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Respiratory complex I, (also known as NADH:ubiquinone oxidoreductase, Type I NADH dehydrogenase and mitochondrial complex I) is the first large
protein complex
A protein complex or multiprotein complex is a group of two or more associated polypeptide chains. Protein complexes are distinct from multienzyme complexes, in which multiple catalytic domains are found in a single polypeptide chain.
Protein c ...
of the
respiratory chain
An electron transport chain (ETC) is a series of protein complexes and other molecules that transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples th ...
s of many organisms from bacteria to humans. It catalyzes the transfer of
electron
The electron ( or ) is a subatomic particle with a negative one elementary electric charge. Electrons belong to the first generation of the lepton particle family,
and are generally thought to be elementary particles because they have no kn ...
s from
NADH
Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an aden ...
to
coenzyme Q10
Coenzyme Q, also known as ubiquinone and marketed as CoQ10, is a coenzyme family that is ubiquitous in animals and most bacteria (hence the name ubiquinone). In humans, the most common form is coenzyme Q10 or ubiquinone-10.
It is a 1,4-benzoq ...
(CoQ10) and translocates protons across the inner
mitochondria
A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...
l membrane in eukaryotes or the plasma membrane of bacteria.
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
A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functionin ...
and
cardiac infarction
A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may tra ...
), Parkinson's disease and others.
Function
Complex I is the first enzyme of the
mitochondrial electron transport chain
An electron transport chain (ETC) is a series of protein complexes and other molecules that transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples thi ...
. There are three energy-transducing enzymes in the electron transport chain - NADH:ubiquinone oxidoreductase (complex I),
Coenzyme Q – cytochrome c reductase
The coenzyme Q : cytochrome ''c'' – oxidoreductase, sometimes called the cytochrome ''bc''1 complex, and at other times complex III, is the third complex in the electron transport chain (), playing a critical role in biochemical generation ...
(complex III), and
cytochrome c oxidase
The enzyme cytochrome c oxidase or Complex IV, (was , now reclassified as a translocasEC 7.1.1.9 is a large transmembrane protein complex found in bacteria, archaea, and mitochondria of eukaryotes.
It is the last enzyme in the respiratory electr ...
(complex IV).
Complex I is the largest and most complicated enzyme of the electron transport chain.
The reaction catalyzed by complex I is:
:NADH + H
+ + CoQ + 4H
+in→ NAD
+ + CoQH
2 + 4H
+out
In this process, the complex translocates four
protons
A proton is a stable subatomic particle, symbol , H+, or 1H+ with a positive electric charge of +1 ''e'' elementary charge. Its mass is slightly less than that of a neutron and 1,836 times the mass of an electron (the proton–electron mass ...
across the inner membrane per molecule of oxidized
NADH
Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an aden ...
,
helping to build the
electrochemical potential
In electrochemistry, the electrochemical potential (ECP), ', is a thermodynamic measure of chemical potential that does not omit the energy contribution of electrostatics. Electrochemical potential is expressed in the unit of J/ mol.
Introductio ...
difference used to produce
ATP. ''
Escherichia coli
''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escher ...
'' 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
+.
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
''Paracoccus denitrificans'', is a coccoid bacterium known for its nitrate reducing properties, its ability to replicate under conditions of hypergravity and for being a relative of the eukaryotic mitochondrion (endosymbiotic theory).
Descripti ...
'' 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
''Rhodothermus marinus'' is a species of bacteria. It is obligately aerobic, moderately halophilic, thermophilic, Gram-negative
Gram-negative bacteria are bacteria that do not retain the crystal violet stain used in the Gram staining method o ...
'' 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.
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.
Complex I may have a role in triggering
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
.
In fact, there has been shown to be a correlation between mitochondrial activities and
programmed cell death
Programmed cell death (PCD; sometimes referred to as cellular suicide) is the death of a cell as a result of events inside of a cell, such as apoptosis or autophagy. PCD is carried out in a biological process, which usually confers advantage durin ...
(PCD) during somatic embryo development.
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
ATP synthase is a protein that catalyzes the formation of the energy storage molecule adenosine triphosphate (ATP) using adenosine diphosphate (ADP) and inorganic phosphate (Pi). It is classified under ligases as it changes ADP by the formation ...
) downstream in the respiratory chain.
Mechanism
Overall mechanism
All redox reactions take place in the hydrophilic domain of complex I. NADH initially binds to complex I, and transfers two electrons to the
flavin mononucleotide
Flavin mononucleotide (FMN), or riboflavin-5′-phosphate, is a biomolecule produced from riboflavin (vitamin B2) by the enzyme riboflavin kinase and functions as the prosthetic group of various oxidoreductases, including NADH dehydrogenase, as ...
(FMN) prosthetic group of the enzyme, creating FMNH
2. The electron acceptor – the isoalloxazine ring – of FMN is identical to that of
FAD
A fad or trend is any form of collective behavior that develops within a culture, a generation or social group in which a group of people enthusiastically follow an impulse for a short period.
Fads are objects or behaviors that achieve short- ...
. The electrons are then transferred through the FMN via a series of iron-sulfur (Fe-S) clusters,
and finally to
coenzyme Q10
Coenzyme Q, also known as ubiquinone and marketed as CoQ10, is a coenzyme family that is ubiquitous in animals and most bacteria (hence the name ubiquinone). In humans, the most common form is coenzyme Q10 or ubiquinone-10.
It is a 1,4-benzoq ...
(ubiquinone). This electron flow changes the redox state of the protein, inducing conformational changes of the protein which alters the p''K'' values of ionizable side chain, and causes four hydrogen ions to be pumped out of the mitochondrial matrix.
Ubiquinone
Coenzyme Q, also known as ubiquinone and marketed as CoQ10, is a coenzyme family that is ubiquitous in animals and most bacteria (hence the name ubiquinone). In humans, the most common form is coenzyme Q10 or ubiquinone-10.
It is a 1,4-benzoq ...
(CoQ) accepts two electrons to be reduced to
ubiquinol
A ubiquinol is an electron-rich (reduced) form of coenzyme Q (ubiquinone). The term most often refers to ubiquinol-10, with a 10-unit tail most commonly found in humans.
The natural ubiquinol form of coenzyme Q is 2,3-dimethoxy-5-methyl-6-poly p ...
(CoQH
2).
Electron transfer mechanism
The proposed pathway for electron transport prior to ubiquinone reduction is as follows: NADH – FMN – N3 – N1b – N4 – N5 – N6a – N6b – N2 – Q, where Nx is a labelling convention for iron sulfur clusters.
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).
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.
Proton translocation mechanism
The coupling of proton translocation and electron transport in Complex I is currently proposed as being indirect (long range conformational changes) as opposed to direct (redox intermediates in the hydrogen pumps as in
heme
Heme, or haem (pronounced / hi:m/ ), is a precursor to hemoglobin, which is necessary to bind oxygen in the bloodstream. Heme is biosynthesized in both the bone marrow and the liver.
In biochemical terms, heme is a coordination complex "consisti ...
groups of Complexes
III and
IV).
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.
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
electron paramagnetic resonance
Electron paramagnetic resonance (EPR) or electron spin resonance (ESR) spectroscopy is a method for studying materials that have unpaired electrons. The basic concepts of EPR are analogous to those of nuclear magnetic resonance (NMR), but the spin ...
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
A ubiquinol is an electron-rich (reduced) form of coenzyme Q (ubiquinone). The term most often refers to ubiquinol-10, with a 10-unit tail most commonly found in humans.
The natural ubiquinol form of coenzyme Q is 2,3-dimethoxy-5-methyl-6-poly p ...
formation step from
semiquinone
Semiquinone (or ubisemiquinone) is a free radical resulting from the removal of one hydrogen atom with its electron during the process of dehydrogenation of a hydroquinone, such as hydroquinone itself or catechol, to a quinone or alternatively the ...
, 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 (
semiquinone
Semiquinone (or ubisemiquinone) is a free radical resulting from the removal of one hydrogen atom with its electron during the process of dehydrogenation of a hydroquinone, such as hydroquinone itself or catechol, to a quinone or alternatively the ...
and
ubiquinol
A ubiquinol is an electron-rich (reduced) form of coenzyme Q (ubiquinone). The term most often refers to ubiquinol-10, with a 10-unit tail most commonly found in humans.
The natural ubiquinol form of coenzyme Q is 2,3-dimethoxy-5-methyl-6-poly p ...
) results in a stroke of two protons entering the intermembrane space.
The resulting
ubiquinol
A ubiquinol is an electron-rich (reduced) form of coenzyme Q (ubiquinone). The term most often refers to ubiquinol-10, with a 10-unit tail most commonly found in humans.
The natural ubiquinol form of coenzyme Q is 2,3-dimethoxy-5-methyl-6-poly p ...
localized to the membrane domain interacts with negatively charged residues in the membrane arm, stabilizing conformational changes.
An
antiporter
An antiporter (also called exchanger or counter-transporter) is a cotransporter and integral membrane protein involved in secondary active transport of two or more different molecules or ions across a phospholipid membrane such as the plasma memb ...
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 pK
a of the residues.
Composition and structure
NADH:ubiquinone oxidoreductase is the largest of the respiratory complexes. In
mammal
Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur or ...
s, the enzyme contains 44 separate water-soluble peripheral membrane proteins, which are anchored to the integral membrane constituents. Of particular functional importance are the
flavin prosthetic group
A prosthetic group is the non-amino acid component that is part of the structure of the heteroproteins or conjugated proteins, being tightly linked to the apoprotein.
Not to be confused with the cofactor that binds to the enzyme apoenzyme (eith ...
(FMN) and eight
iron-sulfur cluster
Iron–sulfur proteins (or iron–sulphur proteins in British spelling) are proteins characterized by the presence of iron–sulfur clusters containing sulfide-linked di-, tri-, and tetrairon centers in variable oxidation states. Iron–sulfur cl ...
s (FeS). Of the 44 subunits, seven are encoded by the
mitochondrial genome
Mitochondrial DNA (mtDNA or mDNA) is the DNA located in mitochondria, cellular organelles within eukaryotic cells that convert chemical energy from food into a form that cells can use, such as adenosine triphosphate (ATP). Mitochondrial D ...
.
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 ''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 o
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.
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. 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.
A recent study used
electron paramagnetic resonance
Electron paramagnetic resonance (EPR) or electron spin resonance (ESR) spectroscopy is a method for studying materials that have unpaired electrons. The basic concepts of EPR are analogous to those of nuclear magnetic resonance (NMR), but the spin ...
(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.
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
''Schizosaccharomyces pombe'', also called "fission yeast", is a species of yeast used in traditional brewing and as a model organism in molecular and cell biology. It is a unicellular eukaryote, whose cells are rod-shaped. Cells typically meas ...
''
*
d Recent research has described
NDUFA4 to be a subunit of
complex IV
The enzyme cytochrome c oxidase or Complex IV, (was , now reclassified as a translocasEC 7.1.1.9 is a large transmembrane protein complex found in bacteria, archaea, and mitochondria of eukaryotes.
It is the last enzyme in the respiratory electr ...
, and not of complex I
Inhibitors
Bullatacin
Bullatacin is a bis(tetrahydrofuranoid) fatty acid lactone found in some fruits from Annonaceae family. It is a member of the class of compounds known as acetogenin
Acetogenins are a class of polyketide natural products found in plants of the f ...
(an
acetogenin
Acetogenins are a class of polyketide natural products found in plants of the family Annonaceae. They are characterized by linear 32- or 34-carbon chains containing oxygenated functional groups including hydroxyls, ketones, epoxides, tetrahydrof ...
found in
Asimina triloba
''Asimina triloba'', the American papaw, pawpaw, paw paw, or paw-paw, among many regional names, is a small deciduous tree native to the eastern United States and Canada, producing a large, yellowish-green to brown fruit. ''Asimina'' is the onl ...
fruit) is the most potent known inhibitor of NADH dehydrogenase (ubiquinone) (IC50=1.2 nM, stronger than rotenone).
The best-known inhibitor of complex I is
rotenone
Rotenone is an odorless, colorless, crystalline isoflavone used as a broad-spectrum insecticide, piscicide, and pesticide. It occurs naturally in the seeds and stems of several plants, such as the jicama vine plant, and the roots of several member ...
(commonly used as an organic pesticide). Rotenone and rotenoids are
isoflavonoids
Isoflavonoids are a class of flavonoid phenolic compounds, many of which are biologically active. Isoflavonoids and their derivatives are sometimes referred to as phytoestrogens, as many isoflavonoid compounds have biological effects via the estro ...
occurring in several genera of tropical plants such as Antonia (''
Loganiaceae
The Loganiaceae are a family of flowering plants classified in order Gentianales. The family includes up to 13 genera, distributed around the world's tropics. There are not any great morphological characteristics to distinguish these taxa from o ...
''),
Derris
''Derris'' is genus of leguminous plants found in Southeast Asia and the southwest Pacific islands, including New Guinea. The roots of '' D. elliptica'' contain rotenone, a strong insecticide and fish poison.
Despite the secondary compounds foun ...
and
Lonchocarpus
''Lonchocarpus'' is a plant genus in the legume family (biology), family (Fabaceae). The species are called lancepods due to their fruit resembling an ornate lance tip or a few beads on a string.
''Cubé'' resin is produced from the roots of '' ...
(''
Faboideae
The Faboideae are a subfamily of the flowering plant family Fabaceae or Leguminosae. An acceptable alternative name for the subfamily is Papilionoideae, or Papilionaceae when this group of plants is treated as a family.
This subfamily is wide ...
'', ''
''). 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
ubiquinone
Coenzyme Q, also known as ubiquinone and marketed as CoQ10, is a coenzyme family that is ubiquitous in animals and most bacteria (hence the name ubiquinone). In humans, the most common form is coenzyme Q10 or ubiquinone-10.
It is a 1,4-benzoq ...
binding site of complex I as well as
piericidin A, another potent inhibitor with a close structural homologue to ubiquinone.
Acetogenin
Acetogenins are a class of polyketide natural products found in plants of the family Annonaceae. They are characterized by linear 32- or 34-carbon chains containing oxygenated functional groups including hydroxyls, ketones, epoxides, tetrahydrof ...
s from
Annonaceae
The Annonaceae are a Family (biology), family of flowering plants consisting of trees, shrubs, or rarely lianas commonly known as the custard apple family or soursop family. With 108 accepted genera and about 2400 known species, it is the largest ...
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.
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.
Complex I is also blocked by
adenosine diphosphate ribose
Adenosine diphosphate ribose (ADPR) is an ester molecule formed into chains by the enzyme poly ADP ribose polymerase. ADPR is created from cyclic ADP-ribose (cADPR) by the CD38 enzyme using nicotinamide adenine dinucleotide (NAD+) as a cofactor.
...
– a reversible
competitive inhibitor
Competitive inhibition is interruption of a chemical pathway owing to one chemical substance inhibiting the effect of another by competing with it for binding or bonding. Any metabolic or chemical messenger system can potentially be affected b ...
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.
The antidiabetic drug
Metformin
Metformin, sold under the brand name Glucophage, among others, is the main first-line medication for the treatment of type 2 diabetes, particularly in people who are overweight. It is also used in the treatment of polycystic ovary syndrome. ...
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.
Inhibition of complex I has been implicated in
hepatotoxicity
Hepatotoxicity (from ''hepatic toxicity'') implies chemical-driven liver damage. Drug-induced liver injury is a cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdrawn fro ...
associated with a variety of drugs, for instance
flutamide
Flutamide, sold under the brand name Eulexin among others, is a nonsteroidal antiandrogen (NSAA) which is used primarily to treat prostate cancer. It is also used in the treatment of androgen-dependent conditions like acne, excessive hair growt ...
and
nefazodone
Nefazodone, sold formerly under the brand names Serzone, Dutonin, and Nefadar among others, is an atypical antidepressant which was first marketed by Bristol-Myers Squibb (BMS) in 1994 but has since largely been discontinued. BMS withdrew it from ...
.
Active/inactive transition
The catalytic properties of eukaryotic complex I are not simple. Two catalytically and structurally distinct forms exist in any given preparation of the enzyme: one is the fully competent, so-called “active” A-form and the other is the catalytically silent, dormant, “inactive”, D-form. After exposure of idle enzyme to elevated, but physiological temperatures (>30 °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~10
4 min
−1). In the presence of divalent cations (Mg
2+, Ca
2+), or at alkaline pH the activation takes much longer.
The high
activation energy
In chemistry and physics, activation energy is the minimum amount of energy that must be provided for compounds to result in a chemical reaction. The activation energy (''E''a) of a reaction is measured in joules per mole (J/mol), kilojoules pe ...
(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
Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile.
When present as a deprotonated catalytic residue, sometime ...
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.
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
Peroxynitrite (sometimes called peroxonitrite) is an ion with the formula ONOO−. It is a structural isomer of nitrate,
Preparation
Peroxynitrite can be prepared by the reaction of superoxide with nitric oxide:
:
It is prepared by the react ...
.
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
Hypoxia means a lower than normal level of oxygen, and may refer to:
Reduced or insufficient oxygen
* Hypoxia (environmental), abnormally low oxygen content of the specific environment
* Hypoxia (medical), abnormally low level of oxygen in the tis ...
, ischemia or when the tissue
nitric oxide
Nitric oxide (nitrogen oxide or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes denoted by a dot in its che ...
:oxygen ratio increases (i.e. metabolic hypoxia).
Production of superoxide
Recent investigations suggest that complex I is a potent source of
reactive oxygen species
In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen.
The reduction of molecular oxygen () p ...
.
Complex I can produce
superoxide
In chemistry, a superoxide is a compound that contains the superoxide ion, which has the chemical formula . The systematic name of the anion is dioxide(1−). The reactive oxygen ion superoxide is particularly important as the product of the ...
(as well as
hydrogen peroxide
Hydrogen peroxide is a chemical compound with the formula . In its pure form, it is a very pale blue liquid that is slightly more viscous than water. It is used as an oxidizer, bleaching agent, and antiseptic, usually as a dilute solution (3% ...
), 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).
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
succinate dehydrogenase
Succinate dehydrogenase (SDH) or succinate-coenzyme Q reductase (SQR) or respiratory complex II is an enzyme complex, found in many bacterial cells and in the inner mitochondrial membrane of eukaryotes. It is the only enzyme that participates i ...
,
glycerol-3-phosphate dehydrogenase
''sn''-Glycerol 3-phosphate is the organic ion with the formula HOCH2CH(OH)CH2OPO32-. It is one of three stereoisomers of the ester of dibasic phosphoric acid (HOPO32-) and glycerol. It is a component of glycerophospholipids. Equally appropriat ...
,
electron-transferring flavoprotein
An electron transfer flavoprotein (ETF) or electron transfer flavoprotein complex (CETF) is a flavoprotein located on the matrix face of the inner mitochondrial membrane and functions as a specific electron acceptor for primary dehydrogenases, tra ...
or
dihydroorotate dehydrogenase
Dihydroorotate dehydrogenase (DHODH) is an enzyme that in humans is encoded by the ''DHODH'' gene on chromosome 16. The protein encoded by this gene catalyzes the fourth enzymatic step, the ubiquinone-mediated oxidation of dihydroorotate to ...
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
Succinic acid () is a dicarboxylic acid with the chemical formula (CH2)2(CO2H)2. The name derives from Latin ''succinum'', meaning amber. In living organisms, succinic acid takes the form of an anion, succinate, which has multiple biological ro ...
concentrations are high and
oxaloacetate
Oxaloacetic acid (also known as oxalacetic acid or OAA) is a crystalline organic compound with the chemical formula HO2CC(O)CH2CO2H. Oxaloacetic acid, in the form of its conjugate base oxaloacetate, is a metabolic intermediate in many processes ...
or
malate
Malic acid is an organic compound with the molecular formula . It is a dicarboxylic acid that is made by all living organisms, contributes to the sour taste of fruits, and is used as a food additive. Malic acid has two stereoisomeric forms (L ...
concentrations are low.
This can take place during tissue ischaemia, when oxygen delivery is blocked.
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 FMNH
2 (or semireduced flavin) to oxygen (O
2). 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.
Pathology
Mutations in the subunits of complex I can cause
mitochondrial diseases
Mitochondrial disease is a group of disorders caused by mitochondrial dysfunction. Mitochondria are the organelles that generate energy for the cell and are found in every cell of the human body except red blood cells. They convert the energy ...
, including
Leigh syndrome
Leigh syndrome (also called Leigh disease and subacute necrotizing encephalomyelopathy) is an inherited neurometabolic disorder that affects the central nervous system. It is named after Archibald Denis Leigh, a British neuropsychiatrist who fir ...
. Point mutations in various complex I subunits derived from mitochondrial DNA (
mtDNA
Mitochondrial DNA (mtDNA or mDNA) is the DNA located in mitochondria, cellular organelles within eukaryotic cells that convert chemical energy from food into a form that cells can use, such as adenosine triphosphate (ATP). Mitochondrial DNA ...
) can also result in
Leber's Hereditary Optic Neuropathy
Leber's hereditary optic neuropathy (LHON) is a mitochondrially inherited (transmitted from mother to offspring) degeneration of retinal ganglion cells (RGCs) and their axons that leads to an acute or subacute loss of central vision; it predomin ...
. There is some evidence that complex I defects may play a role in the etiology of
Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
, perhaps because of reactive oxygen species (complex I can, like
complex III
Complex commonly refers to:
* Complexity, the behaviour of a system whose components interact in multiple ways so possible interactions are difficult to describe
** Complex system, a system composed of many components which may interact with each ...
, leak electrons to oxygen, forming highly toxic
superoxide
In chemistry, a superoxide is a compound that contains the superoxide ion, which has the chemical formula . The systematic name of the anion is dioxide(1−). The reactive oxygen ion superoxide is particularly important as the product of the ...
).
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.
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.
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 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
Succinic acid () is a dicarboxylic acid with the chemical formula (CH2)2(CO2H)2. The name derives from Latin ''succinum'', meaning amber. In living organisms, succinic acid takes the form of an anion, succinate, which has multiple biological ro ...
level. In the presence of succinate mitochondria catalyze reverse electron
transfer
Transfer may refer to:
Arts and media
* ''Transfer'' (2010 film), a German science-fiction movie directed by Damir Lukacevic and starring Zana Marjanović
* ''Transfer'' (1966 film), a short film
* ''Transfer'' (journal), in management studies
...
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 (FMNH
2) 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.
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.
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.
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.
In chloroplasts
A proton-pumping, ubiquinone-using NADH dehydrogenase complex, homologous to complex I, is found in the chloroplast genomes of most
land plant
The Embryophyta (), or land plants, are the most familiar group of green plants that comprise vegetation on Earth. Embryophytes () have a common ancestor with green algae, having emerged within the Phragmoplastophyta clade of green algae as siste ...
s under the name ''ndh''. This complex is inherited from the original symbiosis from cyanobacteria, but has been lost in most eukaryotic algae, some
gymnosperm
The gymnosperms ( lit. revealed seeds) are a group of seed-producing plants that includes conifers, cycads, ''Ginkgo'', and gnetophytes, forming the clade Gymnospermae. The term ''gymnosperm'' comes from the composite word in el, γυμνό ...
s (''Pinus'' and
gnetophytes
Gnetophyta () is a division of plants (alternatively considered the subclass Gnetidae or order Gnetales), grouped within the gymnosperms (which also includes conifers, cycads, and ginkgos), that consists of some 70 species across the three rel ...
), and some very young lineages of
angiosperm
Flowering plants are plants that bear flowers and fruits, and form the clade Angiospermae (), commonly called angiosperms. The term "angiosperm" is derived from the Greek words ('container, vessel') and ('seed'), and refers to those plants th ...
s. The purpose of this complex is originally cryptic as chloroplast does 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.
Genes
The following is a list of humans genes that encode components of complex I:
* NADH dehydrogenase (ubiquinone) 1 alpha subcomplex
**
NDUFA1 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 1, 7.5kDa
**
NDUFA2
NADH dehydrogenase biquinone1 alpha subcomplex subunit 2 is a protein that in humans is encoded by the ''NDUFA2'' gene. The NDUFA2 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane an ...
– 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
** NDUFA4L – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 4-like
** NDUFA4L2 – NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 4-like 2
**
NDUFA5
NADH dehydrogenase biquinone1 alpha subcomplex subunit 5 is an enzyme that in humans is encoded by the ''NDUFA5'' gene. The NDUFA5 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and ...
– 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 biquinone1 alpha subcomplex subunit 9 is an enzyme that in humans is encoded by the NDUFA9 gene. The NDUFA9 protein is a subunit of NADH:ubiquinone oxidoreductase (Complex I of the electron transport chain), which is located i ...
– 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 biquinone1 alpha subcomplex subunit 12 is an enzyme that in humans is encoded by the ''NDUFA12'' gene. The NDUFA12 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane an ...
– NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 12
**
NDUFA13
NADH dehydrogenase biquinone1 alpha subcomplex subunit 13 is an enzyme that in humans is encoded by the ''NDUFA13'' gene. The NDUFA13 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane an ...
– 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 biquinone1 beta subcomplex subunit 9 is an enzyme that in humans is encoded by the ''NDUFB9'' gene. NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 9 is an accessory subunit of the NADH dehydrogenase (ubiquinone) comp ...
– NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 9, 22kDa
**
NDUFB10
NADH dehydrogenase biquinone1 beta subcomplex subunit 10 is an enzyme that in humans is encoded by the ''NDUFB10'' gene. NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 10 is an accessory subunit of the NADH dehydrogenase (ubiquinone) c ...
– NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 10, 22kDa
**
NDUFB11
NADH dehydrogenase biquinone1 beta subcomplex subunit 11, mitochondrial (NADH-ubiquinone oxidoreductase ESSS subunit) is an enzyme that in humans is encoded by the ''NDUFB11'' gene. NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 11 is ...
– 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-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial (NDUFS1) is an enzyme that in humans is encoded by the ''NDUFS1'' gene. The encoded protein, NDUFS1, is the largest subunit of complex I, located on the inner mitochondrial membrane, and ...
– 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 biquinoneiron-sulfur protein 3, mitochondrial is an enzyme that in humans is encoded by the ''NDUFS3'' gene on chromosome 11. This gene encodes one of the iron-sulfur protein (IP) components of mitochondrial NADH:ubiquinone ox ...
– NADH dehydrogenase (ubiquinone) Fe-S protein 3, 30kDa (NADH-coenzyme Q reductase)
**
NDUFS4
NADH dehydrogenase biquinoneiron-sulfur protein 4, mitochondrial (NDUFS4) also known as NADH-ubiquinone oxidoreductase 18 kDa subunit is an enzyme that in humans is encoded by the ''NDUFS4'' gene. This gene encodes a nuclear-encoded accessory sub ...
– NADH dehydrogenase (ubiquinone) Fe-S protein 4, 18kDa (NADH-coenzyme Q reductase)
**
NDUFS5
NADH dehydrogenase biquinoneiron-sulfur protein 5 is an enzyme that in humans is encoded by the ''NDUFS5'' gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." ...
– 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 biquinoneiron-sulfur protein 7, mitochondrial, also knowns as NADH-ubiquinone oxidoreductase 20 kDa subunit, Complex I-20kD (CI-20kD), or PSST subunit is an enzyme that in humans is encoded by the ''NDUFS7'' gene. The NDUFS7 pr ...
– NADH dehydrogenase (ubiquinone) Fe-S protein 7, 20kDa (NADH-coenzyme Q reductase)
**
NDUFS8
NADH dehydrogenase biquinoneiron-sulfur protein 8, mitochondrial also known as NADH-ubiquinone oxidoreductase 23 kDa subunit, Complex I-23kD (CI-23kD), or TYKY subunit is an enzyme that in humans is encoded by the ''NDUFS8'' gene. The NDUFS8 prot ...
– 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
MT-ND1 is a gene of the mitochondrial genome coding for the NADH-ubiquinone oxidoreductase chain 1 (ND1) protein. The ND1 protein is a subunit of NADH dehydrogenase, which is located in the mitochondrial inner membrane and is the largest of the ...
- mitochondrially encoded NADH dehydrogenase subunit 1
**
MT-ND2
MT-ND2 is a gene of the mitochondrial genome coding for the NADH dehydrogenase 2 (ND2) protein. The ND2 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five ...
- mitochondrially encoded NADH dehydrogenase subunit 2
**
MT-ND3
MT-ND3 is a gene of the mitochondrial genome coding for the NADH dehydrogenase 3 (ND3) protein. The ND3 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five ...
- mitochondrially encoded NADH dehydrogenase subunit 3
**
MT-ND4
MT-ND4 is a gene of the mitochondrial genome coding for the NADH-ubiquinone oxidoreductase chain 4 (ND4) protein. The ND4 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the l ...
- mitochondrially encoded NADH dehydrogenase subunit 4
**
MT-ND4L
MT-ND4L is a gene of the mitochondrial genome coding for the NADH-ubiquinone oxidoreductase chain 4L (ND4L) protein. The ND4L protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is th ...
- mitochondrially encoded NADH dehydrogenase subunit 4L
**
MT-ND5
MT-ND5 is a gene of the mitochondrial genome coding for the NADH-ubiquinone oxidoreductase chain 5 protein (ND5). The ND5 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the la ...
- mitochondrially encoded NADH dehydrogenase subunit 5
**
MT-ND6
MT-ND6 is a gene of the mitochondrial genome coding for the NADH-ubiquinone oxidoreductase chain 6 protein (ND6). The ND6 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the la ...
- mitochondrially encoded NADH dehydrogenase subunit 6
References
External links
Institute of Science and Technology Austria (ISTA): Sazanov Group MRC MBU Sazanov group(Require
MDL ChimeComplex I homepageComplex I news facebook page*
{{DEFAULTSORT:Nadh Dehydrogenase
Cellular respiration
Glycolysis
EC 1.6.5
Integral membrane proteins