Respiratory chain, mitochondrial

These include the mitochondrial respiratory chain, key enzymes in fatty acid and amino acid oxidation, and the citric acid cycle. Reoxidation of the reduced flavin in oxygenases and mixed-function oxidases proceeds by way of formation of the flavin radical and flavin hydroperoxide, with the intermediate generation of superoxide and perhydroxyl radicals and hydrogen peroxide. Because of this, flavin oxidases make a significant contribution to the total oxidant stress of the body. 

Khan AA, Schuler MM, Prior MG, et al. 1990. Effects of hydrogen sulfide exposure on lung mitochondrial respiratory chain enzymes in rats. Toxicol Appl Pharmacol 103 482-490. 

Peris E, Estornell E, Cabedo N, Cortes D, Bermejo A. 3-Acetylaltholactone and related styryl-lactones, mitochondrial respiratory chain inhibitors. Phytochemistry 2000 54 311-315. 

In biochemical systems, acid-base and redox reactions are essential. Electron transfer plays an obvious, crucial role in photosynthesis, and redox reactions are central to the response to oxidative stress, and to the innate immune system and inflammatory response. Acid-base and proton transfer reactions are a part of most enzyme mechanisms, and are also closely linked to protein folding and stability. Proton and electron transfer are often coupled, as in almost all the steps of the mitochondrial respiratory chain. 

FIGURE 23.1 Mitochondrial respiratory chain. (Adapted from JF Turrens, BA Freeman, JG Levitt, ID Crapo. Arch Biochem Biophys 217 401-410, 1982.)... 

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. 

As described earlier, superoxide is a well-proven participant in apoptosis, and its role is tightly connected with the release of cytochrome c. It has been proposed that a switch from the normal four-electron reduction of dioxygen through mitochondrial respiratory chain to the one-electron reduction of dioxygen to superoxide can be an initial event in apoptosis development. This proposal was supported by experimental data. Thus, Petrosillo et al. [104] have shown that mitochondrial-produced oxygen radicals induced the dissociation of cytochrome c from bovine heart submitochondrial particles supposedly via cardiolipin peroxidation. Similarly, it has been found [105] that superoxide elicited rapid cytochrome c release in permeabilized HepG2 cells. In contrast, it was also suggested [106] that it is the release of cytochrome c that inhibits mitochondrial respiration and stimulates superoxide production. 

O Donnell et al. [70] found that LOX and not cyclooxygenase, cytochrome P-450, NO synthase, NADPH oxidase, xanthine oxidase, ribonucleotide reductase, or mitochondrial respiratory chain is responsible for TNF-a-mediated apoptosis of murine fibrosarcoma cells. 15-LOX activity was found to increase sharply in heart, lung, and vascular tissues of rabbits by hypercholesterolemia [71], Schnurr et al. [72] demonstrated that there is an inverse regulation of 12/15-LOXs and phospholipid hydroperoxide glutathione peroxidases in cells, which balanced the intracellular concentration of oxidized lipids. 

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). 

There are two kinds of redox interactions, in which ubiquinones can manifest their antioxidant activity the reactions with quinone and hydroquinone forms. It is assumed that the ubiquinone-ubisemiquinone pair (Figure 29.10) is an electron carrier in mitochondrial respiratory chain. There are numerous studies [235] suggesting that superoxide is formed during the one-electron oxidation of ubisemiquinones (Reaction (25)). As this reaction is a reversible one, its direction depends on one-electron reduction potentials of semiquinone and dioxygen. 

MAO is a flavoprotein enzyme that is found on the outer membrane of mitochondria. It oxidatively deami nates short-chain monoamines only, and it is not part of the DM MS. ATP is involved in the transfer of reducing equivalents through the mitochondrial respiratory chain, not the microsomal system. 

Bolanos, J. P., Heales, S. J., Land, J. M. etal. Effect of per-oxynitrite on the mitochondrial respiratory chain differential susceptibility of neurones and astrocytes in primary culture. /. Neurochem. 64 1965-1972,1995. 

Bourgeron, T., Rustin, Chretien, D. etal. Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency Nat. Genet. 11 44—149, 1995. 

Cytochrome c oxidase (an enzyme in the mitochondrial respiratory chain) is sensitive to cyanide action (Way 1984). Due to its inhibition, oxygen cannot be utilized, histotoxic hypoxia develops, and this can lead to deaths of humans and animals (see Section 2.3.3). 

As the AO with a direct nonspecific mechanism of action we have chosen Hypoxene - sodium poly(2,5-dihydroxiphenyl)-4-thiosulfonate. Besides a direct AO effect as a scavenger of free radicals it exerts an anti-hypoxic effect shunting I and II complexes of mitochondrial respiratory chain, which are inhibited as a consequence of hypoxia (Eropkin et al., 2007). Hypoxene was introduced into cell incubation media before illumination and left during cells further incubation. Hypoxene in the concentration of 40pg/ml, comparable to doses applied in vivo, completely blocked C60-induced phototoxicity (Table 7.3). Cellular viability has completely recovered to control level, which is a convincing evidence of free radical nature of cellular damage in photodynamic effect of fullerene. 

As an example calculation, we can consider the passage of a pair of electrons along the mitochondrial respiratory chain from NADH to oxygen during oxidative phosphorylation. The process can be viewed as two half reactions, each with a redox potential ... 

As the power house of the cell, the mitochondrion is essential for energy metabolism. As the motor of cell death (1), this organelle is central to the initiation and regulation of apoptosis. In addition, mitochondria are critically involved in the modulation of intracellular calcium concentration and the mitochondrial respiratory chain is the major source of damaging reactive oxygen species. Mitochondria also play a crucial role in numerous catabolic and anabolic cellular pathways. 

In the hydrogenosomal membranes, EPR spectra showed no trace of the highly characteristic features of the iron-sulfur clusters of complex I (NADH ubiquinone reductase) and the Rieske protein of complex III of the mitochondrial respiratory chain. This is consistent with the absence of... 

Cytochrome bci is a multicomponent enzyme found in the inner mitochron-drial membrane of eukaryotes and in the plasma membrane of bacteria. The cytochrome bci complex functions as the middle component of the mitochondrial respiratory chain, coupling electron transfer between ubiquinone/ ubiquinol (see Figure 7.27) and cytochrome c. 

Mitochondria are the ATP suppliers of the cells and have an important role in modulating intracellular calcium levels and cellular apoptosis. The mitochondrial respiratory chain is furthermore an important suppher of damaging free radicals. Evidence increases that mitochondria are heavily involved in numerous diseases and therefore they may become important targets for the development of new drugs and therapies [47]. 

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