Mitochondrial electron transport metabolism

Mitochondria, nitric oxide synthase and arachidonic acid metabolism are sources of reactive oxygen species during ischemia-reperfusion injury. ROS generation during ischemia-reperfusion may come from several sources, including NOS activity, mitochondrial electron transport, multiple steps in the metabolism of arachidonic... 

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. 

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. 

Figure 7.44 The metabolism and toxicity of MPTP. Diffusion into the brain is followed by metabolism in the astrocyte. The metabolite MPP+ is actively transported into the dopaminergic neuron by DAT. It is accumulated there and is actively taken into mitochondria by another uptake system. Here, it inhibits mitochondrial electron transport between NADH dehydrogenase (NADH DHase) and coenzyme Q (Q10). Consequently, it blocks the electron transport system, depletes ATP, and destroys the neuron. Abbreviations MPTP, 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine DAT, dopamine transporter uptake system.

MPTP is a molecule, which is sufficiently lipophilic to cross the blood-brain barrier and enter the astrocyte cells. Once in these cells, it can be metabolized by monoamine oxidase B to MPDP and then MPP both of which are charged molecules. These metabolites are therefore not able to diffuse out of the astrocyte into the bloodstream and away from the brain. However, the structure of MPP allows it to be taken up by a carrier system and concentrated in dopaminergic neurones. In the neurone, it inhibits the mitochondrial electron transport chain leading to damage to the neurone. 

Chemical reactions involving oxidation and reduction processes (redox reactions) are central to metabolism. The energy derived from the oxidation of carbohydrates is coupled to the synthesis of ATP via a series of redox reactions, the mitochondrial electron-transport chain (see Chap. 14). Moreover, most life on earth is dependent on a series of redox reactions in photosynthesis, the process in which solar energy is used to produce ATP and O2 and to synthesize carbohydrates from CO2. 

Fig. 2.8. Factors controlling the production of free radicals in cells and tissues (Rice-Gvans, 1990a). Free radicals may be generated in cells and tissues through increased radical input mediated by the disruption of internal processes or by external influences, or as a consequence of decreased protective capacity. Increased radical input may arise through excessive leukocyte activation, disrupted mitochondrial electron transport or altered arachidonic acid metabolism. Delocalization or redistribution of transition metal ion complexes may also induce oxidative stress, for example, microbleeding in the brain, in the eye, in the rheumatoid joint. In addition, reduced activities or levels of protectant enzymes, destruction or suppressed production of nucleotide coenzymes, reduced levels of antioxidants, abnormal glutathione metabolism, or leakage of antioxidants through damaged membranes, can all contribute to oxidative stress.

Aerobic respiration The mitochondrial electron-transport chain incorporates cytochrome c, and the oxidation and reduction of the iron atoms in this biomolecule passes electrons through a series or chain of metabolic reactions. This is illustrated in Figure 4.3. 

The metabolic function of the flavin coenzymes is as electron carriers in a wide variety of oxidation and reduction reactions central to aU metabolic processes, including the mitochondrial electron transport chain. Unlike the nicotinamide nucleotide coenzymes (Section 8.4.1), which act as cosubstrates, leaving the catalytic site of the enzyme at the end of the reaction, the flavin coenzymes remain bound to the enzyme throughout the catalytic cycle. 

In general, NAD+ is involved as an election acceptor in energy-yielding metabolism, and the resultant NADH is oxidized by the mitochondrial electron transport chain. The major coenzyme for reductive synthetic reactions is NADPH. An exception here is the pentose phosphate pathway (see Figure 6.4), which reduces NADP+ to NADPH and is the source of about half the reductant for lipogenesis. 

Copper plays an important role in the constituents of many enzymes of the mammalian organism as well as in plants and anthropods. Several classes of oxidizing enzymes for copper have been described, including the cytochrome oxidases which are the terminal oxidases in the mitochondrial electron transport system, a key reaction in energy metabolism (34), and the amine oxidases (35) of which there are a number that contain copper (36,37,38), Lysyl oxidase (39) is probably the most important since it plays a major role in elastin and collagen synthesis... 

Phosphine is known to disrupt protein synthesis and enzymatic activity, particularly in lung and heart cell mitochondria. This can lead to a blockage of the mitochondrial electron transport chain. Phosphine may cause denaturing of various enzymes involved in cellular respiration and metabolism, and may be responsible for denaturing of the oxyhemoglobin molecule. 

The belief that alcoholics are more susceptible to the toxicity of 2,4-DNP during occupational exposure (Perkins 1919) may indicate an interaction with ethanol (and possibly other alcohols) or it may simply be a function of the compromised physiological state of alcoholics. 2,4-DNP appears to markedly increase the rate of ethanol metabolism in rat liver slices by 100-160% (Videla and Israel 1970) and in rats in vivo by 20-30% (Israel et al. 1970). Because 2,4-DNP uncouples mitochondrial electron transport from oxidative phosphorylation, the oxidation of NADH to NAD is accelerated in the mitochondria. Reoxidation of NADH rather than the activity of alcohol dehydrogenase is the rate-limiting step in the metabolism of ethanol, and, therefore, the metabolic effect of 2,4-DNP enhances the clearance of ethanol (Eriksson et al. 1974). Because 2,4-DNP is known to augment the rate of respiration and perspiration, 2.7-8.2% of the initial dose of ethanol was also eliminated by expiration and cutaneous evaporation in the rat (Israel et al. 1970). 

Starch and sucrose, key substrates for the development of dental caries, are exclusively synthesized by plants. They are made in plant leaves by a process called photosynthesis, which utilizes sunlight as the energy source. This chapter outlines the light and dark reactions of photosynthesis and compares the light reaction with mitochondrial electron transport (Sect. 1). The key dark reaction, the production of phosphoglycerate by the enzyme ribulose bisphosphate carboxylase (rubisco), is described along with the production of fructose, sucrose, and starch (Sect. 2). The chapter concludes with a detailed discussion of the roles of starch and sucrose in plant metabolism (Sect. 3). 

The availability of metabolites for sucrose synthesis and the need for products of sucrose degradation regulate gene expression. For respiration, sucrose is hydrolyzed by invertase to free glucose and fructose, which are phosphorylated and undergo glycolysis to pyruvate. The pyruvate is then either metabolized by mitochondrial electron transport to ATP and NADH (respiration), or metabolized to provide starting products for amino acid, lipid, and nucleotide syntheses. 

ROS can be generated from multiple sources. These include mitochondrial electron transport, NOS activity, arachidonic acid metabolism, and xanthine oxidase (produced by hydrolysis of xanthine dehydrogenase). Moreover, altered binding of transition metals such as iron due to acidic conditions in ischemia may increase their participation in the Haber-Weiss reaction (Halliwell, 1992). In addition, P450 enzyme.s and NAD (P)H oxidase are possible sources of ROS. 

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