “deactivated”, 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 deactivated, but not the active form of complex I was susceptible to inhibition by nitrosothiols and peroxynitrite.[32] 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).[33]

Production of superoxide

Recent investigations suggest that complex I is a potent source of reactive oxygen species.[34] 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).[34][35]

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.[36]

Superoxide is a reactive oxygen species that contributes to cellular oxidative stress and is linked to neuromuscular diseases and aging.[37] 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.[38]

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.[39] 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.[40]

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.[41] 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.[42]

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.[43]

Genes

The following is a list of humans genes that encode components of complex I:

References

  1. 1 2 Nakamaru-Ogiso E, Han H, Matsuno-Yagi A, Keinan E, Sinha SC, Yagi T, Ohnishi T. (January 2010). "The ND2 subunit is labeled by a photoaffinity analogue of asimicin, a potent complex I inhibitor.". FEBS Letters 584 (5): 883–8. doi:10.1016/j.febslet.2010.01.004. PMC 2836797. PMID 20074573.
  2. ↑ "Protein Data Bank in Europe: Bringing Structure to Biology". Retrieved 30 March 2014.
  3. 1 2 Berg, J, Tymoczko, J, and L Stryer (2006). Biochemistry (6th ed.). New York: WH Freeman & Company. pp. 509–513.
  4. ↑ Brandt, U (2006). "Energy converting NADH:quinone oxidoreductase (complex I)". Annual Review of Biochemistry 75: 69–92. doi:10.1146/annurev.biochem.75.103004.142539. PMID 16756485.
  5. ↑ Grivennikova VG, Kotlyar AB, Karliner JS, Cecchini G, Vinogradov AD. (August 2007). "Redox-dependent change of nucleotide affinity to the active site of the mammalian complex I.". Biochemistry 46 (38): 10971–8. doi:10.1021/bi7009822. PMC 2258335. PMID 17760425.
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  7. ↑ Petrussa E, Bertolini A, Casolo V, Krajnáková J, Macrì F, Vianello A. (October 2009). "Mitochondrial bioenergetics linked to the manifestation of programmed cell death during somatic embryogenesis of Abies alba.". Planta 231 (1): 93–107. doi:10.1007/s00425-009-1028-x. PMID 19834734.
  8. ↑ Donald J. Voet; Judith G. Voet; Charlotte W. Pratt (2008). "Chapter 18, Mitochondrial ATP synthesis". Principles of Biochemistry, 3rd Edition. Wiley. p. 608. ISBN 978-0-470-23396-2.
  9. 1 2 3 4 Sazanov, Leonid A. (2015-06-01). "A giant molecular proton pump: structure and mechanism of respiratory complex I". Nature Reviews Molecular Cell Biology 16 (6): 375–388. doi:10.1038/nrm3997. ISSN 1471-0072.
  10. ↑ Ohnishi, T. Iron–sulfur clusters/semiquinones in complex I. Biochim. Biophys. Acta 1364, 186–206 (1998).
  11. ↑ Bridges, H. R., Bill, E. & Hirst, J. Mossbauer spectroscopy on respiratory complex I: the iron–sulfur cluster ensemble in the NADH-reduced enzyme is partially oxidized. Biochemistry 51, 149–158 (2012).
  12. 1 2 Efremov, Rouslan G.; Sazanov, Leonid A. (2012-10-01). "The coupling mechanism of respiratory complex I - a structural and evolutionary perspective". Biochimica Et Biophysica Acta 1817 (10): 1785–1795. doi:10.1016/j.bbabio.2012.02.015. ISSN 0006-3002. PMID 22386882.
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  14. ↑ Baranova, Ekaterina A.; Morgan, David J.; Sazanov, Leonid A. (2007-08-01). "Single particle analysis confirms distal location of subunits NuoL and NuoM in Escherichia coli complex I". Journal of Structural Biology 159 (2): 238–242. doi:10.1016/j.jsb.2007.01.009. ISSN 1047-8477. PMID 17360196.
  15. ↑ Brandt, Ulrich (2011-10-01). "A two-state stabilization-change mechanism for proton-pumping complex I". Biochimica Et Biophysica Acta 1807 (10): 1364–1369. doi:10.1016/j.bbabio.2011.04.006. ISSN 0006-3002. PMID 21565159.
  16. ↑ Zickermann, Volker; Wirth, Christophe; Nasiri, Hamid; Siegmund, Karin; Schwalbe, Harald; Hunte, Carola; Brandt, Ulrich (2015-01-02). "Structural biology. Mechanistic insight from the crystal structure of mitochondrial complex I". Science (New York, N.Y.) 347 (6217): 44–49. doi:10.1126/science.1259859. ISSN 1095-9203. PMID 25554780.
  17. ↑ Hunte, Carola; Screpanti, Emanuela; Venturi, Miro; Rimon, Abraham; Padan, Etana; Michel, Hartmut (2005-06-30). "Structure of a Na+/H+ antiporter and insights into mechanism of action and regulation by pH". Nature 435 (7046): 1197–1202. doi:10.1038/nature03692. ISSN 1476-4687. PMID 15988517.
  18. ↑ Voet, Judith G.; Voet, Donald (2004). Biochemistry (3rd ed.). New York: J. Wiley & Sons. pp. 813–826. ISBN 0-471-19350-X.
  19. ↑ Carroll J, Fearnley IM, Skehel JM, Shannon RJ, Hirst J, Walker JE (October 2006). "Bovine complex I is a complex of 45 different subunits". J. Biol. Chem. 281 (43): 32724–7. doi:10.1074/jbc.M607135200. PMID 16950771.
  20. ↑ 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.
  21. ↑ Sazanov LA, Hinchliffe P (March 2006). "Structure of the hydrophilic domain of respiratory complex I from Thermus thermophilus". Science 311 (5766): 1430–6. doi:10.1126/science.1123809. PMID 16469879.
  22. ↑ Roessler MM, King MS, Robinson AJ, Armstrong FA, Harmer J, Hirst J. (February 2010). "Direct assignment of EPR spectra to structurally defined iron-sulfur clusters in complex I by double electron-electron resonance..". Proceedings of the National Academy of Sciences of the United States of America 107 (5): 1930–5. doi:10.1073/pnas.0908050107. PMC 2808219. PMID 20133838.
  23. ↑ Hayashi T., Stuchebrukhov A. (November 2010). "Electron Tunneling in Respiratory Complex I..". Proceedings of the National Academy of Sciences of the United States of America 107 (45): 19157–19162. doi:10.1073/pnas.1009181107. PMC 2984193. PMID 20974925.
  24. ↑ Electron Tunneling Pathways in Respiratory Complex I: 3D Rotating Movie on YouTube
  25. ↑ Cardol P (2011). "Mitochondrial NADH:ubiquinone oxidoreductase (complex I) in eukaryotes: a highly conserved subunit composition highlighted by mining of protein databases.". Biochim Biophys Acta 1807 (11): 1390–7. doi:10.1016/j.bbabio.2011.06.015. PMID 21749854.
  26. ↑ Ogilvie I, Kennaway NG, Shoubridge EA (2005). "A molecular chaperone for mitochondrial complex I assembly is mutated in a progressive encephalopathy.". J Clin Invest 115 (10): 2784–92. doi:10.1172/JCI26020. PMC 1236688. PMID 16200211.
  27. ↑ Moretti C, Grenand P (September 1988). "[The "nivrées", or ichthyotoxic plants of French Guyana]". J Ethnopharmacol (in French) 6 (2): 139–60. doi:10.1016/0378-8741(82)90002-2. PMID 7132401.
  28. ↑ Watabe M, Nakaki T. (July 2008). "Mitochondrial complex I inhibitor rotenone inhibits and redistributes vesicular monoamine transporter 2 via nitration in human dopaminergic SH-SY5Y cells". Molecular Pharmocology 74 (4): 933–40. doi:10.1124/mol.108.048546. PMID 18599602.
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