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Buy or subscribe. Change institution. Learn more. However, doses of 30 mg to mg per day have been suggested. Higher doses may be used in some cases. You should take this supplement with a meal that contains fat. This helps your body absorb it better.

Women who are pregnant or breastfeeding should talk with their healthcare providers before taking any supplements.

Doses of up to mg per day for every kg of body weight do not show toxicity. In some cases, minor side effects can happen. These can include:. These medicines block your body from making coenzyme Q Coenzyme Q might interact with the diabetes medicine insulin, as well as warfarin, a blood thinner.

Coenzyme Q supplementation may not be suitable during some types of cancer treatment. Search Encyclopedia. Coenzyme Q Other name s : Co Q, Q, ubiquinone, ubiquinol General description Coenzyme Q is a fat-soluble type of substance called a quinone.

Medically valid uses Coenzyme Q has been studied for its role in heart failure. Unsubstantiated claims There may be benefits that have not yet been proven through research.

Mitochondria - genetics. Mitochondria - metabolism. Mitochondrial Membranes - metabolism. Mitochondrial respiratory chain. NAD - metabolism. Oxidoreductases - genetics.

Oxidoreductases - metabolism. Oxidoreductases Acting on CH-CH Group Donors - genetics. Oxidoreductases Acting on CH-CH Group Donors - metabolism.

Protein Multimerization. Respiratory chain. Respiratory complexes. Ubiquinone - biosynthesis. CoQ receives electrons from different redox pathways, mainly NADH and FADH2 from tricarboxylic acid pathway, dihydroorotate dehydrogenase, electron transfer flavoprotein dehydrogenase and glycerolphosphate dehydrogenase that support key aspects of the metabolism.

Here we explore some lines of evidence supporting the idea of the interaction of CoQ with the respiratory chain complexes, contributing to their superassembly, including respirasome, and its role in reactive oxygen species production in the mitochondrial inner membrane.

We also review the current knowledge about the involvement of mitochondrial genome defects and electron transfer flavoprotein dehydrogenase mutations in the induction of secondary CoQ deficiency. This mechanism would imply specific interactions coupling CoQ itself or the CoQ-biosynthetic apparatus with the respiratory chain components.

These interactions would regulate mitochondrial CoQ steady-state levels and function. Paolo Bernardi. Coenzyme Q CoQ is a unique electron carrier in the mitochondrial respiratory chain, which is synthesized on-site by a nuclear encoded multiprotein complex.

Netherlands: Elsevier B.

Both agree in the number of respiratory complexes I-IV that participate in the mETC, but while the random collision model proposes that Complexes I-IV do not interact physically and that electrons are transferred between them by coenzyme Q and cytochrome c, the solid model proposes that all complexes super-assemble in the so-called respirasome.

Recently, the plasticity model has been developed to incorporate the solid and the random collision model as extreme situations of a dynamic organization, allowing super-assembly free movement of the respiratory complexes.

In this review, we evaluate the supporting evidences of each model and the implications of the super-assembly in the physiological role of coenzyme Q. The classical electron transfer chain was described as the functional sequence of 4 major multi-subunit enzymatic complexes, randomly dispersed in the inner mitochondrial membrane and designated as NADH-coenzyme Q CoQ reductase Complex I, C I , succinate-CoQ reductase Complex II, C II , ubiquinol-cytochrome c reductase Complex III, C III , and cytochrome c oxidase Complex IV, C IV ; in this view, the enzyme complexes are connected by 2 mobile redox-active molecules, i.

a lipophilic quinone, designated CoQ or ubiquinone, embedded in the membrane lipid bilayer, and a hydrophilic heme protein, cytochrome c, localized on the external surface of the inner membrane [Green and Tzagoloff, ].

glycerolphosphate dehydrogenase, ETF-ubiquinone oxidoreductase, dihydroorotate dehydrogenase, choline dehydrogenase, sulfide CoQ reductase SQR , and proline dehydrogenase besides alternative NADH dehydrogenases in mitochondria from several organisms, especially plants and fungi.

Moreover, alternative or branched pathways of electron transfer, differing from CoQ, also occur, e. alternative ubiquinol oxidases from bacteria and plant and fungi mitochondria [Lenaz and Genova, ].

The traditional description considers the 4 complexes originally described by Green and Tzagoloff [] to be the structural core of the respiratory chain. Subsequently, other accessory enzymes feeding electrons to the chain have been added.

Nevertheless, a substantial difference exists between 3 of the original complexes C I , C III , and C IV and Complex II, since the latter shares some important properties with the accessory enzymes, i.

they give electrons to CoQ without creation of a transmembrane proton gradient; in other words they are required for oxidative phosphorylation OXPHOS but do not participate directly in energy conservation. The systematic resolution and reconstitution of the 4 respiratory complexes from mitochondria were accomplished by Hatefi et al.

CoQ and cytochrome c. This proposal was substantially confirmed over the following years, leading to the postulation by Hackenbrock et al. The organization of the respiratory chain has represented a major research subject in the s, culminating with the acceptation of the RCM by the majority of scientists in the field.

a The integral proteins of the inner membrane are randomly distributed in the bilayer, and phospholipid dilution of the mitochondrial membrane proteins slows down electron transfer [Schneider et al.

b Electron transfer in the CoQ and cytochrome c region obeys pool behavior according to the equation developed for CoQ by Kröger and Klingenberg []. c Electron transfer follows saturation kinetics with respect to CoQ and cytochrome c concentrations [MacLennan et al.

On the other hand, circumstantial evidence against a random distribution of respiratory complexes came from early investigations reporting isolation of Complex I-III [Hatefi et al. The view of preferential associations between complexes was never abandoned, but only a minority of scientists was favoring such a possibility [Lenaz and Genova, ].

Much more recently, new evidence of multi-complex units in yeast and mammalian mitochondria has been obtained introducing blue native polyacrylamide gel electrophoresis BN-PAGE [Schägger and Pfeiffer, ].

Since these initial studies, respiratory supercomplexes have been identified in mitochondria from many different species [Wittig and Schägger, ; Lenaz and Genova, ].

Associations of Complex II with other complexes of the OXPHOS system could not be identified in most of the studies. However, monomeric to trimeric forms of Complex II [Sousa et al.

In addition, no evidence for supercomplex association has been found for other ancillary enzymes feeding electrons to CoQ; thus the supercomplex organization appears to be a prerogative of the energy-conserving respiratory complexes. However, it has been suggested that a multifunctional fatty acid β-oxidation complex is formed within mitochondria that is physically associated with OXPHOS supercomplexes and promotes metabolic channeling of electrons directly from fatty acid β-oxidation to the respiratory chain [Wang et al.

Partial elucidation of the interaction of the individual respiratory complexes within the supercomplex was achieved by single-particle electron microscopy. Dudkina et al. Class averages in single-particle processing showed characteristic F-shaped side views of the particle volume and roughly triangular top views.

Shortly later, Schäfer et al. The dimensions of the supercomplex in the membrane plane are 28 by 24 nm. On the basis of the structural information gained by the 3D maps, they could propose a model of the spatial organization and mutual arrangement of all partner enzymes, showing extensive interaction of Complex III with the membrane arm of Complex I, while Complex IV, when present, interacts with the distal portion of the same arm.

Furthermore, on the same basis, the ubiquinone and cytochrome c binding sites of each complex in the supercomplex I 1 III 2 IV 1 appeared to be in proximity to the binding site of the succeeding complex in the respiratory chain, thus supporting the idea that direct substrate channeling occurs in the supercomplex with short diffusion distances for the mobile electron carriers.

Recently, new 3D maps at nanoscale resolution allowed interpretation of the architecture of mammalian respirasomes at the level of the secondary structure. Interestingly, in the new model by Dudkina et al.

In particular, the section through the model on the level of the membrane demonstrates gaps between Complexes III 2 and IV within the membrane, whereas the same 2 complexes appear to contact each other in their matrix portions close to the membrane.

Althoff et al. Moreover, at Å resolution the membrane-embedded part of the supercomplex shows intermediate values of density between that of soluble protein and the hydrophobic membrane interior, suggesting that the supercomplex is held together at least partly by lipid-protein interactions.

Likely, a gap filled with membrane lipid would also facilitate the diffusion of ubiquinol between Complex I and Complex III, and it is interesting to note that the CoQ-binding sites in Althoff's model fig. It is proposed that the proximal monomer may be more effective in ubiquinol oxidation, while the distal one may be needed to transfer the electrons to cytochrome c via its flexible Rieske domain in accordance with the half-of-the-sites reactivity model of Complex III [Castellani et al.

Furthermore, a trajectory of 10 nm is envisaged in the respirasome along which cytochrome c may travel to shuttle electrons towards Complex IV fig. A , B Respirasome 3D map and fitted X-ray structures. C , D Electron transfer pathways in the supercomplex.

A Cryo-EM 3D map as seen from the 2 opposite sides left , from the matrix top right , and the intermembrane space lower right. The amphipol belt is shown in red. The circle marks the gap between Complex I and Complex III. Electron trajectories are marked in black. The dashed circle marks the distal cytochrome c binding site which is unoccupied in the supercomplex.

Straight arrows in C and D indicate the shortest distances from the cytochrome c binding sites on Complex III to the site of cytochrome c oxidation in Complex IV. The shorter proximal branch may be preferred for electron transport. Taken from Althoff et al. It has to be kept in mind that, besides the lack of a crystal structure of the mammalian Complex I, several uncertainties are still present in the interpretation of the 3D maps: for example, in the maps there are additional density areas that cannot be filled by the current structural models of Complexes III and IV, suggesting that additional proteins may participate in the supercomplexes.

This is the case of SCAFI, a recently reported protein required for the super-assembly of Complexes III and IV that is not present in the free complexes [Lapuente-Brun et al. All purified preparations of mitochondrial electron transfer enzymes are isolated as lipoprotein complexes, the extent of associated lipid depending upon the particular method used for isolation and the phospholipid composition reflecting that for the mitochondrial inner membrane.

Predominant phospholipids include cardiolipin, phosphatidylcholine, phosphatidylethanolamine, and lesser amounts of neutral lipids and phosphatidylinositol. A dispersive solubilization effect and a catalytic effect, which can be specifically fulfilled only by cardiolipin, are 2 of the distinguished roles for such membrane lipids.

In addition, they can participate in the molecular linkage between the respiratory complexes and, particularly in the case of Complex I and Complex III, can provide a sufficiently lipophilic environment for the interaction of the lipophilic electron carrier ubiquinone [Lenaz and Genova, ].

The forces responsible for supercomplex association appear to strongly depend on the lipid content and composition and likely the shape of the inner mitochondrial membrane [Lenaz and Genova, ]. In other words, it appears that dilution of the proteins with an excess of phospholipids may weaken the forces holding together the respiratory complexes.

Among lipids, cardiolipin and phosphatidylethanolamine are crucial for mitochondrial functions; both are non-bilayer-forming phospholipids due to their small polar heads compared with the bulky non-polar tails [van den Brink-van der Laan et al.

Cardiolipin, the signature phospholipid of mitochondria, is a lipid dimer that is required for a diverse range of mitochondrial activities beyond the process of ATP production.

Thus, derangements in cardiolipin metabolism lead to pathological conditions. Cardiolipin is synthesized in mitochondria; after its biosynthesis, the acyl chain composition of cardiolipin is modified by 3 distinct remodeling enzymes that produce the tissue-specific mature form of cardiolipin.

Mutations of these enzymes produce modified molecules that have been linked to mitochondrial dysfunction [Claypool and Koehler, ]. The phospholipids in closest vicinity to the protein surface, as well as those in the free bilayer, are highly mobile and free to exchange, but cardiolipin is tightly bound, being more likely buried within the protein complexes [Kang et al.

The absolute requirement of cardiolipin for the activity of cytochrome oxidase, Complex I, and Complex III suggests that this phospholipid plays a crucial role in the coupled electron transfer process [Fry and Green, , ].

There are now extensive indications that cardiolipin stabilizes respiratory supercomplexes as well as the individual complexes. Evidence for this function has been largely collected in yeast mutants. In a yeast mutant lacking cardiolipin, the III 2 IV 2 supercomplex was significantly less stable than supercomplexes in the parental strain.

Other phospholipids that are increased in the mutant, including phosphatidylethanolamine and phosphatidylglycerol, could not substitute for cardiolipin and could not prevent dissociation of supercomplexes [Zhang et al.

The putative direct protein-protein interaction of cytochrome oxidase and Complex III in yeast is proposed to involve also one molecule of cardiolipin and one of phosphatidylethanolamine tightly bound in a cavity of the membrane-imbedded domain of Complex III [Lange et al.

Site-directed mutagenesis investigations on specific cardiolipin interaction for supercomplex formation in the cytochrome bc 1 complex [Wenz et al. In addition, the stability and assembly of Complex IV were found to be reduced in yeast cells lacking Taz1 [Brandner et al.

Mutations of Tafazzin approved symbol: TAZ in humans result in Barth syndrome, a cardio-skeletal myopathy with neutropenia, characterized by respiratory chain dysfunction. Significantly, McKenzie et al. It is well documented that exposure of mitochondria to reactive oxygen species ROS can affect the respiratory activity via oxidative damage of cardiolipin which is required for the optimal functioning of the enzyme complexes [Paradies et al.

Genova et al. Evidently, the distortion of the lipid bilayer induced by peroxidation and the alteration of the tightly bound phospholipids determine dissociation of the supercomplex originally present in the lipid-poor preparation.

In contrast with cardiolipin depletion that destabilizes supercomplexes, a recent study reported that phosphatidylethanolamine depletion tends to favor the formation of larger supercomplexes between Complex III and IV in mitochondria of Saccharomyces cerevisiae [Böttinger et al.

The reason why cardiolipin and phosphatidylethanolamine, both non-bilayer-forming phospholipids, behave in an opposite way on supercomplex stability has been ascribed to their different charge, the former being an anionic phospholipid and the latter zwitterionic [Böttinger et al.

The organization of the mitochondrial respiratory chain as supercomplexes has been sustained on structural evidence at first, the co-migration of respiratory complexes either in BN-PAGE or in sucrose gradients and by electron microscopy structural analysis upon purification.

Despite that, 2 fundamental assumptions have been established to propose a radical change in our understanding of the structural organization of the mitochondrial electron transport chain.

First, the RCM has to be discarded in favor of a model in which respiratory complexes are organized in respirasomes containing Complex I, III, and IV; solid model.

Second, all the other structures observed in the purification protocols should be considered breaking pieces of the original respirasome.

None of these methodologies, however, have been able to provide experimental support to sustain these critical assumptions.

Very relevant, they have been unable to determine if the supercomplexes containing Complexes I, III, and IV the so-called respirasome were able to respire. Without solving this, even if accepted as real entities, supercomplexes could have roles different from these of respiration i.

storage of yet inactive respiratory complexes, structural organizers of the inner membrane, etc. It was demonstrated that purified respirasomes were able to respire in a Clark's electrode [Acín-Peréz et al. Therefore, we reasoned that the variety of associations between respiratory complexes was larger than the respirasome and that the free complexes likely co-exist with supercomplexes.

In this context we proposed an integrated model, the plasticity model, for the organization of the mitochondrial electron transport chain. The previous opposed models, solid versus fluid, would be 2 extremely allowed and functional situations of a dynamic range of molecular associations between respiratory complexes [Acín-Peréz et al.

The stoichiometry of the complexes and the variable stability of different free versus associated structures under different physiological conditions would allow a landscape of structural options fig.

Plasticity model of the mitochondrial OXPHOS system organization. The shape and color code for representing the individual complexes can be seen in A ; coenzyme Q is represented as small red stars and cytochrome c as purple triangles.

For supercomplexes in C , only one complex unit of each type is represented in the different supercomplex associations, although the actual stoichiometry may vary.

Image is taken from Acín-Peréz et al. The proportion of the different ratios between complexes and supercomplexes is cell type specific and responds to physiological stimuli see below. Free Complex I was virtually absent, because it is rapidly degraded in the absence of Complex III [Acín-Peréz et al.

Several in vitro studies support the idea that electron transfer in the respiratory chain can occur in the absence of supercomplexes. A fundamental prediction of the plasticity model is that in vivo the mitochondrial respiratory chain should be able to work when the formation of supercomplexes is prevented.

Mice missing functional alternative oxidases AOX were also lacking supercomplexes containing Complex IV and therefore the respirasome. This possibility is already present in nature, since the mitochondrial electron transport chain is branched in plants, fungi, yeast, and lower metazoans.

Thus, AOX are able to oxidize CoQ to water, supplanting in that way the combined role of Complex III, cytochrome c, and Complex IV. Under these conditions, Complex I works perfectly in combination with AOX and in the absence of Complexes III and IV [Maas et al.

Expression of functional AOX in mammalian cells is feasible [Perales-Clemente et al. Therefore, in vivo Complex I-dependent respiration does not require supercomplex formation. This demonstrates that the respiratory complexes can work either as free entities or as associated entities.

What could then be the functional role for these associations? Some observations in the literature indirectly support the view that the supercomplex organization may not be fixed but be in equilibrium with randomly dispersed complexes in living cells under physiological conditions.

Besides phospholipid composition that may change by genetic or dietary reasons but involves a relatively long time-scale, some biochemical parameters at a shorter time-scale have been suggested to affect the supramolecular structure of the respiratory complexes. These are the mitochondrial membrane potential and the phosphorylation state of the protein subunits of the complexes.

Nevertheless, a recent study [Muster et al. By fusing cells containing mitochondria with respiratory complexes labeled with different fluorescent proteins and resolving their time-dependent re-localization in living cells, the authors found that a complete reshuffling of respiratory complexes throughout the entire chondriome in single HeLa cells occurs within h by organelle fusion and fission.

Moreover, polykaryons of fused cells completely re-mixed their complexes in h in a progressive way. Nevertheless, the distribution of respiratory complexes and ATP synthase in fused hybrid mitochondria is not homogeneous but patterned: in co-expressing cells, Complex II is more homogeneously distributed than Complexes I and V, arguing for its higher mobility and less integration in supercomplexes.

Being these experiments the very first attempt to follow the temporal dynamic of respiratory complexes in situ , they are still very limited because the cristae and individual complexes or supercomplexes could not be discriminated by fluorescent microscopy.

In addition, in order to minimize the interference in function or structure, subunits of less pronounced functional importance and peripheral to the complex structure were chosen for labeling [Muster et al. This is especially relevant, because in some cases i. the labeled kDa Complex I protein , the sub-assembles could be either part of membrane-associated or matrix-associated subcomplexes [Dieteren et al.

More recently, the extension of these studies to the other proton-translocating respiratory complexes I and III reveals that under conditions of low potential the sum of the flux control coefficients exceeded 1, whereas at high potential the coefficients were much lower [Quarato et al.

Although the interpretation of the results in such a complex system is very difficult, the authors suggested that such a change in control strength might be featured in terms of an equilibrium between different organizational structures of the enzymatic complexes constituting the mitochondrial OXPHOS.

In particular, the results were compatible with a random organization of cytochrome oxidase with respect to other complexes at high membrane potential state 4 and with a respirasome organization at lower membrane potential state 3 ; since the respiratory rate was high in state 3 conditions, the supercomplex organization would produce an extra advantage by raising the rate by channeling.

We concluded that ΔΨ is predominantly responsible for the tight control exerted by cytochrome c oxidase over endogenous respiration, whereas ΔpH seems irrelevant in this respect [Dalmonte et al. In this respect, recent investigations have revealed a surprising interplay between pH gradients, lipid composition and packing, and membrane cristae shape [Khalifat et al.

In potato tuber mitochondria, it was found that hypoxia dissociates the supercomplex I-III 2 -IV into individual Complex I plus Complex III-IV units [Ramirez-Aguilar et al. It has been established that some of the mitochondrial complexes are subjected to reversible phosphorylation and dephosphorylation [Acín-Peréz et al.

Phosphorylation of Complex I has been shown to modify the activity of the enzyme and its ROS-generating capacity [Raha et al. Cyclic AMP-dependent phosphorylation of the kDa subunit of Complex I, encoded by the nuclear NDUFS4 gene, is required for import of the subunit.

Modulation of subunit phosphorylation by intramitochondrial protein kinase A and phosphoprotein phosphatase contributes to the stability of Complex I and stimulation of its activity [de Rasmo et al. It is tempting to speculate that the increase of activity of Complex I and the decrease of ROS generation by phosphorylation may be, in part, the result of an enhanced stability of the I-III supercomplex; however, no studies to date have established any correlation between them.

Phosphorylation of structural subunits of Complex III has also been reported, although its functional role remains undetermined [Zhao et al. Lee et al. The same effect on cytochrome oxidase kinetics was observed in a cell culture system after treatments that would increase protein phosphorylation e.

elevation of cAMP levels by glucagon addition or by forskolin activation of adenylyl cyclase. Complex IV is a target of the intramitochondrial cAMP-PKA signaling pathway [Acín-Peréz et al.

Complex IV activity increases with the rise in mitochondrial matrix cAMP by cell-permeant cAMP analogs or by activating the soluble matrix adenylyl cyclase. The inhibition of PKA both in cell culture and in isolated mitochondria resulted in a decreased Complex IV activity [Acín-Peréz et al.

Mitochondrial PKA-dependent phosphorylation of Complex IV was down-regulated in both cell culture and animal models of cytochrome c oxidase COX deficiency. This promoted a ROS-dependent increase in mitochondrial biogenesis as a compensatory mechanism [Acín-Peréz et al.

The expression of mitochondrial-targeted soluble adenylyl cyclase, which increases mitochondrial matrix cAMP, restored mitochondrial function and normalized ROS production and mitochondrial biogenesis in COX-deficient cells. This study represents the first example of a direct positive modulation of COX with clear implications for plausible therapeutic treatments of mitochondrial dysfunction [Acín-Peréz et al.

Phosphorylation in Complex IV subunits was reported by mass spectrometry analysis [Helling et al. The amino acid residue S58 in COXIV-1 same as S34 published by Helling et al.

A S58 COXIV-1 phosphorylation was proposed to have a dual function by promoting COXIV-1 phosphorylation coupled to prevention of COX allosteric inhibition by ATP. This mechanism would allow the cells to rapidly adapt to changes in substrate use and substrate storage [Acín-Peréz et al.

Stable phosphorylation sites in Complex IV are also detectable at tyrosine, serine, and threonine in subunit II and III, as well as at specific amino acid residues in subunits IV, Vab, VIabc, VIIabc, and VIII [Helling et al. binding of EGFR-pY to subunit II, viral protein HBx to subunit III, PKCe to subunit IV, NO synthase to subunit Va, subunit RIa of PKA to subunit Vb, and androgen receptor to subunit Vb.

It is tempting to speculate that endocrine alterations may affect the assembly of Complex IV by hyper- or hypophosphorylation of some subunits in the complex. Indeed, cAMP- and PKA-dependent phosphorylation of Complex IV in heart mitochondria [Rosca et al. Nevertheless, caution must be exerted when interpreting the role of posttranslational changes in supercomplex formation, since no causal correlation has yet been established.

The notion of the CoQ pool as the mechanism for integrated electron transfer from dehydrogenases to cytochromes, described by the hyperbolic relationship between the observed rate of electron transfer of the entire respiratory chain and the rate of either reduction or oxidation of CoQ [Kröger and Klingenberg, ], has been widely accepted and is covered in all biochemistry textbooks.

Here, 2 separate points are discussed regarding this purpose. First, is the discovery of supercomplexes compatible with the existence of a pool of free CoQ molecules in the inner membrane?

And second, if such pool exists, does it have a specific function in electron transfer? There is no doubt that a mobile pool of CoQ coexists with protein-bound CoQ. The extent to which CoQ is bound to mitochondrial proteins is an important parameter in relation to its function.

If we consider bound CoQ in a stoichiometry with the complexes interacting with the quinone C I , C II , C III in mitochondria of bovine heart, we come up to about 0. The CoQ pool is required for electron transfer from Complex II to Complex III; indeed Complex II kinetically follows pool behavior in mitochondria after extraction and reconstitution [Kröger and Klingenberg, ] with CoQ [Stoner, ] in accordance with the lack of supercomplexes found by both BN-PAGE and flux control analysis see previous section.

Furthermore, other enzymes such as glycerolphosphate dehydrogenase, ETF dehydrogenase, dihydroorotate dehydrogenase, choline dehydrogenase, SQR, and proline dehydrogenase, which are present in lower amounts and are likely to be rate-limiting in an integrated electron transfer, are probably inserted in the respiratory chain by interaction through the CoQ pool [Genova and Lenaz, ].

A study addressed to this problem demonstrated that in mitochondria of brown fat the inhibition curve of glycerol phosphate-cytochrome c reductase is sigmoidal in the presence of myxothiazol and antimycin, suggesting the presence of a homogeneous CoQ pool between glycerol phosphate dehydrogenase mtGPDH and Complex III [Rauchová et al.

More recently, it has been shown that the delivery of electrons from mtGPDH to Complex III in mitochondria of human neutrophils takes place in the absence of supercomplex organization and of NAD-linked respiration [van Raam et al.

Preliminary studies by BN-PAGE show that mtGPDH does not appear to be linked to any of the respiratory complexes [Genova ML, Rauchová M, Rauchová H, unpubl. data] but associates in homooligomers as well as in supercomplexes that, however, do not contain either Complexes I, III, or IV [Mracek et al.

The hyperbolic relation experimentally found by Gutman [] between the rate of reverse electron transfer and succinate oxidase is in complete accordance with the pool equation.

This observation poses a puzzling question [Lenaz and Genova, ]: if all or most Complex I units are associated with Complex III and the interaction of CoQ in the pool with the quinone-binding site in common between the 2 enzymes is necessarily slow, then how can QH 2 reduced by Complex II interact from the pool with the CoQ site in Complex I at a rate compatible with the steady state kinetics of reverse electron transfer?

The intriguing idea that Complex I may possess 2 different quinone-binding sites for direct and for reverse electron transfer, respectively, is compatible with the proposal that 2 different routes may exist for forward and reverse electron transfer within Complex I [Grivennikova et al.

These 2 sites might become alternatively accessible depending on the magnitude of the membrane potential. The model hypothesis depicted by Piccoli et al. The notion that probably all of Complex I is bound in a supercomplex would seem to exclude a function for the CoQ pool in electron transfer from NADH.

This is not the case, as shown in the discussion in other sections of this review. As it was mentioned above, CoQ ubiquinone is required for the transfer of electrons from NADH- or FAD-dependent enzymes to the respiratory Complex III within the inner mitochondrial membrane.

For more than 40 years, it has generally been accepted that CoQ exerted its role by freely diffusing through the membrane and behaving as a homogenous pool available to any enzyme that required it, according to the RCM proposed to explain the organization of the mitochondrial electron transport chain [Lenaz and Genova, ].

Some reports studying the reduction of CoQ in isolated mitochondria determined that succinate and NADH could reduce a limited and specific fraction of the total CoQ pool [Jørgensen et al. More recently, Rossignol and co-workers clearly demonstrated that the CoQ content in the mitochondrial inner membrane is not homogenous [Benard et al.

When they measured the levels of reduced CoQ and cytochrome c in state 3 isolated mitochondria, they found one CoQ fraction that was utilized during steady-state respiration, another fraction that acted as a reserve to maintain normal energy fluxes in case of perturbation e.

as a consequence of respiratory complex inhibition or mitochondrial disease , and a third fraction that is unable to participate in succinate-dependent respiration. Although similar assays analyzing NADH dependent respiration have not been performed, these results are not compatible with a single CoQ pool.

Several reports have confirmed that respiratory supercomplexes contain also CoQ and that it is able to transfer electrons from Complex I to Complex III [Acín-Peréz et al. Recently, it was demonstrated that the physical assembly between Complexes I and III determines a preferential pathway for electrons mediated by a dedicated subset of CoQ molecules we name them CoQ NADH.

This compartmentalization prevents significant cross talk between NADH oxidation Complex I dependent and FAD oxidation CoQ FAD pool from any non-Complex I-dependent oxidation if we assume that no further compartmentalization of the CoQ pool occurs , at least until the electrons reach cytochrome c.

In that way, the CoQ pool behavior will fully apply to all enzymes that deliver electrons to the CoQ FAD succinate dehydrogenase, glycerolphosphate dehydrogenase, ETF-ubiquinone oxidoreductase, dihydroorotate dehydrogenase, choline dehydrogenase, SQR, and proline dehydrogenase.

The segmentation of CoQ into the NADH- and the FAD-dedicated fractions has an unexpected consequence. Those Complex III molecules that physically interact with Complex I in the formation of supercomplexes are also dedicated to CoQ NADH oxidization CIII NADH , while those Complex III molecules that are free of interaction with Complex I are mainly responsible for CoQ FAD oxidization.

Complex I has a very high affinity for Complex III, to the extent that this association is preferred to the Complex I free state when the CI:CIII stoichiometry decreases abnormally due to the partial loss of Complex III.

In this situation, CoQ NADH oxidization is preferentially maintained despite the risk of compromising the oxidation of CoQ FAD [Lapuente-Brun et al. Therefore, the supercomplex organization of the mitochondrial electron transport chain has deeper functional consequences than expected.

Adaptation to mitochondrial respiratory substrates that generate different proportions of NADH and FAD as when mitochondria rely on fatty acids rather than glucose during fasting requires adjustments to the capacity for electron transport via the NADH and FAD routes.

Regulated modifications of the proportion of respiratory supercomplexes allow this adaptation [Lapuente-Brun et al. At present, no known molecular mechanism can be invoked to explain the exquisite regulation of the balance between NADH Complex III Complex III dedicated to Complex I and FAD Complex III.

Further understanding of this behavior is of paramount importance. A very relevant question derived from the plasticity model proposal is how the respiratory supercomplexes are generated and how this is related with the assembly of complexes themselves.

After 1 h of pulse- and short-chase periods for 0. This is the case for Complexes I, III, and IV. Thus, most of the signal corresponding to the mtDNA encoded Complex IV subunits COI, COII, and COIII had not reached the mature Complex IV until 12 h of chase.

The same observation was true for the mtDNA-encoded subunits of Complex I and for the Complex III subunit cyt b. Complex V subunits behave differently, since all the radioactive signal for A6 and A8 was already incorporated in the mature Complex V even at very short chase periods.

This is probably due to the fact that they incorporate at the end of the assembly process [Tzagoloff et al.

The labeling of large supercomplexes showed a different pattern depending on if they contained Complex IV or not. The labeling of the supercomplexes did not reach the characteristic pattern until 12 h of chase. These results support the idea that supercomplexes are structures formed by the specific and ordered association of individual complexes [Acín-Peréz et al.

A recent report proposed a different path for supercomplex formation [Moreno Lastres et al. They used a different, although similar, experimental approach and depleted cells of OXPHOS complexes by treatment with doxycycline which reversibly inhibits mitochondrial translation.

Then, upon drug removal, they followed complex and supercomplex assembly by BN-PAGE and immunodetection of individual proteins as markers of the overall complexes or subcomplexes.

They also assumed that every co-migration in a gel is due to physical interaction between the co-migrating entities. This analysis led them to propose that the biogenesis of the respirasome involves the coordinated and sequential association of specific combinations of partially assembled respiratory complexes and free subunits.

At this step the NADH dehydrogenase module of Complex I is added [Moreno Lastres et al. So, the respirasome assembly is intimately linked to the Complex I assembly. The model could be invoked to explain the lack of Complex I in the absence of Complex III [Acín-Peréz et al.

However, it cannot explain the normal assembly, stability, and functionality of Complex I in cells lacking Complex IV [Balsa et al. It cannot explain either the stability or function of Complex I in fungi that lack Complex III and IV but naturally respire by AOX [Maas et al.

In addition, it cannot explain the existence of mice lacking respirasomes because they lost SCAFI [Lapuente-Brun et al. On the contrary, the existence of protein factors that regulate the assembly of the different respiratory complexes into respirasomes is fully compatible with the sequential formation of first complexes and then supercomplexes [Acín-Peréz et al.

Three independent reports recently described 2 related S. A table showing the levels of evidence scores for qualifying human studies cited in this summary is presented below.

For an explanation of the scores and additional information about levels of evidence analysis for cancer, see Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies.

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This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the use of coenzyme Q10 in the treatment of people with cancer.

It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions. This summary is reviewed regularly and updated as necessary by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board , which is editorially independent of the National Cancer Institute NCI.

The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health NIH. Board members review recently published articles each month to determine whether an article should:.

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PDQ® Integrative, Alternative, and Complementary Therapies Editorial Board. PDQ Coenzyme Q Bethesda, MD: National Cancer Institute.

Permission to use images outside the context of PDQ information must be obtained from the owner s and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online , a collection of over 2, scientific images.

The information in these summaries should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer. gov on the Managing Cancer Care page. More information about contacting us or receiving help with the Cancer.

gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer. Coenzyme Q 10 is made naturally by the human body. Coenzyme Q 10 helps cells to produce energy, and it acts as an antioxidant. Coenzyme Q 10 has shown an ability to stimulate the immune system and to protect the heart from damage caused by certain chemotherapy drugs.

Low blood levels of coenzyme Q 10 have been detected in patients with some types of cancer. No report of a randomized clinical trial of coenzyme Q 10 as a treatment for cancer has been published in a peer-reviewed scientific journal.

Coenzyme Q 10 is marketed in the United States as a dietary supplement. Coenzyme Q 10 is used by cells of the body in a process known variously as: Aerobic respiration. Aerobic metabolism. Oxidative metabolism.

Cell respiration. Protect the heart from anthracycline -induced cardiotoxicity anthracyclines are a family of chemotherapy drugs, including doxorubicin , that have the potential to damage the heart.

Am J Health Syst Pharm 56 6 : , Biochem Biophys Res Commun 2 : , Biochem Biophys Res Commun 1 : , Prog Drug Res , Int J Clin Pharmacol Ther 36 9 : , Cancer Chemother Rep 2 4 4 : , Ubiquinone concentrations in tumours and some normal tissues in man.

Nature 29 : , Br J Exp Pathol 70 1 : , Am J Med Sci 4 : , J Invest Dermatol 3 : , Clin Biochem 33 4 : , Experientia 26 9 : , Gann 69 4 : , Proc Natl Acad Sci U S A 70 2 : , Pathol Microbiol Basel 38 6 : , In: Folkers K, Yamamura Y, eds.

Vol 1. Folkers K, Shizukuishi S, Takemura K, et al. Res Commun Chem Pathol Pharmacol 38 2 : , Article CAS PubMed PubMed Central Google Scholar Lester, R.

Google Scholar Green, D. Google Scholar King, T. CAS PubMed Google Scholar Tsou, C. Article CAS PubMed PubMed Central Google Scholar Pumphrey, A. Article CAS PubMed PubMed Central Google Scholar Folch, J. CAS PubMed Google Scholar Goodwin, T.

CAS Google Scholar Goldberger, R. Google Scholar Download references. Author information Authors and Affiliations Department of Biochemistry, University of Leicester, ERIC R.

BURGOS Authors ERIC R. REDFEARN View author publications. View author publications. Rights and permissions Reprints and permissions. About this article Cite this article REDFEARN, E. Copy to clipboard. This article is cited by Comprehensive transcriptomic and proteomic analyses of antroquinonol biosynthetic genes and enzymes in Antrodia camphorata Xiaofeng Liu Yongjun Xia Lianzhong Ai AMB Express Zum histochemischen Nachweis von Enzymen des energieliefernden Stoffwechsels in Dermatophyten der Gattungen Microsporum, Epidermophyton und Keratinomyces W.

Meinhof Archiv f�r Klinische und Experimentelle Dermatologie �ber die Histotopie von Ubichinon in menschlicher Haut O. Braun-Falco D. Petzoldt Archiv f�r Klinische und Experimentelle Dermatologie Comments By submitting a comment you agree to abide by our Terms and Community Guidelines.

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