Ubiquinone complex

The main part of the electron transport chain consists of three large protein complexes embedded in the inner mitochondrial membrane, called NADH dehydrogenase, the cytochrome bcx complex and cytochrome oxidase. Electrons flow from NADH to oxygen through these three complexes as shown in Fig. 1. Each complex contains several electron carriers (see below) that work sequentially to carry electrons down the chain. Two small electron carriers are also needed to link these large complexes ubiquinone, which is also called coenzyme Q (abbreviated here as CoQ), and cytochrome c (Fig. 1). 

Most of the carriers of the photosynthetic electron transfer chain are included in large transmembrane protein complexes, two in the case of bacterial photosynthesis and three for oxygenic photosynthesis. On a time-scale of several seconds, these complexes can be considered as immobilized in the membrane. Two types of soluble electron carriers establish a link between the membrane complexes ubiquinone or plastoquinone diffuse in the lipid phase of the membrane, while cyt c2 or plastocyanin which are hydrosoluble, diffuse in the periplasmic space or the internal aquous phase of the thylakoid. In a classical view of the photosynthetic apparatus, the soluble carriers are supposed to diffuse rapidly over long distances therefore, we can expect that in the dark or under weak illumination, the carriers of the electron transfer chain are close to thermodynamic equilibrium. In such circumstances, the localization of the different electron carriers within the membrane should be of little functional importance. 

Walker, J. E., 1992. The NADH ubiquinone oxidoreducta.se (Complex I) of respiratory chains. Quarterly Reviews of Biophysics 25 253-324. 

Ubiquinones function within the mitochondria of cells to mediate the respiration process in which electrons are transported from the biological reducing agent NADH to molecular oxygen. Through a complex series of steps, the ultimate result is a cycle whereby NADH is oxidized to NAD+, O2 is reduced to water, and energy is produced. Ubiquinone acts only as an intermediary and is itself unchanged. 

Atovaquone, a hydroxynaphthoquinone, selectively inhibits the respiratory chain of protozoan mitochondria at the cytochrome bcl complex (complex III) by mimicking the natural substrate, ubiquinone. Inhibition of cytochrome bcl disrupts the mitochondrial electron transfer chain and leads to a breakdown of the mitochondrial membrane potential. Atovaquone is effective against all parasite stages in humans, including the liver stages. 

Electrons from NADH, together with two protons, are transferred to ubiquinone to form ubiquinol by complex I (NADH ubiquinone oxidoreductase). Complex I... 

Complexes of the Mitochondrial Electron-Transport Chain Complex I (NADH Ubiquinone Oxidoreductase)... 

Complex II contains four peptides, the two largest form succinate dehydrogenase, the largest has covalently boiuid flavin adenine dinucleotide (FAD) which reacts with succinate, and the other has three iron-sulphur centers. Smaller subunits anchor the two larger subunits to the membrane and form the UQ binding site. Ubiquinone is the electron acceptor but complex II does not pump protons (see below). 

Another pathway is the L-glycerol 3-phosphate shuttle (Figure 11). Cytosolic dihydroxyacetone phosphate is reduced by NADFl to s.n-glycerol 3-phosphate, catalyzed by s,n-glycerol 3-phosphate dehydrogenase, and this is then oxidized by s,n-glycerol 3-phosphate ubiquinone oxidoreductase to dihydroxyacetone phosphate, which is a flavoprotein on the outer surface of the inner membrane. By this route electrons enter the respiratory chain.from cytosolic NADH at the level of complex III. Less well defined is the possibility that cytosolic NADH is oxidized by cytochrome bs reductase in the outer mitochondrial membrane and that electrons are transferred via cytochrome b5 in the endoplasmic reticulum to the respiratory chain at the level of cytochrome c (Fischer et al., 1985). 

This complex consists of at least 25 separate polypeptides, seven of which are encoded by mtDNA. Its catalytic action is to transfer electrons from NADH to ubiquinone, thus replenishing NAD concentrations. Complex I deficiency has been described in myopathic syndromes, characterized by exercise intolerance and lactic acidemia. In at least some patients it has been demonstrated that the defect is tissue specific and a defect in nuclear DNA is assumed. Muscle biopsy findings in these patients are typical of those in many respiratory chain abnormalities. Instead of the even distribution of mitochondria seen in normal muscle fibers, mitochondria are seen in dense clusters, especially at the fiber periphery, giving rise to the ragged-red fiber (Figure 10). This appearance is a hallmark of many mitochondrial myopathies. 

This complex consists of four subunits, all of which are encoded on nuclear DNA, synthesized on cytosolic ribosomes, and transported into mitochondria. The succinate dehydrogenase (SDH) component of the complex oxidizes succinate to fumarate with transfer of electrons via its prosthetic group, FAD, to ubiquinone. It is unique in that it participates both in the respiratory chain and in the tricarboxylic acid (TC A) cycle. Defects of complex II are rare and only about 10 cases have been reported to date. Clinical syndromes include myopathy, but the major presenting features are often encephalopathy, with seizures and psychomotor retardation. Succinate oxidation is severely impaired (Figure 11). 

Ubiquinone or Q (coenjyme Q) (Figure 12-5) finks the flavoproteins to cytochrome h, the member of the cytochrome chain of lowest redox potential. Q exists in the oxidized quinone or reduced quinol form under aerobic or anaerobic conditions, respectively. The structure of Q is very similar to that of vitamin K and vitamin E (Chapter 45) and of plastoquinone, found in chloroplasts. Q acts as a mobile component of the respiratory chain that collects reducing equivalents from the more fixed flavoprotein complexes and passes them on to the cytochromes. 

Figure 12-7. Proposed sites of inhibition (0) of the respiratory chain by specific drugs, chemicals, and antibiotics. The sites that appear to support phosphorylation are indicated. BAL, dimercaprol. TTFA, an Fe-chelating agent. Complex I, NADHiubiquinone oxidoreductase complex II, succinate ubiquinone oxidoreductase complex III, ubiquinohferricytochrome c oxidoreductase complex IV, ferrocytochrome ctoxygen oxidoreductase. Other abbreviations as in Figure 12-4.

Figure 12-8. Principles of the chemiosmotic theory of oxidative phosphorylation. The main proton circuit is created by the coupling of oxidation in the respiratory chain to proton translocation from the inside to the outside of the membrane, driven by the respiratory chain complexes I, III, and IV, each of which acts as a protonpump. Q, ubiquinone C, cytochrome c F Fq, protein subunits which utilize energy from the proton gradient to promote phosphorylation. Uncoupling agents such as dinitrophenol allow leakage of H" across the membrane, thus collapsing the electrochemical proton gradient. Oligomycin specifically blocks conduction of H" through Fq.

Barker CD, Reda T, Hirst J. 2007. The flavoprotein suhcomplex of complex I (NADH ubiquinone oxidoreductase) from bovine heart mitochondria Insights into the mechanisms of NADH oxidation and NAD reduction from protein film voltammetry. Biochemistry 46 3454-3464. 

Saruta, F., Kuramochi, T., Nakamura, K, Takamiya, S., Yu, Y., Aoki, T., Sekimizu, K., Kojima, S. and Kita, K. (1995) Stage-specific isoforms of complex II (succinate-ubiquinone oxidoreductase) in mitochondria from the parasitic nematode, Ascaris suum. Journal of Biological Chemistry 270, 928-932. 

Smith, R.J., Capaldi, R.A., Muchmone, D., and Dahlquist, F. (1978) Cross-linking of ubiquinone cytoch-nome c reductase (complex III) with periodate-cleavable bifunctional reagents. Biochemistry 17, 3719-3723. 

Now, we may consider in detail the mechanism of oxygen radical production by mitochondria. There are definite thermodynamic conditions, which regulate one-electron transfer from the electron carriers of mitochondrial respiratory chain to dioxygen these components must have the one-electron reduction potentials more negative than that of dioxygen Eq( 02 /02]) = —0.16 V. As the reduction potentials of components of respiratory chain are changed from 0.320 to +0.380 V, it is obvious that various sources of superoxide production may exist in mitochondria. As already noted earlier, the two main sources of superoxide are present in Complexes I and III of the respiratory chain in both of them, the role of ubiquinone seems to be dominant. Although superoxide may be formed by the one-electron oxidation of ubisemiquinone radical anion (Reaction (1)) [10,22] or even neutral semiquinone radical [9], the efficiency of these ways of superoxide formation in mitochondria is doubtful. 

The efficiency of vitamin E in the suppression of free radical-mediated damage induced by iron overload has been studied in animals and humans. Galleano and Puntarulo [46] showed that iron overload increased lipid and protein peroxidation in rat liver. Vitamin E supplementation successfully suppressed these effects and led to an increase in a-tocopherol, ubiquinone-9, and ubiquinone-10 contents in liver. Important results were obtained by Roob et al. [47] who found that vitamin E supplementation attenuated lipid peroxidation (measured as plasma MDA and plasma lipid peroxides) in patients on hemodialysis after receiving iron hydroxide sucrose complex intravenously during hemodialysis session. These findings support the proposal that iron overload enhances free radical-mediated damage in humans. 

NADH-ubiquinone reductase) and the second one was complex II (succinate-ubiquinone reductase). Chiesi and Schwaller [101] found that quercetin and tannin inhibited neuronal constitutive endothelial NO synthase. 

Ubiquinones (coenzymes Q) Q9 and Qi0 are essential cofactors (electron carriers) in the mitochondrial electron transport chain. They play a key role shuttling electrons from NADH and succinate dehydrogenases to the cytochrome b-c1 complex in the inner mitochondrial membrane. Ubiquinones are lipid-soluble compounds containing a redox active quinoid ring and a tail of 50 (Qio) or 45 (Q9) carbon atoms (Figure 29.10). The predominant ubiquinone in humans is Qio while in rodents it is Q9. Ubiquinones are especially abundant in the mitochondrial respiratory chain where their concentration is about 100 times higher than that of other electron carriers. Ubihydroquinone Q10 is also found in LDL where it supposedly exhibits the antioxidant activity (see Chapter 23). 

In the mitochondria, ONOO- can mediate damage to OXPHOS by nitrosylat-ing/oxidizing tyrosine or thiol functional groups, rendering catalytic inactivation of complex I [NADH ubiquinone oxidoreductase], complex II [succinate ubiquinone oxidoreductase] and complex V (FI, FO-ATPase), thereby impeding ETC/ OXPHOS... 

Mitchell, P. (1975) Protonmotive redox mechanism of the cytochrome b-c1 complex in the respiratory chain protonmotive ubiquinone cycle, FEBS Lett., 56, 1-6. 

The most recent model of this membrane, the fluid mosaic model [13] is pictured in cartoon fashion in Fig. 2. In this model, the transduction proteins (complexes I-IV) are randomly dispersed in the membrane and redox equivalents are delivered from one complex to another via the mobile electron carriers cytochrome c and ubiquinone. It is necessary that cytochrome c be able to move relatively facilely from one complex to another. Thus the binding constants cannot be too high without making the associated OS rates too slow. Conversely, to prevent unproductive short circuits via cytochrome c from complex I directly to IV, there must exist molecular recognition which favors selective binding of cytochrome c to hcj and cytochrome oxidase (and perhaps disfavors binding to complex 1 or II). 

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