Effect Mitochondria

The control mechanisms operating on the TCA cycle are similar to those described for glycolysis above, that is allosteric and covalent. As might be predicted, it is the concentration of acetyl-CoA and the ATP-to-ADP and NADH-to-NAD+ ratios which are crucially important as these indicate energy status within each mitochondrion and implicitly therefore the energy status of the whole cell. High concentrations of ATP or NADH slow down the cycle, an effect which is partly mediated by covalent modification. 

In this model, cellular stress mediates the release of cytochrome C from the mitochondrion. The proapoptotic proteins Bax and BH3 proteins support the release of cytochrome C, while the antiapoptotic Bcl2 protein has an inhibitory effect. Cytosolic cytochrome C binds to the cofactor Apaf 1, which then associates via its CARD motif with procaspase 9 to a complex termed apopto-some. In this complex, procaspase 9 is processed to the mature caspase which subsequently activates downstream effector caspases and commits the cell to death. 

The effect of small-molecule modifiers on isocitrate dehydrogenase is appropriate in that a high-energy charge favors inhibition of isocitrate dehydrogenase and thus favors an accumulation of mitochondrial citrate. This leads to an increased flow of citrate from the mitochondrion to the cytosol where the citrate can exert its multiple positive effects on biosynthesis and its negative effects on glycolysis. 

The combined effect of exchanging extramitochon-drial ADP-3 and H2P04 for mitochondrial ATP-4 and OH is to move one proton into the mitochondrial matrix for every molecule of ATP that the mitochondrion releases into the cytosol. This proton translocation must be considered, along with the movement of protons through the ATP synthase, to account for the P-to-O ratio of oxidative phosphorylation. If three protons pass through the ATP synthase, and the adenine nucleotide and Pj transport systems move one additional proton, then four protons in total move into the matrix for each ATP molecule provided to the cytosol. 

Similarly, factors that stimulate acetyl-CoA carboxylase, the first enzyme in the pathway for fatty acid synthesis, also discourage fatty acid catabolism. This dual effect occurs because the first enzyme in the pathway leads to the formation of malonyl-CoA, which is a potent inhibitor of carnitine acyltransferase I. This inhibition prevents the transport of fatty acids into the mitochondrion, thereby, preventing fatty acid breakdown. 

The reducing equivalents of cytosolic NADH are transferred into mitochondria via shuttle mechanisms, such as the one involving aspartate and malate, shown in Fig. 11-19 (page 333). The net effect of this shuttle is the transport of NADH into the mitochondrion. 

Chloramphenicol blocks translation in bacteria by inhibiting peptidyltransferase of the large ribosomal subunit. It does not interfere with peptidyltransferase in the large subunit of eukaryotic ribosomes. However, the mitochondrion of animal cells contains ribosomes that are similar to bacterial ribosomes, and chloramphenicol can block protein synthesis in this organelle. This could contribute to the side effects of this drug when used in the treatment of animals. 

The relationship between the work rate (rate of delivery of ATP out of the mitochondrion) and [ADPC] is illustrated in Figure 7.12. Flux through the ANT transporter increases with [ADPC], with higher flux possible at higher NADH concentration, due to the effect of NADH on AT, which drives ANT. 

Protoporphyrinogen oxidase converts protoporphyrinogen IX to the fully desaturated porphyrin in a reaction that uses O2 as the terminal electron acceptor (Fig. 3). The crystal structure of the homodimeric enzyme shows it has one FAD per monomer, which presumably mediates the porphyrin oxidation reaction (19). Like the decarboxylation mediated by coproporphyrinogen oxidase, this reaction also occurs in the mitochondrion. Mutations in the protoporphyrinogen oxidase gene are responsible for variegate porphyria (21). Acute attacks of this disease can be effectively treated by intravenous administration of hematin. 

Fig. 23.1. ADP-driven volume and structural changes of mitochondria. Depending on the ADP concentration, the morphology of the interior changes as well as the volume of the mitochondrion, effectively regulating ATP production. Reproduced with permission [6]...

The overall effect of the malatc-asparlate shuttle is to transfer the equivalent of tw o electrons from the cytoplasm to the mitochondrion. The cycle is thought to be driven by cytoplasmic acid (H"). The concentration of protons in the cytoplasm is greater than that in the mitochondrion, which has an alkaline interior. This concentration gradient is thought to drive the membrane-bound glutamate/aspartate exchanger. 

In mammals, mercury is generally immunosuppressive, and apoptosis has been suggested as a possible mechanism for immunosuppression. Apoptosis may be induced in human CD4+ T cells at concentrations as low as 0.5 /xM HgCl2 (ref. 114), comparable to the results with lake trout thymocytes75. The target organelle for this apoptotic effect in human T cells is the mitochondrion, and the induction of oxidative... 

Transport of acetyl CoA from mitochondria to cytosol. The transport of the acetyl unit of acetyl CoA is moved out of the mitochondrion as citrate and reformed to acetyl CoA in the cytosol. The resulting oxaloacetate can participate in effective conversion of NADH to NADPH, the latter participating in cholesterol and fatty-acid synthesis. The acetyl carbons of... 

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