Respiratory complex I - Knowledge (XXG)

585:). 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. 684:(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. 2407:

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. 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.

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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) of NADH oxidation with subsequent ubiquinone reduction. After one or several turnovers the enzyme becomes active and can catalyse physiological NADH:ubiquinone reaction at a much higher rate (k~10 min). In the presence of divalent cations (Mg, Ca), or at alkaline pH the activation takes much longer.

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The catalytic properties of eukaryotic complex I are not simple. Two catalytically and structurally distinct forms exist in any given preparation of the enzyme: one is the fully competent, so-called “active” A-form and the other is the catalytically silent, dormant, “inactive”, D-form. After exposure

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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

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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:

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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

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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. The high reduction potential of the N2 cluster and the relative proximity of the other clusters

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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

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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

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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

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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

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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

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During reverse electron transfer, complex I might be the most important site of superoxide production within mitochondria, with around 3-4% of electrons being diverted to superoxide formation. Reverse electron transfer, the process by which electrons from the reduced ubiquinol pool (supplied by

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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

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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

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Brain ischemia/reperfusion injury is mediated via complex I impairment. Recently it was found that oxygen deprivation leads to conditions in which mitochondrial complex I lose its natural cofactor, flavin mononucleotide (FMN) and become inactive. When oxygen is present the enzyme catalyzes a

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path leads from cluster N2 to the N-terminal beta-sheet of the 49-kDa subunit. All 45 subunits of the bovine NDHI have been sequenced. Each complex contains noncovalently bound FMN, coenzyme Q and several iron-sulfur centers. The bacterial NDHs have 8-9 iron-sulfur centers.

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are even more potent inhibitors of complex I. They cross-link to the ND2 subunit, which suggests that ND2 is essential for quinone-binding. Rolliniastatin-2, an acetogenin, is the first complex I inhibitor found that does not share the same binding site as rotenone.

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This enzyme is essential for the normal functioning of cells, and mutations in its subunits lead to a wide range of inherited neuromuscular and metabolic disorders. Defects in this enzyme are responsible for the development of several pathological processes such as

445:, showing that in the tested conditions, the coupling ion is H. 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 620:

mechanism (Na/H swap) has been proposed using evidence of conserved Asp residues in the membrane arm. The presence of Lys, Glu, and His residues enable for proton gating (a protonation followed by deprotonation event across the membrane) driven by the

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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

7561: 2247:(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 5152:

Muller FL, Liu Y, Abdul-Ghani MA, Lustgarten MS, Bhattacharya A, Jang YC, Van Remmen H (January 2008). "High rates of superoxide production in skeletal-muscle mitochondria respiring on both complex I- and complex II-linked substrates".

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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. All thirteen of the

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activity, which may lead to Parkinson's disease. 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.

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so that fraction of electrons from succinate is directed upstream to FMN of complex I. Reverse electron transfer results in a reduction of complex I FMN, increased generation of ROS, followed by a loss of the reduced cofactor

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of NADH oxidation – by binding to the enzyme at the nucleotide binding site. Both hydrophilic NADH and hydrophobic ubiquinone analogs act at the beginning and the end of the internal electron-transport pathway, respectively.

601:, providing evidence for the "single stroke" H translocation mechanism (i.e. all four protons move across the membrane at the same time). Alternative theories suggest a "two stroke mechanism" where each reduction step ( 572:

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

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Petrussa E, Bertolini A, Casolo V, Krajnáková J, Macrì F, Vianello A (December 2009). "Mitochondrial bioenergetics linked to the manifestation of programmed cell death during somatic embryogenesis of Abies alba".

2268:. 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 588:

The N2 cluster's proximity to a nearby cysteine residue results in a conformational change upon reduction in the nearby helices, leading to small but important changes in the overall protein conformation. Further

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Superoxide is a reactive oxygen species that contributes to cellular oxidative stress and is linked to neuromuscular diseases and aging. NADH dehydrogenase produces superoxide by transferring one electron from

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irreversibly blocks critical cysteine residues, abolishing the ability of the enzyme to respond to activation, thus inactivating it irreversibly. The A-form of complex I is insensitive to sulfhydryl reagents.

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It was found that these conformational changes may have a very important physiological significance. The inactive, but not the active form of complex I was susceptible to inhibition by nitrosothiols and

2170:). 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. Rotenone binds to the 6351: 5975: 4461:

Watabe M, Nakaki T (October 2008). "Mitochondrial complex I inhibitor rotenone inhibits and redistributes vesicular monoamine transporter 2 via nitration in human dopaminergic SH-SY5Y cells".

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Saada A, Vogel RO, Hoefs SJ, van den Brand MA, Wessels HJ, Willems PH, Venselaar H, Shaag A, Barghuti F, Reish O, Shohat M, Huynen MA, Smeitink JA, van den Heuvel LP, Nijtmans LG (June 2009).

2341:). The radical flavin leftover is unstable, and transfers the remaining electron to the iron-sulfur centers. It is the ratio of NADH to NAD that determines the rate of superoxide formation. 465:

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

2296:), 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). 7565: 2212:

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.

637:, the enzyme contains 44 separate water-soluble peripheral membrane proteins, which are anchored to the integral membrane constituents. Of particular functional importance are the 5694:

Binukumar BK, Bal A, Kandimalla R, Sunkaria A, Gill KD (April 2010). "Mitochondrial energy metabolism impairment and liver dysfunction following chronic exposure to dichlorvos".

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serves to maintain photosynthesis in stressful situations. This makes it at least partially dispensable in favorable conditions. It is evident that angiosperm lineages without

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physiological reaction of NADH oxidation by ubiquinone, supplying electrons downstream of the respiratory chain (complexes III and IV). Ischemia leads to dramatic increase of

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enzyme. The Na/H antiport activity seems not to be a general property of complex I. However, the existence of Na-translocating activity of the complex I is still in question.

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Hunte C, Screpanti E, Venturi M, Rimon A, Padan E, Michel H (June 2005). "Structure of a Na+/H+ antiporter and insights into mechanism of action and regulation by pH".

6452: 6344: 6314: 296: 5968: 2403:) and impairment of mitochondria energy production. The FMN loss by complex I and I/R injury can be alleviated by the administration of FMN precursor, riboflavin. 125: 113: 4631:"Mitochondrial complex I inhibition triggers NAD+-independent glucose oxidation via successive NADPH formation, "futile" fatty acid cycling, and FADH2 oxidation" 6248: 315: 3957:

Gabaldón T, Rainey D, Huynen MA (May 2005). "Tracing the evolution of a large protein complex in the eukaryotes, NADH:ubiquinone oxidoreductase (Complex I)".

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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).

6337: 4053:"Mitochondrial NADH:ubiquinone oxidoreductase (complex I) in eukaryotes: a highly conserved subunit composition highlighted by mining of protein databases" 5239:"Production of reactive oxygen species by complex I (NADH:ubiquinone oxidoreductase) from Escherichia coli and comparison to the enzyme from mitochondria" 6933: 5961: 5008:

Hansford RG, Hogue BA, Mildaziene V (February 1997). "Dependence of H2O2 formation by rat heart mitochondria on substrate availability and donor age".

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Balsa, Eduardo; Marco, Ricardo; Perales-Clemente, Ester; Szklarczyk, Radek; Calvo, Enrique; Landázuri, Manuel O.; Enríquez, José Antonio (2012-09-05).

39:). 3. The energy from the redox reaction results in conformational change allowing hydrogen ions to pass through four transmembrane helix channels. 6928: 7019: 6601: 6388: 6219: 578: 390: 5843: 4192:"Mutations in NDUFAF3 (C3ORF60), encoding an NDUFAF4 (C6ORF66)-interacting complex I assembly protein, cause fatal neonatal mitochondrial disease" 593:

studies of the electron transfer have demonstrated that most of the energy that is released during the subsequent CoQ reduction is on the final

6687: 5105:"Reverse electron transfer results in a loss of flavin from mitochondrial complex I: Potential mechanism for brain ischemia reperfusion injury" 2362: 3204: 519:

All redox reactions take place in the hydrophilic domain of complex I. NADH initially binds to complex I, and transfers two electrons to the

6496: 5614:"Mitochondrial complex I activity and oxidative damage to mitochondrial proteins in the prefrontal cortex of patients with bipolar disorder" 6445: 3918:"Higher plant-like subunit composition of mitochondrial complex I from Chlamydomonas reinhardtii: 31 conserved components among eukaryotes" 535:(ubiquinone). This electron flow changes the redox state of the protein, inducing conformational changes of the protein which alters the p 5053:"The dependence of brain mitochondria reactive oxygen species production on oxygen level is linear, except when inhibited by antimycin A" 7596: 6368: 5917: 5429:"Mitochondrial respiration and respiration-associated proteins in cell lines created through Parkinson's subject mitochondrial transfer" 616:

localized to the membrane domain interacts with negatively charged residues in the membrane arm, stabilizing conformational changes. An

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Abrosimov, Roman; Baeken, Marius W.; Hauf, Samuel; Wittig, Ilka; Hajieva, Parvana; Perrone, Carmen E.; Moosmann, Bernd (2024-01-25).

4418:"Natural substances (acetogenins) from the family Annonaceae are powerful inhibitors of mitochondrial NADH dehydrogenase (Complex I)" 7257: 6732: 6557: 3662: 3263:"Mössbauer spectroscopy on respiratory complex I: the iron-sulfur cluster ensemble in the NADH-reduced enzyme is partially oxidized" 2419:

A proton-pumping, ubiquinone-using NADH dehydrogenase complex, homologous to complex I, is found in the chloroplast genomes of most

3545: 3994:"Direct assignment of EPR spectra to structurally defined iron-sulfur clusters in complex I by double electron-electron resonance" 7058: 6856: 6491: 2443:. The purpose of this complex is originally cryptic as chloroplasts do not participate in respiration, but now it is known that 308: 7225: 7053: 6717: 6438: 681: 590: 7048: 6834: 6792: 6258: 6088: 6076: 6025: 5902: 2427:. This complex is inherited from the original symbiosis from cyanobacteria, but has been lost in most eukaryotic algae, some 235: 7413: 5791: 5427:

Esteves AR, Lu J, Rodova M, Onyango I, Lezi E, Dubinsky R, Lyons KE, Pahwa R, Burns JM, Cardoso SM, Swerdlow RH (May 2010).

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Dunning CJ, McKenzie M, Sugiana C, Lazarou M, Silke J, Connelly A, Fletcher JM, Kirby DM, Thorburn DR, Ryan MT (July 2007).

3468:(August 2007). "Single particle analysis confirms distal location of subunits NuoL and NuoM in Escherichia coli complex I". 259: 389:. There are three energy-transducing enzymes in the electron transport chain - NADH:ubiquinone oxidoreductase (complex I), 7581: 6097: 5795: 7528: 5513:"Critical Role of Flavin and Glutathione in Complex I-Mediated Bioenergetic Failure in Brain Ischemia/Reperfusion Injury" 6638: 6580: 6470: 6084: 2313: 2197: 5190:"Krebs cycle metabolites and preferential succinate oxidation following neonatal hypoxic-ischemic brain injury in mice" 6692: 5836: 528: 6329: 5280:"The mechanism of superoxide production by NADH:ubiquinone oxidoreductase (complex I) from bovine heart mitochondria" 4913:

Moncada S, Erusalimsky JD (March 2002). "Does nitric oxide modulate mitochondrial energy generation and apoptosis?".

2918:"-->H+/2e- stoichiometry in NADH-quinone reductase reactions catalyzed by bovine heart submitochondrial particles" 451:

complex I, but in this case, H transport was not influenced by Na, and Na transport was not observed. Possibly, the

6866: 6861: 6665: 6531: 7398: 4143:"Human CIA30 is involved in the early assembly of mitochondrial complex I and mutations in its gene cause disease" 2193:

long-term systemic inhibition of complex I by rotenone can induce selective degeneration of dopaminergic neurons.

7514: 7501: 7488: 7475: 7462: 7449: 7436: 6591: 6414: 6185: 5882: 5877: 5653:

Morán M, Rivera H, Sánchez-Aragó M, Blázquez A, Merinero B, Ugalde C, Arenas J, Cuezva JM, Martín MA (May 2010).

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residues exposed at the surface of the enzyme. Treatment of the D-form of complex I with the sulfhydryl reagents

2093: 531:. The electrons are then transferred through the FMN via a series of iron-sulfur (Fe-S) clusters, and finally to 428: 7408: 4817:"Attenuation of oxidative damage by targeting mitochondrial complex I in neonatal hypoxic-ischemic brain injury" 502:

As a result of a two NADH molecule being oxidized to NAD+, three molecules of ATP can be produced by Complex V (

7362: 7305: 6782: 6660: 6180: 6140: 6015: 5815: 1201: 1157: 1127: 1090: 1060: 1023: 993: 963: 957: 927: 921: 891: 885: 855: 849: 819: 813: 783: 777: 747: 741: 447: 386: 253: 158: 70: 47: 3360:"Evidence for two sites of superoxide production by mitochondrial NADH-ubiquinone oxidoreductase (complex I)" 7310: 6829: 6616: 6205: 6121: 6032: 5912: 5897: 5892: 2301: 2285: 539:

values of ionizable side chain, and causes four hydrogen ions to be pumped out of the mitochondrial matrix.

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complex I has two energy coupling sites (one Na independent and the other Nadependent), as observed for the

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Sazanov LA (June 2015). "A giant molecular proton pump: structure and mechanism of respiratory complex I".

2970:"Sodium influence on energy transduction by complexes I from Escherichia coli and Paracoccus denitrificans" 2836:"Two protons are pumped from the mitochondrial matrix per electron transferred between NADH and ubiquinone" 2488:– NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 4, 9kDa - recently described to be part of complex IV 441:

complex I (NADH dehydrogenase) is capable of proton translocation in the same direction to the established

6824: 6481: 6409: 6164: 6113: 6080: 5872: 5829: 5339:"Superoxide radical formation by pure complex I (NADH:ubiquinone oxidoreductase) from Yarrowia lipolytica" 2366: 2350: 432: 30: 4864:

Stepanova A, Konrad C, Guerrero-Castillo S, Manfredi G, Vannucci S, Arnold S, Galkin A (September 2019).

4293:"Essential structural factors of annonaceous acetogenins as potent inhibitors of mitochondrial complex I" 3719:

Balsa E, Marco R, Perales-Clemente E, Szklarczyk R, Calvo E, Landázuri MO, Enríquez JA (September 2012).

2877:"The proton pumping stoichiometry of purified mitochondrial complex I reconstituted into proteoliposomes" 7331: 7250: 7198: 6938: 6814: 6650: 6628: 6058: 5942: 5867: 5811: 5563:

Stepanova A, Sosunov S, Niatsetskaya Z, Konrad C, Starkov AA, Manfredi G, et al. (September 2019).

4506:"A competitive inhibition of the mitochondrial NADH-ubiquinone oxidoreductase (complex I) by ADP-ribose" 2395: 2201: 520: 481: 342: 320: 7403: 4094:"A molecular chaperone for mitochondrial complex I assembly is mutated in a progressive encephalopathy" 228: 2329:

concentrations are low. This can take place during tissue ischaemia, when oxygen delivery is blocked.

7039: 6945: 6802: 6751: 6697: 6393: 6229: 6159: 6047: 5291: 4005: 3833: 3776: 3603: 2104: 649: 582: 457: 394: 397:(complex IV). Complex I is the largest and most complicated enzyme of the electron transport chain. 7586: 7367: 6309: 645: 137: 5468:

Galkin A (November 2019). "Brain Ischemia/Reperfusion Injury and Mitochondrial Complex I Damage".

4369:"The ND2 subunit is labeled by a photoaffinity analogue of asimicin, a potent complex I inhibitor" 256: 7300: 6969: 6737: 6611: 6383: 6200: 5922: 5493: 5033: 4938: 4486: 3857: 3802: 3627: 3576: 3177: 3125: 2947: 334: 180: 5565:"Redox-Dependent Loss of Flavin by Mitochondrial Complex I in Brain Ischemia/Reperfusion Injury" 5188:

Sahni PV, Zhang J, Sosunov S, Galkin A, Niatsetskaya Z, Starkov A, et al. (February 2018).

3546:"Structural biology. Mechanistic insight from the crystal structure of mitochondrial complex I" 7591: 6959: 6762: 6543: 5988: 5937: 5932: 5766: 5711: 5676: 5635: 5594: 5542: 5485: 5450: 5409: 5360: 5319: 5260: 5219: 5170: 5134: 5082: 5025: 4990: 4930: 4895: 4846: 4815:

Kim M, Stepanova A, Niatsetskaya Z, Sosunov S, Arndt S, Murphy MP, et al. (August 2018).

4797: 4756: 4707: 4648: 4611: 4576: 4527: 4478: 4443: 4398: 4349: 4314: 4273: 4265: 4221: 4172: 4123: 4074: 4033: 3974: 3939: 3898: 3849: 3794: 3742: 3701: 3658: 3619: 3568: 3526: 3485: 3446: 3391: 3340: 3292: 3243: 3200: 3169: 3117: 3081: 3040: 2991: 2939: 2898: 2857: 2816: 2293: 2269: 2244: 247: 4367:

Nakamaru-Ogiso E, Han H, Matsuno-Yagi A, Keinan E, Sinha SC, Yagi T, Ohnishi T (March 2010).

3319:"The coupling mechanism of respiratory complex I - a structural and evolutionary perspective" 3011:"Redox-dependent change of nucleotide affinity to the active site of the mammalian complex I" 2812: 7346: 7341: 7315: 7243: 6772: 6565: 6283: 6278: 6151: 6005: 5786: 5756: 5746: 5703: 5666: 5625: 5584: 5576: 5532: 5524: 5477: 5440: 5399: 5391: 5350: 5309: 5299: 5250: 5209: 5201: 5162: 5124: 5116: 5072: 5064: 5017: 4980: 4972: 4922: 4885: 4877: 4836: 4828: 4787: 4746: 4738: 4697: 4689: 4656: 4638: 4603: 4566: 4558: 4517: 4470: 4433: 4425: 4388: 4380: 4341: 4304: 4255: 4211: 4203: 4162: 4154: 4113: 4105: 4064: 4023: 4013: 3966: 3929: 3888: 3841: 3784: 3732: 3691: 3654: 3611: 3560: 3516: 3477: 3436: 3426: 3381: 3371: 3330: 3282: 3274: 3233: 3161: 3109: 3071: 3030: 3022: 2981: 2929: 2888: 2847: 2808: 2252: 641: 437: 3544:

Zickermann V, Wirth C, Nasiri H, Siegmund K, Schwalbe H, Hunte C, Brandt U (January 2015).

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leads to decreased mitochondrial electron transfer activities and decreased ATP synthesis.

7393: 7377: 7290: 6677: 6570: 6360: 2125: 673:

the translocation of three protons may be coordinated by a lateral helix connecting them.

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Cardol P, Vanrobaeys F, Devreese B, Van Beeumen J, Matagne RF, Remacle C (October 2004).

480:. In fact, there has been shown to be a correlation between mitochondrial activities and 5953: 5295: 4832: 4661: 4009: 3837: 3780: 3765:"Structure of the hydrophilic domain of respiratory complex I from Thermus thermophilus" 3607: 192: 7542: 7431: 7372: 5787:

Institute of Science and Technology Austria (ISTA): Sazanov Group MRC MBU Sazanov group

5761: 5730: 5655:"Mitochondrial bioenergetics and dynamics interplay in complex I-deficient fibroblasts" 5589: 5564: 5537: 5512: 5511:

Kahl A, Stepanova A, Konrad C, Anderson C, Manfredi G, Zhou P, et al. (May 2018).

5404: 5379: 5314: 5279: 5214: 5189: 5129: 5104: 5077: 5052: 4985: 4960: 4890: 4865: 4841: 4816: 4751: 4726: 4702: 4677: 4571: 4438: 4417: 4393: 4368: 4216: 4191: 4167: 4142: 4118: 4093: 4028: 3993: 3821: 3760: 3465: 3441: 3414: 3410: 3386: 3359: 3314: 3287: 3262: 3035: 3010: 2354: 2216: 291: 163: 118: 5630: 5613: 4866:"Deactivation of mitochondrial complex I after hypoxia-ischemia in the immature brain" 4522: 4505: 4309: 4292: 3238: 3221: 3009:

Grivennikova VG, Kotlyar AB, Karliner JS, Cecchini G, Vinogradov AD (September 2007).

2934: 2917: 271: 7575: 7336: 7295: 6461: 5927: 5497: 5445: 5428: 4345: 2852: 2835: 2391: 2265: 2141: 266: 4942: 4594:

Nadanaciva S, Will Y (2011). "New insights in drug-induced mitochondrial toxicity".

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Roessler MM, King MS, Robinson AJ, Armstrong FA, Harmer J, Hirst J (February 2010).

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do not last long from their young ages, but how gymnosperms survive on land without

2073: 2051: 2029: 2007: 1980: 1937: 1913: 1889: 1865: 1841: 1817: 1793: 1769: 1745: 1721: 1697: 1673: 1649: 1625: 1601: 1577: 1553: 1529: 1505: 1481: 1457: 1433: 1409: 1385: 1361: 1337: 1313: 1289: 1265: 1241: 1212: 1182: 1175: 1168: 1138: 1108: 1101: 1071: 1041: 1034: 1004: 974: 938: 902: 866: 830: 794: 758: 7285: 7094: 7069: 6727: 6606: 6519: 6224: 6210: 6132: 5887: 5856: 5037: 4727:"Ischemic A/D transition of mitochondrial complex I and its role in ROS generation" 4545:

Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F (March 2012).

4490: 3861: 3806: 3647: 3631: 2951: 2692:– NADH dehydrogenase (ubiquinone) Fe-S protein 8, 23kDa (NADH-coenzyme Q reductase) 2686:– NADH dehydrogenase (ubiquinone) Fe-S protein 7, 20kDa (NADH-coenzyme Q reductase) 2680:– NADH dehydrogenase (ubiquinone) Fe-S protein 6, 13kDa (NADH-coenzyme Q reductase) 2674:– NADH dehydrogenase (ubiquinone) Fe-S protein 5, 15kDa (NADH-coenzyme Q reductase) 2668:– NADH dehydrogenase (ubiquinone) Fe-S protein 4, 18kDa (NADH-coenzyme Q reductase) 2662:– NADH dehydrogenase (ubiquinone) Fe-S protein 3, 30kDa (NADH-coenzyme Q reductase) 2656:– NADH dehydrogenase (ubiquinone) Fe-S protein 2, 49kDa (NADH-coenzyme Q reductase) 2650:– NADH dehydrogenase (ubiquinone) Fe-S protein 1, 75kDa (NADH-coenzyme Q reductase) 2322: 2273: 2175: 2155: 638: 532: 503: 86: 82: 4384: 3678:

Carroll J, Fearnley IM, Skehel JM, Shannon RJ, Hirst J, Walker JE (October 2006).

2365:.There is some evidence that complex I defects may play a role in the etiology of 666: 527:. The electron acceptor – the isoalloxazine ring – of FMN is identical to that of 142: 130: 7556: 5806: 5671: 5654: 5528: 4776:"S-nitrosation of mitochondrial complex I depends on its structural conformation" 4742: 4693: 4069: 4052: 3934: 3917: 3893: 3876: 3521: 3504: 3335: 3318: 2986: 2969: 2893: 2876: 7509: 7444: 7280: 6364: 5395: 4678:"Characterisation of the active/de-active transition of mitochondrial complex I" 4291:

Miyoshi H, Ohshima M, Shimada H, Akagi T, Iwamura H, McLaughlin JL (July 1998).

2436: 2370: 2357:. Point mutations in various complex I subunits derived from mitochondrial DNA ( 2146: 602: 598: 420: 275: 7537: 5284:

Proceedings of the National Academy of Sciences of the United States of America

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Proceedings of the National Academy of Sciences of the United States of America

3737: 3720: 2560:

NDUFAF4 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, assembly factor 4

2557:

NDUFAF3 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, assembly factor 3

2554:

NDUFAF2 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, assembly factor 2

633:

NADH:ubiquinone oxidoreductase is the largest of the respiratory complexes. In

6846: 6508: 6068: 5984: 5907: 5707: 5481: 5051:

Stepanova A, Konrad C, Manfredi G, Springett R, Ten V, Galkin A (March 2019).

5021: 3970: 3481: 3195:

Voet DJ, Voet GJ, Pratt CW (2008). "Chapter 18, Mitochondrial ATP synthesis".

3113: 2799:

Brandt U (2006). "Energy converting NADH:quinone oxidoreductase (complex I)".

2440: 2428: 2420: 2382: 2374: 2289: 2224: 2185: 2181: 2171: 2129:

fruit) is the most potent known inhibitor of NADH dehydrogenase (ubiquinone) (

2120: 2116: 617: 540: 5120: 4881: 4652: 4630: 4269: 4244:"NDUFA4 is a subunit of complex IV of the mammalian electron transport chain" 4158: 3721:"NDUFA4 is a subunit of complex IV of the mammalian electron transport chain" 2463:

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

492: 7483: 7457: 6777: 6010: 5304: 5103:

Stepanova A, Kahl A, Konrad C, Ten V, Starkov AS, Galkin A (December 2017).

4018: 3789: 3764: 3564: 3431: 3376: 2318: 2220: 2209: 2178:, another potent inhibitor with a close structural homologue to ubiquinone. 2160: 613: 606: 594: 544: 477: 5770: 5715: 5680: 5639: 5598: 5546: 5489: 5454: 5413: 5364: 5355: 5338: 5323: 5264: 5223: 5174: 5138: 5086: 4994: 4934: 4899: 4850: 4801: 4792: 4775: 4760: 4711: 4615: 4580: 4482: 4474: 4402: 4277: 4225: 4176: 4127: 4078: 4037: 3978: 3943: 3902: 3853: 3798: 3746: 3705: 3696: 3679: 3623: 3572: 3530: 3489: 3450: 3395: 3344: 3296: 3173: 3121: 3085: 3044: 2995: 2943: 2902: 2820: 2545:

NDUFAB1 – NADH dehydrogenase (ubiquinone) 1, alpha/beta subcomplex, 1, 8kDa

2394:

level. In the presence of succinate mitochondria catalyze reverse electron

2136:=1.2 nM, stronger than rotenone). The best-known inhibitor of complex I is 5751: 5580: 5029: 4531: 4447: 4353: 4318: 3247: 3076: 3059: 2861: 361: 353: 6923: 6797: 6430: 6419: 6042: 5821: 3505:"A two-state stabilization-change mechanism for proton-pumping complex I" 2530:

NDUFA11 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 11, 14.7kDa

2248: 2166: 2137: 1926: 74: 17: 5205: 3845: 3615: 966: 930: 894: 858: 822: 786: 750: 73:

of many organisms from bacteria to humans. It catalyzes the transfer of

7083: 7078: 6998: 5852: 5166: 4976: 4562: 4416:

Degli Esposti M, Ghelli A, Ratta M, Cortes D, Estornell E (July 1994).

2747: 2619: 2613: 2551:– NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, assembly factor 1 2548: 2539: 2533: 2524: 2509:

NDUFA7 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 7, 14.5kDa

2494:

NDUFA4L2 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 4-like 2

2228: 1902: 1662: 1566: 1494: 1470: 1326: 1254: 1204: 1160: 1130: 1121: 1093: 1063: 1026: 996: 960: 924: 888: 852: 816: 780: 744: 710: 609:) results in a stroke of two protons entering the intermembrane space. 223: 204: 50: 5255: 5238: 5098: 5096: 5068: 4429: 3278: 3026: 660:

proteins, which comprise NADH dehydrogenase I, are encoded within the

473:

ATP-hydrolysis or by complexes III and IV during succinate oxidation.

7496: 7266: 7188: 7183: 7153: 7148: 7028: 7008: 7003: 6993: 6988: 6983: 6978: 5991: 4109: 2788:(6th ed.). New York: WH Freeman & Company. pp. 509–513. 2759: 2753: 2741: 2735: 2729: 2723: 2712: 2706: 2700: 2689: 2683: 2677: 2671: 2665: 2659: 2653: 2647: 2636: 2630: 2607: 2601: 2595: 2589: 2574: 2568: 2518: 2512: 2503: 2497: 2485: 2476: 2470: 2326: 2227:. Further, complex I inhibition was shown to trigger NAD-independent 2151: 2100: 1969: 1950: 1878: 1854: 1830: 1806: 1782: 1758: 1734: 1710: 1686: 1638: 1614: 1590: 1542: 1518: 1446: 1422: 1398: 1374: 1350: 1302: 1278: 1230: 1195: 1151: 1084: 1054: 1017: 987: 951: 915: 879: 843: 807: 771: 735: 700: 634: 338: 303: 199: 187: 175: 3165: 2586:

NDUFB5 – NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 5, 16kDa

2583:

NDUFB4 – NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 4, 15kDa

2580:

NDUFB3 – NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 3, 12kDa

2491:

NDUFA4L – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 4-like

2482:

NDUFA3 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 3, 9kDa

2140:(commonly used as an organic pesticide). Rotenone and rotenoids are 7557:"3.D.1 The H+ or Na+-translocating NADH Dehydrogenase (NDH) Family" 4926: 3060:"Mitochondrial complex I in the network of known and unknown facts" 2639:– NADH dehydrogenase (ubiquinone) 1, subcomplex unknown, 2, 14.5kDa 2284:

Recent investigations suggest that complex I is a potent source of

7470: 7208: 7203: 7193: 7178: 7173: 7168: 7163: 7158: 7143: 7138: 7133: 7128: 7123: 7118: 7113: 7108: 7103: 6899: 6886: 6293: 6288: 2369:, perhaps because of reactive oxygen species (complex I can, like 2358: 696: 373: 3875:

Tocilescu MA, Zickermann V, Zwicker K, Brandt U (December 2010).

6273: 6268: 6263: 6253: 6243: 6036: 5659:

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

2633:– NADH dehydrogenase (ubiquinone) 1, subcomplex unknown, 1, 6kDa 2622:– NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 11, 17.3kDa 2256: 2144:

occurring in several genera of tropical plants such as Antonia (

2130: 2070: 2048: 2026: 2004: 1977: 1934: 1910: 1907:

NADH dehydrogenase 1 alpha subcomplex subunit 10, mitochondrial

1886: 1862: 1838: 1814: 1790: 1766: 1742: 1718: 1694: 1670: 1646: 1622: 1598: 1574: 1550: 1526: 1502: 1478: 1454: 1430: 1406: 1382: 1358: 1334: 1310: 1286: 1262: 1238: 1209: 1179: 1172: 1165: 1135: 1105: 1098: 1068: 1038: 1031: 1001: 971: 935: 899: 863: 827: 791: 755: 716: 574: 424: 211: 78: 7239: 6434: 6333: 5957: 5825: 2527:– NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 10, 42kDa 2473:– NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 1, 7.5kDa 1499:

NADH dehydrogenase 1 beta subcomplex subunit 11, mitochondrial

1307:

NADH dehydrogenase 1 alpha subcomplex subunit 9, mitochondrial

2616:– NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 10, 22kDa 2521:– NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 9, 39kDa 2515:– NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 8, 19kDa 2506:– NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 6, 14kDa 2500:– NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 5, 13kDa 1835:

NADH dehydrogenase 1 beta subcomplex subunit 5, mitochondrial

1739:

NADH dehydrogenase 1 beta subcomplex subunit 2, mitochondrial

1691:

NADH dehydrogenase 1 beta subcomplex subunit 8, mitochondrial

4547:"Cellular and molecular mechanisms of metformin: an overview" 3415:"Structural basis for the mechanism of respiratory complex I" 2610:– NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 9, 22kDa 2604:– NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 8, 19kDa 2598:– NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 7, 18kDa 2592:– NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 6, 17kDa 2479:– NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 2, 8kDa 956:

NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial

7562:

Creative Commons Attribution-ShareAlike 3.0 Unported License

2577:– NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 2, 8kDa 2571:– NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 1, 7kDa 2317:

this process can be a very potent source of superoxide when

5378:

Chou AP, Li S, Fitzmaurice AG, Bronstein JM (August 2010).

89:

membrane in eukaryotes or the plasma membrane of bacteria.

7560:, which is licensed in a way that permits reuse under the 7235: 5801: 4237: 4235: 3824:(May 2010). "The architecture of respiratory complex I". 2067:

NADH dehydrogenase 1 alpha subcomplex, assembly factor 4

2023:

NADH dehydrogenase 1 alpha subcomplex, assembly factor 2

2001:

NADH dehydrogenase 1 alpha subcomplex, assembly factor 1

884:

NADH dehydrogenase iron-sulfur protein 2, mitochondrial

848:

NADH dehydrogenase iron-sulfur protein 3, mitochondrial

776:

NADH dehydrogenase iron-sulfur protein 8, mitochondrial

740:

NADH dehydrogenase iron-sulfur protein 7, mitochondrial

5237:

Esterházy D, King MS, Yakovlev G, Hirst J (March 2008).

3877:"Quinone binding and reduction by respiratory complex I" 3680:"Bovine complex I is a complex of 45 different subunits" 3653:(3rd ed.). New York: J. Wiley & Sons. pp. 2542:– NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 13 2536:– NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 12 2045:

NADH dehydrogenase 1 alpha subcomplex assembly factor 3

1283:

NADH dehydrogenase iron-sulfur protein 4, mitochondrial

1235:

NADH dehydrogenase iron-sulfur protein 6, mitochondrial

7551: 2750:- mitochondrially encoded NADH dehydrogenase subunit 4L 2715:– NADH dehydrogenase (ubiquinone) flavoprotein 3, 10kDa 2709:– NADH dehydrogenase (ubiquinone) flavoprotein 2, 24kDa 2703:– NADH dehydrogenase (ubiquinone) flavoprotein 1, 51kDa 1931:

NADH dehydrogenase 1 alpha subcomplex subunit 4-like 2

5612:

Andreazza AC, Shao L, Wang JF, Young LT (April 2010).

5380:"Mechanisms of rotenone-induced proteasome inhibition" 4092:

Ogilvie I, Kennaway NG, Shoubridge EA (October 2005).

2916:

Galkin AS, Grivennikova VG, Vinogradov AD (May 1999).

2762:- mitochondrially encoded NADH dehydrogenase subunit 6 2756:- mitochondrially encoded NADH dehydrogenase subunit 5 2744:- mitochondrially encoded NADH dehydrogenase subunit 4 2738:- mitochondrially encoded NADH dehydrogenase subunit 3 2732:- mitochondrially encoded NADH dehydrogenase subunit 2 2726:- mitochondrially encoded NADH dehydrogenase subunit 1 2627:

NADH dehydrogenase (ubiquinone) 1, subcomplex unknown

7526: 4676:

Babot M, Birch A, Labarbuta P, Galkin A (July 2014).

3308: 3306: 648:(FeS). Of the 44 subunits, seven are encoded by the 7422: 7386: 7355: 7324: 7273: 7092: 7067: 7037: 7017: 6967: 6958: 6912: 6875: 6843: 6811: 6759: 6750: 6706: 6674: 6647: 6625: 6588: 6579: 6556: 6528: 6505: 6478: 6469: 6402: 6376: 6302: 6193: 6177: 6149: 6130: 6111: 6066: 6057: 5998: 4731: