Jump to content

Respiratory complex I

From Wikipedia, the free encyclopedia
(Redirected from Mitochondrial complex 1)
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.

Respiratory complex I, EC 7.1.1.2 (also known as NADH:ubiquinone oxidoreductase, Type I NADH dehydrogenase and mitochondrial complex I) is the first large protein complex of the respiratory chains of many organisms from bacteria to humans. It catalyzes the transfer of electrons from NADH to coenzyme Q10 (CoQ10) and translocates protons across the inner mitochondrial membrane in eukaryotes or the plasma membrane of bacteria.

Respiratory complex I
Identifiers
SymbolRespiratory complex I
OPM superfamily246
OPM protein6g72
Membranome255
Identifiers
EC no.7.1.1.2
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Search
PMCarticles
PubMedarticles
NCBIproteins

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 ischemia/reperfusion damage (stroke and cardiac infarction), Parkinson's disease and others.[citation needed]

Function

[edit]
NAD+ to NADH.
FMN to FMNH2.
CoQ to CoQH2.

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).[1] Complex I is the largest and most complicated enzyme of the electron transport chain.[2]

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,[3][4][5] 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+.[6] 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.[6] 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.[7]

Complex I may have a role in triggering apoptosis.[8] In fact, there has been shown to be a correlation between mitochondrial activities and programmed cell death (PCD) during somatic embryo development.[9]

Complex I is not homologous to Na+-translocating NADH Dehydrogenase (NDH) Family (TC# 3.D.1), a member of the Na+ transporting Mrp superfamily.

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

Mechanism

[edit]

Overall mechanism

[edit]

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,[10] 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).[1]

Electron transfer mechanism

[edit]

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.[10] 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).[12][13]

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.[14]

Proton translocation mechanism

[edit]

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).[10] 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.[15]

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.[16] 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).[14][17] 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.[18][19]

The resulting ubiquinol localized to the membrane domain interacts with negatively charged residues in the membrane arm, stabilizing conformational changes.[10] An antiporter mechanism (Na+/H+ swap) has been proposed using evidence of conserved Asp residues in the membrane arm.[20] 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.[10]

Composition and structure

[edit]

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.[21][22][23]

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.[24] 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.[25]

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.[26] All 45 subunits of the bovine NDHI have been sequenced.[27][28] Each complex contains noncovalently bound FMN, coenzyme Q and several iron-sulfur centers. The bacterial NDHs have 8-9 iron-sulfur centers.

A recent study used electron paramagnetic resonance (EPR) spectra and double electron-electron resonance (DEER) to determine the path of electron transfer through the iron-sulfur complexes, which are located in the hydrophilic domain. Seven of these clusters form a chain from the flavin to the quinone binding sites; the eighth cluster is located on the other side of the flavin, and its function is unknown. The EPR and DEER results suggest an alternating or “roller-coaster” potential energy profile for the electron transfer between the active sites and along the iron-sulfur clusters, which can optimize the rate of electron travel and allow efficient energy conversion in complex I.[29]

Conserved subunits of Complex I[30]
# 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,d 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[31]
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

Notes:

  • 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
  • d Recent research has described NDUFA4 to be a subunit of complex IV, and not of complex I[34]

Inhibitors

[edit]

Inhibition of complex I is the mode of action of the METI acaricides and insecticides: fenazaquin, fenpyroximate, pyrimidifen, pyridaben, tebufenpyrad, and tolfenpyrad.[35][36][37] They are assigned to IRAC group 21A. Perhaps the best-known inhibitor of complex I is rotenone, which is used as a piscicide and previously commonly used as an organic pesticide, but now banned in many countries. It is in IRAC group 21B. Rotenone and 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.[39] Rolliniastatin-2, an acetogenin, is the first complex I inhibitor found that does not share the same binding site as rotenone.[40] 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).[41]

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.[42]

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.[43] 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.[44]

Inhibition of complex I has been implicated in hepatotoxicity associated with a variety of drugs, for instance flutamide and nefazodone.[45] Further, complex I inhibition was shown to trigger NAD+-independent glucose catabolism.[46]

Active/inactive transition

[edit]

The catalytic properties of eukaryotic complex I are not simple. Two catalytically and structurally distinct forms exist in any given preparation of the enzyme: one is the fully competent, so-called “active” A-form and the other is the catalytically silent, dormant, “inactive”, D-form. After exposure of idle enzyme to elevated, but physiological temperatures (>30 °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 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.[47][48]

It was found that these conformational changes may have a very important physiological significance. The inactive, but not the active form of complex I was susceptible to inhibition by nitrosothiols and peroxynitrite.[49] 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, ischemia [50][51] or when the tissue nitric oxide:oxygen ratio increases (i.e. metabolic hypoxia).[52]

Production of superoxide

[edit]

Recent investigations suggest that complex I is a potent source of reactive oxygen species.[53] 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).[53][54][55]

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.[56] Reverse electron transfer, the process by which electrons from the reduced ubiquinol pool (supplied by succinate dehydrogenase, glycerol-3-phosphate dehydrogenase, electron-transferring flavoprotein or dihydroorotate dehydrogenase in mammalian mitochondria) pass through complex I to reduce NAD+ to NADH, driven by the inner mitochondrial membrane potential electric potential. Although it is not precisely known under what pathological conditions reverse-electron transfer would occur in vivo, in vitro experiments indicate that this process can be a very potent source of superoxide when succinate concentrations are high and oxaloacetate or malate concentrations are low.[57] This can take place during tissue ischaemia, when oxygen delivery is blocked.[58]

Superoxide is a reactive oxygen species that contributes to cellular oxidative stress and is linked to neuromuscular diseases and aging.[59] NADH dehydrogenase produces superoxide by transferring one electron from FMNH2 (or semireduced flavin) to oxygen (O2). 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.[60][61]

Pathology

[edit]

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.[62] 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.[63]

Brain ischemia/reperfusion injury is mediated via complex I impairment.[64] 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.[65][66] When oxygen is present the enzyme catalyzes a physiological reaction of NADH oxidation by ubiquinone, supplying electrons downstream of the respiratory chain (complexes III and IV). Ischemia leads to dramatic increase of succinate level. In the presence of succinate mitochondria catalyze reverse electron transfer so that fraction of electrons from succinate is directed upstream to FMN of complex I. Reverse electron transfer results in a reduction of complex I FMN,[56] increased generation of ROS, followed by a loss of the reduced cofactor (FMNH2) 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.[66]

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.[67] 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.[68]

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.[69]

In chloroplasts

[edit]

A proton-pumping, ubiquinone-using NADH dehydrogenase complex, homologous to complex I, is found in the chloroplast genomes of most land plants under the name ndh. This complex is inherited from the original symbiosis from cyanobacteria, but has been lost in most eukaryotic algae, some gymnosperms (Pinus and gnetophytes), and some very young lineages of angiosperms. The purpose of this complex is originally cryptic as chloroplasts do not participate in respiration, but now it is known that ndh serves to maintain photosynthesis in stressful situations. This makes it at least partially dispensable in favorable conditions. It is evident that angiosperm lineages without ndh do not last long from their young ages, but how gymnosperms survive on land without ndh for so long is unknown.[70]

Genes

[edit]

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

  • NADH dehydrogenase (ubiquinone) 1 alpha subcomplex
    • NDUFA1 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 1, 7.5kDa
    • NDUFA2 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 2, 8kDa
    • NDUFA3 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 3, 9kDa
    • NDUFA4 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 4, 9kDa - recently described to be part of complex IV[34]
    • NDUFA4L – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 4-like
    • NDUFA4L2 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 4-like 2
    • NDUFA5 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 5, 13kDa
    • NDUFA6 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 6, 14kDa
    • NDUFA7 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 7, 14.5kDa
    • NDUFA8 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 8, 19kDa
    • NDUFA9 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 9, 39kDa
    • NDUFA10 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 10, 42kDa
    • NDUFA11 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 11, 14.7kDa
    • NDUFA12 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 12
    • NDUFA13 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 13
    • NDUFAB1 – NADH dehydrogenase (ubiquinone) 1, alpha/beta subcomplex, 1, 8kDa
    • NDUFAF1 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, assembly factor 1
    • NDUFAF2 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, assembly factor 2
    • NDUFAF3 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, assembly factor 3
    • NDUFAF4 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, assembly factor 4
  • NADH dehydrogenase (ubiquinone) 1 beta subcomplex
    • NDUFB1 – NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 1, 7kDa
    • NDUFB2 – NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 2, 8kDa
    • NDUFB3 – NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 3, 12kDa
    • NDUFB4 – NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 4, 15kDa
    • NDUFB5 – NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 5, 16kDa
    • NDUFB6 – NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 6, 17kDa
    • NDUFB7 – NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 7, 18kDa
    • NDUFB8 – NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 8, 19kDa
    • NDUFB9 – NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 9, 22kDa
    • NDUFB10 – NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 10, 22kDa
    • NDUFB11 – NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 11, 17.3kDa
  • NADH dehydrogenase (ubiquinone) 1, subcomplex unknown
    • NDUFC1 – NADH dehydrogenase (ubiquinone) 1, subcomplex unknown, 1, 6kDa
    • NDUFC2 – NADH dehydrogenase (ubiquinone) 1, subcomplex unknown, 2, 14.5kDa
  • NADH dehydrogenase (ubiquinone) Fe-S protein
    • NDUFS1 – NADH dehydrogenase (ubiquinone) Fe-S protein 1, 75kDa (NADH-coenzyme Q reductase)
    • NDUFS2 – NADH dehydrogenase (ubiquinone) Fe-S protein 2, 49kDa (NADH-coenzyme Q reductase)
    • NDUFS3 – NADH dehydrogenase (ubiquinone) Fe-S protein 3, 30kDa (NADH-coenzyme Q reductase)
    • NDUFS4 – NADH dehydrogenase (ubiquinone) Fe-S protein 4, 18kDa (NADH-coenzyme Q reductase)
    • NDUFS5 – NADH dehydrogenase (ubiquinone) Fe-S protein 5, 15kDa (NADH-coenzyme Q reductase)
    • NDUFS6 – NADH dehydrogenase (ubiquinone) Fe-S protein 6, 13kDa (NADH-coenzyme Q reductase)
    • NDUFS7 – NADH dehydrogenase (ubiquinone) Fe-S protein 7, 20kDa (NADH-coenzyme Q reductase)
    • NDUFS8 – NADH dehydrogenase (ubiquinone) Fe-S protein 8, 23kDa (NADH-coenzyme Q reductase)
  • NADH dehydrogenase (ubiquinone) flavoprotein 1
    • NDUFV1 – NADH dehydrogenase (ubiquinone) flavoprotein 1, 51kDa
    • NDUFV2 – NADH dehydrogenase (ubiquinone) flavoprotein 2, 24kDa
    • NDUFV3 – NADH dehydrogenase (ubiquinone) flavoprotein 3, 10kDa
  • mitochondrially encoded NADH dehydrogenase subunit
    • MT-ND1 - mitochondrially encoded NADH dehydrogenase subunit 1
    • MT-ND2 - mitochondrially encoded NADH dehydrogenase subunit 2
    • MT-ND3 - mitochondrially encoded NADH dehydrogenase subunit 3
    • MT-ND4 - mitochondrially encoded NADH dehydrogenase subunit 4
    • MT-ND4L - mitochondrially encoded NADH dehydrogenase subunit 4L
    • MT-ND5 - mitochondrially encoded NADH dehydrogenase subunit 5
    • MT-ND6 - mitochondrially encoded NADH dehydrogenase subunit 6

References

[edit]
  1. ^ a b Berg J, Tymoczko J, Stryer L (2006). Biochemistry (6th ed.). New York: WH Freeman & Company. pp. 509–513.
  2. ^ 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.
  3. ^ Wikström M (April 1984). "Two protons are pumped from the mitochondrial matrix per electron transferred between NADH and ubiquinone". FEBS Letters. 169 (2): 300–4. doi:10.1016/0014-5793(84)80338-5. PMID 6325245.
  4. ^ Galkin A, Dröse S, Brandt U (December 2006). "The proton pumping stoichiometry of purified mitochondrial complex I reconstituted into proteoliposomes". Biochimica et Biophysica Acta (BBA) - Bioenergetics. 1757 (12): 1575–81. doi:10.1016/j.bbabio.2006.10.001. PMID 17094937.
  5. ^ Galkin AS, Grivennikova VG, Vinogradov AD (May 1999). "-->H+/2e- stoichiometry in NADH-quinone reductase reactions catalyzed by bovine heart submitochondrial particles". FEBS Letters. 451 (2): 157–61. doi:10.1016/s0014-5793(99)00575-x. PMID 10371157. S2CID 2337382.
  6. ^ a b Batista AP, Pereira MM (March 2011). "Sodium influence on energy transduction by complexes I from Escherichia coli and Paracoccus denitrificans". Biochimica et Biophysica Acta (BBA) - Bioenergetics. 1807 (3): 286–92. doi:10.1016/j.bbabio.2010.12.008. PMID 21172303.
  7. ^ Grivennikova VG, Kotlyar AB, Karliner JS, Cecchini G, Vinogradov AD (September 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.
  8. ^ Chomova M, Racay P (March 2010). "Mitochondrial complex I in the network of known and unknown facts". General Physiology and Biophysics. 29 (1): 3–11. doi:10.4149/gpb_2010_01_3. PMID 20371875.
  9. ^ 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". Planta. 231 (1): 93–107. doi:10.1007/s00425-009-1028-x. PMID 19834734. S2CID 25828432.
  10. ^ a b c d e Sazanov LA (June 2015). "A giant molecular proton pump: structure and mechanism of respiratory complex I". Nature Reviews. Molecular Cell Biology. 16 (6): 375–88. doi:10.1038/nrm3997. PMID 25991374. S2CID 31633494.
  11. ^ Voet DJ, Voet GJ, Pratt CW (2008). "Chapter 18, Mitochondrial ATP synthesis". Principles of Biochemistry, 3rd Edition. Wiley. p. 608. ISBN 978-0-470-23396-2.
  12. ^ Ohnishi T (May 1998). "Iron-sulfur clusters/semiquinones in complex I". Biochimica et Biophysica Acta (BBA) - Bioenergetics. 1364 (2): 186–206. doi:10.1016/s0005-2728(98)00027-9. PMID 9593887.
  13. ^ Bridges HR, Bill E, Hirst J (January 2012). "Mössbauer spectroscopy on respiratory complex I: the iron-sulfur cluster ensemble in the NADH-reduced enzyme is partially oxidized". Biochemistry. 51 (1): 149–58. doi:10.1021/bi201644x. PMC 3254188. PMID 22122402.
  14. ^ a b Efremov RG, Sazanov LA (October 2012). "The coupling mechanism of respiratory complex I - a structural and evolutionary perspective". Biochimica et Biophysica Acta (BBA) - Bioenergetics. 1817 (10): 1785–95. doi:10.1016/j.bbabio.2012.02.015. PMID 22386882.
  15. ^ Treberg JR, Quinlan CL, Brand MD (August 2011). "Evidence for two sites of superoxide production by mitochondrial NADH-ubiquinone oxidoreductase (complex I)". The Journal of Biological Chemistry. 286 (31): 27103–10. doi:10.1074/jbc.M111.252502. PMC 3149303. PMID 21659507.
  16. ^ Berrisford JM, Sazanov LA (October 2009). "Structural basis for the mechanism of respiratory complex I". The Journal of Biological Chemistry. 284 (43): 29773–83. doi:10.1074/jbc.m109.032144. PMC 2785608. PMID 19635800.
  17. ^ Baranova EA, Morgan DJ, Sazanov LA (August 2007). "Single particle analysis confirms distal location of subunits NuoL and NuoM in Escherichia coli complex I". Journal of Structural Biology. 159 (2): 238–42. doi:10.1016/j.jsb.2007.01.009. PMID 17360196.
  18. ^ Brandt U (October 2011). "A two-state stabilization-change mechanism for proton-pumping complex I". Biochimica et Biophysica Acta (BBA) - Bioenergetics. 1807 (10): 1364–9. doi:10.1016/j.bbabio.2011.04.006. PMID 21565159.
  19. ^ Zickermann V, Wirth C, Nasiri H, Siegmund K, Schwalbe H, Hunte C, Brandt U (January 2015). "Structural biology. Mechanistic insight from the crystal structure of mitochondrial complex I" (PDF). Science. 347 (6217): 44–9. doi:10.1126/science.1259859. PMID 25554780. S2CID 23582849.
  20. ^ 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". Nature. 435 (7046): 1197–202. Bibcode:2005Natur.435.1197H. doi:10.1038/nature03692. PMID 15988517. S2CID 4372674.
  21. ^ Voet JG, Voet D (2004). Biochemistry (3rd ed.). New York: J. Wiley & Sons. pp. 813–826. ISBN 0-471-19350-X.
  22. ^ Carroll J, Fearnley IM, Skehel JM, Shannon RJ, Hirst J, Walker JE (October 2006). "Bovine complex I is a complex of 45 different subunits". The Journal of Biological Chemistry. 281 (43): 32724–7. doi:10.1074/jbc.M607135200. PMID 16950771.
  23. ^ 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 Metabolism. 16 (3): 378–86. doi:10.1016/j.cmet.2012.07.015. PMID 22902835.
  24. ^ Sazanov LA, Hinchliffe P (March 2006). "Structure of the hydrophilic domain of respiratory complex I from Thermus thermophilus". Science. 311 (5766): 1430–6. Bibcode:2006Sci...311.1430S. doi:10.1126/science.1123809. PMID 16469879. S2CID 1892332.
  25. ^ Efremov RG, Baradaran R, Sazanov LA (May 2010). "The architecture of respiratory complex I". Nature. 465 (7297): 441–5. Bibcode:2010Natur.465..441E. doi:10.1038/nature09066. PMID 20505720. S2CID 4372778.
  26. ^ Tocilescu MA, Zickermann V, Zwicker K, Brandt U (December 2010). "Quinone binding and reduction by respiratory complex I". Biochimica et Biophysica Acta (BBA) - Bioenergetics. 1797 (12): 1883–90. doi:10.1016/j.bbabio.2010.05.009. PMID 20493164.
  27. ^ Cardol P, Vanrobaeys F, Devreese B, Van Beeumen J, Matagne RF, Remacle C (October 2004). "Higher plant-like subunit composition of mitochondrial complex I from Chlamydomonas reinhardtii: 31 conserved components among eukaryotes". Biochimica et Biophysica Acta (BBA) - Bioenergetics. 1658 (3): 212–24. doi:10.1016/j.bbabio.2004.06.001. PMID 15450959.
  28. ^ Gabaldón T, Rainey D, Huynen MA (May 2005). "Tracing the evolution of a large protein complex in the eukaryotes, NADH:ubiquinone oxidoreductase (Complex I)". Journal of Molecular Biology. 348 (4): 857–70. doi:10.1016/j.jmb.2005.02.067. PMID 15843018.
  29. ^ 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. Bibcode:2010PNAS..107.1930R. doi:10.1073/pnas.0908050107. PMC 2808219. PMID 20133838.
  30. ^ Cardol P (November 2011). "Mitochondrial NADH:ubiquinone oxidoreductase (complex I) in eukaryotes: a highly conserved subunit composition highlighted by mining of protein databases". Biochimica et Biophysica Acta (BBA) - Bioenergetics. 1807 (11): 1390–7. doi:10.1016/j.bbabio.2011.06.015. PMID 21749854.
  31. ^ Ogilvie I, Kennaway NG, Shoubridge EA (October 2005). "A molecular chaperone for mitochondrial complex I assembly is mutated in a progressive encephalopathy". The Journal of Clinical Investigation. 115 (10): 2784–92. doi:10.1172/JCI26020. PMC 1236688. PMID 16200211.
  32. ^ Dunning CJ, McKenzie M, Sugiana C, Lazarou M, Silke J, Connelly A, Fletcher JM, Kirby DM, Thorburn DR, Ryan MT (July 2007). "Human CIA30 is involved in the early assembly of mitochondrial complex I and mutations in its gene cause disease". The EMBO Journal. 26 (13): 3227–37. doi:10.1038/sj.emboj.7601748. PMC 1914096. PMID 17557076.
  33. ^ 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). "Mutations in NDUFAF3 (C3ORF60), encoding an NDUFAF4 (C6ORF66)-interacting complex I assembly protein, cause fatal neonatal mitochondrial disease". American Journal of Human Genetics. 84 (6): 718–27. doi:10.1016/j.ajhg.2009.04.020. PMC 2694978. PMID 19463981.
  34. ^ a b Balsa, Eduardo; Marco, Ricardo; Perales-Clemente, Ester; Szklarczyk, Radek; Calvo, Enrique; Landázuri, Manuel O.; Enríquez, José Antonio (2012-09-05). "NDUFA4 is a subunit of complex IV of the mammalian electron transport chain". Cell Metabolism. 16 (3): 378–386. doi:10.1016/j.cmet.2012.07.015. ISSN 1932-7420. PMID 22902835.
  35. ^ Jeschke, Peter; Witschel, Matthias; Krämer, Wolfgang; Schirmer, Ulrich (25 January 2019). "32.3 Inhibitors of Mitochondrial Electron Transport: Acaricides and Insecticides". Modern Crop Protection Compounds (3rd ed.). Wiley‐VCH. pp. 1156–1201. ISBN 9783527699261.{{cite book}}: CS1 maint: date and year (link)
  36. ^ Bajda, Sabina; Dermauw, Wannes; Panteleri, Rafaela; Sugimoto, Naoya (January 2017). "A mutation in the PSST homologue of complex I (NADH:ubiquinone oxidoreductase) from Tetranychus urticae is associated with resistance to METI acaricides". Insect Biochemistry and Molecular Biology. 80: 79–90. ISSN 0965-1748.
  37. ^ De Rouck, Sander; İnak, Emre; Dermauw, Wannes; Van Leeuwen, Thomas (August 2023). "A review of the molecular mechanisms of acaricide resistance in mites and ticks". Insect Biochemistry and Molecular Biology. 159: 103981. ISSN 0965-1748.
  38. ^ Moretti C, Grenand P (September 1982). "[The "nivrées", or ichthyotoxic plants of French Guyana]". Journal of Ethnopharmacology (in French). 6 (2): 139–60. doi:10.1016/0378-8741(82)90002-2. PMID 7132401.
  39. ^ Nakamaru-Ogiso E, Han H, Matsuno-Yagi A, Keinan E, Sinha SC, Yagi T, Ohnishi T (March 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.
  40. ^ Degli Esposti M, Ghelli A, Ratta M, Cortes D, Estornell E (July 1994). "Natural substances (acetogenins) from the family Annonaceae are powerful inhibitors of mitochondrial NADH dehydrogenase (Complex I)". The Biochemical Journal. 301 ( Pt 1) (Pt 1): 161–7. doi:10.1042/bj3010161. PMC 1137156. PMID 8037664.
  41. ^ Miyoshi H, Ohshima M, Shimada H, Akagi T, Iwamura H, McLaughlin JL (July 1998). "Essential structural factors of annonaceous acetogenins as potent inhibitors of mitochondrial complex I". Biochimica et Biophysica Acta (BBA) - Bioenergetics. 1365 (3): 443–52. doi:10.1016/s0005-2728(98)00097-8. PMID 9711297.
  42. ^ 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". Molecular Pharmacology. 74 (4): 933–40. doi:10.1124/mol.108.048546. PMID 18599602. S2CID 1844073.
  43. ^ Zharova TV, Vinogradov AD (July 1997). "A competitive inhibition of the mitochondrial NADH-ubiquinone oxidoreductase (complex I) by ADP-ribose". Biochimica et Biophysica Acta (BBA) - Bioenergetics. 1320 (3): 256–64. doi:10.1016/S0005-2728(97)00029-7. PMID 9230920.
  44. ^ Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F (March 2012). "Cellular and molecular mechanisms of metformin: an overview". Clinical Science. 122 (6): 253–70. doi:10.1042/CS20110386. PMC 3398862. PMID 22117616.
  45. ^ Nadanaciva S, Will Y (2011). "New insights in drug-induced mitochondrial toxicity". Current Pharmaceutical Design. 17 (20): 2100–12. doi:10.2174/138161211796904795. PMID 21718246.
  46. ^ Abrosimov, Roman; Baeken, Marius W.; Hauf, Samuel; Wittig, Ilka; Hajieva, Parvana; Perrone, Carmen E.; Moosmann, Bernd (2024-01-25). "Mitochondrial complex I inhibition triggers NAD+-independent glucose oxidation via successive NADPH formation, "futile" fatty acid cycling, and FADH2 oxidation". GeroScience. doi:10.1007/s11357-023-01059-y. ISSN 2509-2723. PMC 11226580.
  47. ^ Babot M, Birch A, Labarbuta P, Galkin A (July 2014). "Characterisation of the active/de-active transition of mitochondrial complex I". Biochimica et Biophysica Acta (BBA) - Bioenergetics. 1837 (7): 1083–92. doi:10.1016/j.bbabio.2014.02.018. PMC 4331042. PMID 24569053.
  48. ^ Dröse S, Stepanova A, Galkin A (July 2016). "Ischemic A/D transition of mitochondrial complex I and its role in ROS generation". Biochimica et Biophysica Acta (BBA) - Bioenergetics. 1857 (7): 946–57. doi:10.1016/j.bbabio.2015.12.013. PMC 4893024. PMID 26777588.
  49. ^ Galkin A, Moncada S (December 2007). "S-nitrosation of mitochondrial complex I depends on its structural conformation". The Journal of Biological Chemistry. 282 (52): 37448–53. doi:10.1074/jbc.M707543200. PMID 17956863.
  50. ^ Kim M, Stepanova A, Niatsetskaya Z, Sosunov S, Arndt S, Murphy MP, et al. (August 2018). "Attenuation of oxidative damage by targeting mitochondrial complex I in neonatal hypoxic-ischemic brain injury". Free Radical Biology & Medicine. 124: 517–524. doi:10.1016/j.freeradbiomed.2018.06.040. PMC 6389362. PMID 30037775.
  51. ^ Stepanova A, Konrad C, Guerrero-Castillo S, Manfredi G, Vannucci S, Arnold S, Galkin A (September 2019). "Deactivation of mitochondrial complex I after hypoxia-ischemia in the immature brain". Journal of Cerebral Blood Flow and Metabolism. 39 (9): 1790–1802. doi:10.1177/0271678X18770331. PMC 6727140. PMID 29629602.
  52. ^ Moncada S, Erusalimsky JD (March 2002). "Does nitric oxide modulate mitochondrial energy generation and apoptosis?". Nature Reviews. Molecular Cell Biology. 3 (3): 214–20. doi:10.1038/nrm762. PMID 11994742. S2CID 29513174.
  53. ^ a b Murphy MP (January 2009). "How mitochondria produce reactive oxygen species". The Biochemical Journal. 417 (1): 1–13. doi:10.1042/BJ20081386. PMC 2605959. PMID 19061483.
  54. ^ Hansford RG, Hogue BA, Mildaziene V (February 1997). "Dependence of H2O2 formation by rat heart mitochondria on substrate availability and donor age". Journal of Bioenergetics and Biomembranes. 29 (1): 89–95. doi:10.1023/A:1022420007908. PMID 9067806. S2CID 7501110.
  55. ^ Stepanova A, Konrad C, Manfredi G, Springett R, Ten V, Galkin A (March 2019). "The dependence of brain mitochondria reactive oxygen species production on oxygen level is linear, except when inhibited by antimycin A". Journal of Neurochemistry. 148 (6): 731–745. doi:10.1111/jnc.14654. PMC 7086484. PMID 30582748.
  56. ^ a b Stepanova A, Kahl A, Konrad C, Ten V, Starkov AS, Galkin A (December 2017). "Reverse electron transfer results in a loss of flavin from mitochondrial complex I: Potential mechanism for brain ischemia reperfusion injury". Journal of Cerebral Blood Flow and Metabolism. 37 (12): 3649–3658. doi:10.1177/0271678X17730242. PMC 5718331. PMID 28914132.
  57. ^ 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". The Biochemical Journal. 409 (2): 491–9. doi:10.1042/BJ20071162. PMID 17916065.
  58. ^ Sahni PV, Zhang J, Sosunov S, Galkin A, Niatsetskaya Z, Starkov A, et al. (February 2018). "Krebs cycle metabolites and preferential succinate oxidation following neonatal hypoxic-ischemic brain injury in mice". Pediatric Research. 83 (2): 491–497. doi:10.1038/pr.2017.277. PMC 5866163. PMID 29211056.
  59. ^ Esterházy D, King MS, Yakovlev G, Hirst J (March 2008). "Production of reactive oxygen species by complex I (NADH:ubiquinone oxidoreductase) from Escherichia coli and comparison to the enzyme from mitochondria". Biochemistry. 47 (12): 3964–71. doi:10.1021/bi702243b. PMID 18307315.
  60. ^ Kussmaul L, Hirst J (May 2006). "The mechanism of superoxide production by NADH:ubiquinone oxidoreductase (complex I) from bovine heart mitochondria". Proceedings of the National Academy of Sciences of the United States of America. 103 (20): 7607–12. Bibcode:2006PNAS..103.7607K. doi:10.1073/pnas.0510977103. PMC 1472492. PMID 16682634.
  61. ^ Galkin A, Brandt U (August 2005). "Superoxide radical formation by pure complex I (NADH:ubiquinone oxidoreductase) from Yarrowia lipolytica". The Journal of Biological Chemistry. 280 (34): 30129–35. doi:10.1074/jbc.M504709200. PMID 15985426.
  62. ^ Chou AP, Li S, Fitzmaurice AG, Bronstein JM (August 2010). "Mechanisms of rotenone-induced proteasome inhibition". Neurotoxicology. 31 (4): 367–72. doi:10.1016/j.neuro.2010.04.006. PMC 2885979. PMID 20417232.
  63. ^ Esteves AR, Lu J, Rodova M, Onyango I, Lezi E, Dubinsky R, Lyons KE, Pahwa R, Burns JM, Cardoso SM, Swerdlow RH (May 2010). "Mitochondrial respiration and respiration-associated proteins in cell lines created through Parkinson's subject mitochondrial transfer". Journal of Neurochemistry. 113 (3): 674–82. doi:10.1111/j.1471-4159.2010.06631.x. PMID 20132468.
  64. ^ Galkin A (November 2019). "Brain Ischemia/Reperfusion Injury and Mitochondrial Complex I Damage". Biochemistry. Biokhimiia. 84 (11): 1411–1423. doi:10.1134/S0006297919110154. PMID 31760927. S2CID 207990089.
  65. ^ Kahl A, Stepanova A, Konrad C, Anderson C, Manfredi G, Zhou P, et al. (May 2018). "Critical Role of Flavin and Glutathione in Complex I-Mediated Bioenergetic Failure in Brain Ischemia/Reperfusion Injury". Stroke. 49 (5): 1223–1231. doi:10.1161/STROKEAHA.117.019687. PMC 5916474. PMID 29643256.
  66. ^ a b Stepanova A, Sosunov S, Niatsetskaya Z, Konrad C, Starkov AA, Manfredi G, et al. (September 2019). "Redox-Dependent Loss of Flavin by Mitochondrial Complex I in Brain Ischemia/Reperfusion Injury". Antioxidants & Redox Signaling. 31 (9): 608–622. doi:10.1089/ars.2018.7693. PMC 6657304. PMID 31037949.
  67. ^ Andreazza AC, Shao L, Wang JF, Young LT (April 2010). "Mitochondrial complex I activity and oxidative damage to mitochondrial proteins in the prefrontal cortex of patients with bipolar disorder". Archives of General Psychiatry. 67 (4): 360–8. doi:10.1001/archgenpsychiatry.2010.22. PMID 20368511.
  68. ^ Morán M, Rivera H, Sánchez-Aragó M, Blázquez A, Merinero B, Ugalde C, Arenas J, Cuezva JM, Martín MA (May 2010). "Mitochondrial bioenergetics and dynamics interplay in complex I-deficient fibroblasts". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1802 (5): 443–53. doi:10.1016/j.bbadis.2010.02.001. PMID 20153825.
  69. ^ Binukumar BK, Bal A, Kandimalla R, Sunkaria A, Gill KD (April 2010). "Mitochondrial energy metabolism impairment and liver dysfunction following chronic exposure to dichlorvos". Toxicology. 270 (2–3): 77–84. doi:10.1016/j.tox.2010.01.017. PMID 20132858.
  70. ^ Sabater, B (19 November 2021). "On the Edge of Dispensability, the Chloroplast ndh Genes". International Journal of Molecular Sciences. 22 (22): 12505. doi:10.3390/ijms222212505. PMC 8621559. PMID 34830386.
[edit]

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.

Retrieved from "https://en.wikipedia.org/w/index.php?title=Respiratory_complex_I&oldid=1263280765"