The Mitochondrial Electron-Transport Chain

In eukaryotic cells, electron transport and oxidative phosphorylation occur in mitochondria. Mitochondria have both an outer membrane and an inner membrane with extensive infoldings called cristae (fig. 14.2). The inner membrane separates the internal matrix space from the intermembrane space between the inner and outer membranes. The outer membrane has only a few known enzymatic activities and is permeable to molecules with molecular weights up to about 5,000. By contrast, the inner membrane is impermeable to most ions and polar molecules, and its proteins include the enzymes that catalyze oxygen consumption and formation of ATP. The role of mitochondria in 02 uptake, or respiration, was demonstrated in 1913 by Otto Warburg but was not fully confirmed until 1948, when Eugene Kennedy and Albert Lehninger showed that mitochondria carry out the reactions of the TCA cycle, the transport of electrons to 02, and the formation of ATP. 

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The decline in immune function may pardy depend on a deficiency of coenzyme Q, a group of closely related quinone compounds (ubiquinones) that participate in the mitochondrial electron transport chain (49). Concentrations of coenzyme Q (specifically coenzyme Q q) appear to decline with age in several organs, most notably the thymus. 

FIGURE 21.3 % J and % values for the components of the mitochondrial electron transport chain. Values indicated are consensus values for animal mitochondria. Black bars represent %r red bars,. ... 

The Stoichiometry of Proton Pumping by the Mitochondrial Electron-Transport Chain 129... 

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

Polymorphonuclear leucocytes (PMNs) employ a system comprising myeloperoxidase, hydrogen peroxide, and a halide factor to kill microorganisms and tumour cells. This process is sometimes loosely called the respiratory burst , which refers to the sudden rise in oxygen consumption by the phagocytosing neutrophils that is independent of the mitochondrial electron transport chain. 

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). 

FIGURE 32-7 Sources of free radical formation which may contribute to injury during ischemia-reperfusion. Nitric oxide synthase, the mitochondrial electron-transport chain and metabolism of arachidonic acid are among the likely contributors. CaM, calcium/calmodulin FAD, flavin adenine dinucleotide FMN, flavin mononucleotide HtT, tetrahydrobiopterin HETES, hydroxyeicosatetraenoic acids L, lipid alkoxyl radical LOO, lipid peroxyl radical NO, nitric oxide 0 "2, superoxide radical. 

Figure 5.17 The mitochondrial electron-transport chain. (From Voet and Voet, 2004. Reproduced with permission from John Wiley Sons., Inc.)...

Iron is also a key constitnent of many enzymes involved in electron transfer reactions, inclnding those involved in the mitochondrial electron transport chain conpled to the synthesis of ATP. 

Mitochondria have their own limited genome, the remnants of the genome of the microorganism from which they are derived. Mitochondrial genes code for 13 proteins that are synthesized in the mitochondria and are critical parts of the mitochondrial electron transport chain. 

Coenzyme QIO (21) is one of the essential enzymes in the mitochondrial electron transport chain, participating in the aerobic respiration cycle. The role of Co-QlO as a cardioprotective substance and an antioxidant are well studied. Recently, it was found that Co-QlO is also capable of attenuating the intracellular deposition of Ap in transgenic AD mouse models. Additionally, the same group reported that Co-QlO administration also led to reduction of preexisting plaque burden in the same model. Such properties are suggestive of a potential therapeutic role for Co-QlO in AD. 

Electrons are removed from NADH and delivered to the mitochondrial electron transport chain where they ultimately are transferred to oxygen (see Chapter 7). 

Furthermore, Marshall et al. developed the extractable MBF tracer 7 -[ F] fluoro-6, 7 -dihydrorotenone (p F]FDHR) [72]. p F]FDHR is a derivative of the neutral and lipophilic lead compound rotenone that binds to the complex I of the mitochondrial electron transport chain [73-76]. It was prepared from 7 -tosyl-oxy-6, 7 -dihydroroten-12-ol (DHR-ol-OTos) in two steps. After nucleophilic substitution of DHR-ol-OTos with p F]fluoride, the intermediate was oxidized with manganese dioxide to yield the target compound [ F]FDHR (Fig. 11). 

Recently introduced insecticide/acaricides, pyrimidifen and fenaza-quin (Figure 3.13), also inhibit the mitochondrial electron transport chain by binding with complex I at coenzyme site Q. 

Cytochrome c and Cytochrome c Oxidase. - The mitochondrial electron transport chain is the site at which most of the free energy to be obtained from the oxidation of substrates is released and conserved as the energy-rich molecule ATP. In the final stage of this process, CcO, which is supplied with electrons by cyt c, catalyses the four-electron reduction of oxygen to water. Both are haem proteins, with CcO containing two haem and three copper centres, and both exhibit peroxidase-type activity. 

Decreased metabolism of lipids. Decreased mitochondrial oxidation of fatty acids is another possible cause of ethanol-induced steatosis. Other possible causes are vitamin deficiencies and the inhibition of the mitochondrial electron transport chain. 

The drug interferes with the mitochondrial electron transport chain. It seems that this is due to a high affinity of the drug for lipids such as cardiolipin, a component of the mitochondrial inner membrane. It therefore accumulates there. 

This may be due to the interference with the mitochondrial electron transport chain. Thus, cadmium binds to complex III at the Q0 site between semi-ubiquinone and heme b566. This stops delivery of electrons to the heme and allows accumulation of semi-ubiquinone, which in turn transfers the electrons to oxygen and produces superoxide. 

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