Mitochondrial synthesis

The membrane potential in chloroplasts is almost entirely composed of the (ZpH component. The thylakoid membrane is permeable to Mg2+ and CP ions, so electrical neutrality is maintained. This differs from mitochondrial ATP synthesis where both a pH and an electrochemical potential exist. Because the chloroplast gradient is primarily SZj H in nature, three protons must move across the membrane to synthesize an ATP, rather than the two that move during mitochondrial synthesis of a single ATP. The ATP and NADPH from synthesis are both formed on the stromal side of the thylakoid membrane. They are available for the fixation of C02, which occurs in the stroma. See Figure 3-3. 

Coenzyme QIO is a powerful antioxidant naturally occurring in the mitochondria of myocardium, and it is an electron carrier in the mitochondrial synthesis of ATP. Patients with heart failure have lower myocardial levels of coenzyme QIO, but supplementation has been demonstrated to have variable benefits in randomized controlled trials. One meta-analysis on the use in congestive heart failure showed improvements in stroke volume, ejection fraction, cardiac output, cardiac index, and end diastolic volume index. " Another antioxidant associated with beneficial effects in cardiac patients is lycopene, a natural constituent of tomatoes. Lycopene is the major carotenoid found in human serum, and epidemiological studies have indicated an effect of dietary supplementation in reducing heart disease. Few dietary interventions have been reported one study showed a mild but significant hypocholesterolemic effect, and another showed a significant reduction in LDL oxidation. " Animal studies show an antiatherogenic effect of DHEA, and a review of the clinical trials and studies on DHEA in males with coronary heart disease reported a favorable or neutral effect. Plasma levels of DHEA are decreased in patients with chronic heart failure in proportion to its severity. ... 

Dihydroxy-5-cholenic acid, postulated as an intermediate in the mitochondrial synthesis of chenodeoxycholate from 7a-hydroxycholesterol [180,181], and a closely allied product, 3a,7a-dihydroxy-4-cholenic acid, have each been isolated from bile of hens and humans. Incubation of 3)8,7a-dihydroxy-5-cholenic acid with rat or carp hepatic microsomal preparations fortified with NADPH provided 3-oxo-7a-hydroxy-4-cholenic acid. Administration of the A acid to rats with cannulated bile ducts provided biliary metabolites identified as chenodeoxycholate, a- and )8-muricholates. Similar incubation of 3-oxo-7a-hydroxy-4-cholenic... 

Rubin, M.S., Tzagoloff, A. Assembly of the mitochondrial membrane system, X. Mitochondrial synthesis of three of the subunit proteins of yeast cytochrome oxidase. J. biol. Chem. 248, 4275-4279 (1973)... 

It could be suggested that mitochondrial synthesis of all types of stable RNAs is coordinately regulated and that this property depends on the fact that a single.form of mitochondrial RNA polymerase is deputed to the synthesis of the different types of mitochondrial RNAs. 

The second system is an elongation process and represents the classical mechanism of mitochondrial synthesis —in contrast to the condensation mechanism often called cytoplasmic mechanism —a certain part of which is also realizable in mitochondria. 

Besides the two classical mechanisms of saturated fatty acid synthesis, i.e., by condensation (cytoplasmic synthesis) and by elongation (mitochondrial synthesis), a mechanism of synthesis in micro-somes has recently been postulated. 

Dahlen and Porter (1968) studied the products of beef heart mitochondrial synthesis. The gas chromatographic peaks presented in their report were very similar to mass peaks characteristically seen in rabbit heart mitochondria. These authors, however, were able to appreciate a difiPerent spectrum of products depending upon the primer (acyl-CoA) used. When octanoate was the primer and the product was hydrogenated, the radioactivity was recovered in deca-noate, laurate, and myristate. The products were further analyzed by chromatography on silicic acid columns and more than half of the radioactive products were /3-hydroxy fatty acids. When linoleate was added as primer, most of the radioactivity was found in arachidonic acid. 

This discussion will concern only mitochondrial synthesis since this is the major mechanism in heart. Where would control be exerted Since the system has not been dissected, we do not know which is the rate-limiting step. All the equilibria for the enzymes of fatty acid oxidation are close to unity and easily reversed except for the thiolase step, which greatly favors cleavage. Whether or not the synthetic sequence proves to be the reverse of the oxidation sequence, the initial condensation will almost surely prove to be rate-limiting and the step at which control is exerted. As discussed above, Seubert s demonstration of mitochondrial feitty acid synthesis by enzymes of oxidation (Seubert et al., 1957) required an irreversible reductive step, or else the thiolase equilibrium would prevail. 

Mitochondrial monoamine oxidase, 1, 253 Mitomycin synthesis, 7, 658, 659 Mitomycin-A, 7, 93 Mitomycin-B, 7, 93 Mitomycin-C, 7, 93 as antitumor drug, 4, 374 Mixed function oxidases, 1, 224 Mobam... 

This is a crucial point because (as we will see) proton transport is coupled with ATP synthesis. Oxidation of one FADHg in the electron transport chain results in synthesis of approximately two molecules of ATP, compared with the approximately three ATPs produced by the oxidation of one NADH. Other enzymes can also supply electrons to UQ, including mitochondrial 5w-glyc-erophosphate dehydrogenase, an inner membrane-bound shuttle enzyme, and the fatty acyl-CoA dehydrogenases, three soluble matrix enzymes involved in fatty acid oxidation (Figure 21.7 also see Chapter 24). The path of electrons from succinate to UQ is shown in Figure 21.8. 

In 1961, Peter Mitchell, a British biochemist, proposed that the energy stored in a proton gradient across the inner mitochondrial membrane by electron transport drives the synthesis of ATP in cells. The proposal became known as... 

The mitochondrial complex that carries out ATP synthesis is called ATP synthase or sometimes FjFo-ATPase (for the reverse reaction it catalyzes). ATP synthase was observed in early electron micrographs of submitochondrial particles (prepared by sonication of inner membrane preparations) as round, 8.5-nm-diameter projections or particles on the inner membrane (Figure 21.23). In micrographs of native mitochondria, the projections appear on the matrixfacing surface of the inner membrane. Mild agitation removes the particles from isolated membrane preparations, and the isolated spherical particles catalyze ATP hydrolysis, the reverse reaction of the ATP synthase. Stripped of these particles, the membranes can still carry out electron transfer but cannot synthesize ATP. In one of the first reconstitution experiments with membrane proteins, Efraim Racker showed that adding the particles back to stripped membranes restored electron transfer-dependent ATP synthesis. 

Assuming that 3 H are transported per ATP synthesized in the mitochondrial matrix, the membrane potential difference is 0.18 V (negative inside), and the pH difference is 1 unit (acid outside, basic inside), calculate the largest ratio of [ATP]/[ADP] [P,] under which synthesis of ATP can occur. 

COMPARTMENTALIZED PYRUVATE CARBOXYLASE DEPENDS ON METABOLITE CONVERSION AND TRANSPORT The second interesting feature of pyruvate carboxylase is that it is found only in the matrix of the mitochondria. By contrast, the next enzyme in the gluconeogenic pathway, PEP carboxykinase, may be localized in the cytosol or in the mitochondria or both. For example, rabbit liver PEP carboxykinase is predominantly mitochondrial, whereas the rat liver enzyme is strictly cytosolic. In human liver, PEP carboxykinase is found both in the cytosol and in the mitochondria. Pyruvate is transported into the mitochondrial matrix, where it can be converted to acetyl-CoA (for use in the TCA cycle) and then to citrate (for fatty acid synthesis see Figure 25.1). /Uternatively, it may be converted directly to 0/ A by pyruvate carboxylase and used in glu-... 

Succinyl-CoA derived from propionyl-CoA can enter the TCA cycle. Oxidation of succinate to oxaloacetate provides a substrate for glucose synthesis. Thus, although the acetate units produced in /3-oxidation cannot be utilized in glu-coneogenesis by animals, the occasional propionate produced from oxidation of odd-carbon fatty acids can be used for sugar synthesis. Alternatively, succinate introduced to the TCA cycle from odd-carbon fatty acid oxidation may be oxidized to COg. However, all of the 4-carbon intermediates in the TCA cycle are regenerated in the cycle and thus should be viewed as catalytic species. Net consumption of succinyl-CoA thus does not occur directly in the TCA cycle. Rather, the succinyl-CoA generated from /3-oxidation of odd-carbon fatty acids must be converted to pyruvate and then to acetyl-CoA (which is completely oxidized in the TCA cycle). To follow this latter route, succinyl-CoA entering the TCA cycle must be first converted to malate in the usual way, and then transported from the mitochondrial matrix to the cytosol, where it is oxida-... 

Ketone body synthesis occurs only in the mitochondrial matrix. The reactions responsible for the formation of ketone bodies are shown in Figure 24.28. The first reaction—the condensation of two molecules of acetyl-CoA to form acetoacetyl-CoA—is catalyzed by thiolase, which is also known as acetoacetyl-CoA thiolase or acetyl-CoA acetyltransferase. This is the same enzyme that carries out the thiolase reaction in /3-oxidation, but here it runs in reverse. The second reaction adds another molecule of acetyl-CoA to give (i-hydroxy-(i-methyl-glutaryl-CoA, commonly abbreviated HMG-CoA. These two mitochondrial matrix reactions are analogous to the first two steps in cholesterol biosynthesis, a cytosolic process, as we shall see in Chapter 25. HMG-CoA is converted to acetoacetate and acetyl-CoA by the action of HMG-CoA lyase in a mixed aldol-Claisen ester cleavage reaction. This reaction is mechanistically similar to the reverse of the citrate synthase reaction in the TCA cycle. A membrane-bound enzyme, /3-hydroxybutyrate dehydrogenase, then can reduce acetoacetate to /3-hydroxybutyrate. 

The acetyl-CoA derived from amino acid degradation is normally insufficient for fatty acid biosynthesis, and the acetyl-CoA produced by pyruvate dehydrogenase and by fatty acid oxidation cannot cross the mitochondrial membrane to participate directly in fatty acid synthesis. Instead, acetyl-CoA is linked with oxaloacetate to form citrate, which is transported from the mitochondrial matrix to the cytosol (Figure 25.1). Here it can be converted back into acetyl-CoA and oxaloacetate by ATP-citrate lyase. In this manner, mitochondrial acetyl-CoA becomes the substrate for cytosolic fatty acid synthesis. (Oxaloacetate returns to the mitochondria in the form of either pyruvate or malate, which is then reconverted to acetyl-CoA and oxaloacetate, respectively.)... 

Synthesis of imidazo[l,2-d]pyridazines and their interaction with central and peripheral-type (mitochondrial) benzodiazepine receptors 98JHC1205. 

Coenzyme Qio (ubiquinone) is a coenzyme in the mitochondrial respiratoiy chain. It has a side chain made up of 10 isoprene units. Its synthesis can be inhibited by... 

The synthesis of virtually all proteins in a cell begins on ribosomes in the cytosol (except a few mitochondrial, and in the case of plants, a few chloroplast proteins that are synthesized on ribosomes inside these organelles). The fate of a protein molecule depends on its amino acid sequence, which can contain sorting signals that direct it to its corresponding organelle. Whereas proteins of mitochondria, peroxisomes, chloroplasts and of the interior of the nucleus are delivered directly from the cytosol, all other organelles receive their set of proteins indirectly via the ER. These proteins enter the so-called secretory pathway (Fig. 1). 

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