Mitochondrial respiratory

Luft, R., Ikkos, D., Palmieri, G., Emster, L., Aftelius, B. (1962). A case of severe hypermetabolism of non-thyroid origin with a defect in the maintenance of mitochondrial respiratory control A correlated clinical, biochemical and morphological study. J. Clin. Invest. 41, 1776-1804. 

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. 

Schults BE, Chan SI. 2001. Structures and proton-pumping strategies of mitochondrial respiratory enzymes. Annu Rev Biophys Biomol Struct 30 23. 

Flutolanil is an inhibitor of succinate dehydrogenase complex (Complex II), in the mitochondrial respiratory electron transport chain. ... 

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. 

Note that both acetogenins and styryl-lactones are cytotoxic for mammalian cells, as the result of distinct biochemical pathways, which, however, have their molecular origin near or in the mitochondrial membrane and/or the mitochondrial respiratory system (61,62). Acetogenins were first characterized as the active principles responsible for... 

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. 

The brain has a number of characteristics that make it especially susceptible to free- radical-mediated injury. Brain lipids are highly enriched in polyunsaturated fatty acids and many regions of the brain, for example, the substantia nigra and the striatum, have high concentrations of iron. Both these factors increase the susceptibility of brain cell membranes to lipid peroxidation. Because the brain is critically dependent on aerobic metabolism, mitochondrial respiratory activity is higher than in many other tissues, increasing the risk of free radical Teak from mitochondria conversely, free radical damage to mitochondria in brain may be tolerated relatively poorly because of this dependence on aerobic metabolism. 

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. 

Tune, B.M., Sibley, R.K. and Hsu, C.Y. (1988). The mitochondrial respiratory toxicity of cephalosporin antibiotics. An inhibitory effect on substrate uptake. J. Pharmacol. Exp. Ther. 245 1054-1059. 

The mitochondrial respiratory parameters have also been employed to determine the toxicity of surfactants, including anionic (LAS), nonionic (NPEO) and their metabolites, sulfophenyl carboxylates (SPCs), NP and nonylphenoxy carboxylate (NPECi) [37]. The system employed was the in vitro response of submitochondrial particles from beef heart. The EC50 toxicity calculated as the reduction rate of NAD+ ranged from 0.61 mg L-1 for a commercial LAS mixture to 18 000 mg L-1 for SPCs, and 1.3 mg L-1, 8.2 and 1.8mgL 1 for NPEOio, NPECi and NP, respectively. These results indicate that from the toxicity perspective, LAS is the compound demanding increased attention, while for NPEO, the parental compound and the metabolites must be quantified. 

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