Mitochondria respiratory chain

P8. Pitkanen, S., Merante, F., McLeod, D. R., Applegarth, D., Tong, T., and Robinson, B. H., Familial mitochondrial myopathy with cataracts and lactic acidosis A defect in Complex I (NADH-dehydrogenase) of the mitochondria respiratory chain. Pediatr. Res. 39, 513-521 (1996). 

Fig. 39.2 Suggested effects leading to neuroprotective activity of hupA in AD. HupA is considered to modulate the APP processing by inducing the activity of a-secretase. The increased activity of a-secretase causes enhancement of nutritional APP (sAPPa) and consequently inhibition the A[i pathway. These APP-modulating effects are mediated through Ml muscarinic receptor-mediated PKC-dependent cascade and Trk receptor-mediated ERK/MAPK-dependent cascade and caused by increased levels of ACh and NGF in the synaptic junction. Increased release of sAPPa and decreased A(3 release from APP followed by inhibition of A[i fibril formations affects the regulation of the expression of apoptotic proteins, attenuates oxidative stress, and allows the mitochondria, respiratory chain, and TCA cycle to function normally. APP amyloid precursor protein, PKC protein kinase C. ERK extracellular signal-regulating kinase, MAPK mitogen-activated protein kinase, TCA tricarboxylic acid cycle (citric acid cycle)...

Mitochondria have their own DNA (mtDNA) and genetic continuity. This DNA only encodes 13 peptide subunits synthesized in the matrix that are components of complexes I, III, IV, and V of the respiratory chain. Most mitochondrial proteins are synthesized on cytoplasmic ribosomes and imported by specific mechanisms to their specific locations in the mitochondrion (see below). 

The central role of the mitochondrion is immediately apparent, since it acts as the focus of carbohydrate, hpid, and amino acid metabohsm. It contains the enzymes of the citric acid cycle, P-oxidation of fatty acids, and ketogenesis, as well as the respiratory chain and ATP synthase. 

Not all the cellular DNA is in the nucleus some is found in the mitochondria. In addition, mitochondria contain RNA as well as several enzymes used for protein synthesis. Interestingly, mitochond-rial RNA and DNA bear a closer resemblance to the nucleic acid of bacterial cells than they do to animal cells. For example, the rather small DNA molecule of the mitochondrion is circular and does not form nucleosomes. Its information is contained in approximately 16,500 nucleotides that func-tion in the synthesis of two ribosomal and 22 transfer RNAs (tRNAs). In addition, mitochondrial DNA codes for the synthesis of 13 proteins, all components of the respiratory chain and the oxidative phosphorylation system. Still, mitochondrial DNA does not contain sufficient information for the synthesis of all mitochondrial proteins most are coded by nuclear genes. Most mitochondrial proteins are synthesized in the cytosol from nuclear-derived messenger RNAs (mRNAs) and then transported into the mito-chondria, where they contribute to both the structural and the functional elements of this organelle. Because mitochondria are inherited cytoplasmically, an individual does not necessarily receive mitochondrial nucleic acid equally from each parent. In fact, mito-chondria are inherited maternally. 

Mitochondrial DNA is inherited maternally. What makes mitochondrial diseases particularly interesting from a genetic point of view is that the mitochondrion has its own DNA (mtDNA) and its own transcription and translation processes. The mtDNA encodes only 13 polypeptides nuclear DNA (nDNA) controls the synthesis of 90-95% of all mitochondrial proteins. All known mito-chondrially encoded polypeptides are located in the inner mitochondrial membrane as subunits of the respiratory chain complexes (Fig. 42-3), including seven subunits of complex I the apoprotein of cytochrome b the three larger subunits of cytochrome c oxidase, also termed complex IV and two subunits of ATPase, also termed complex V. 

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. 

FIGURE 19-1 Biochemical anatomy of a mitochondrion. The convolutions (cristae) of the inner membrane provide a very large surface area. The inner membrane of a single liver mitochondrion may have more than 10,000 sets of electron-transfer systems (respiratory chains) and ATP synthase molecules, distributed over the membrane surface. Heart mitochondria, which have more profuse cristae and thus a much larger area of inner membrane, contain more than three times as many sets of electron-transfer systems as liver mitochondria. The mitochondrial pool of coenzymes and intermediates is functionally separate from the cytosolic pool. The mitochondria of invertebrates, plants, and microbial eukaryotes are similar to those shown here, but with much variation in size, shape, and degree of convolution of the inner membrane. 

Current estimates are that three protons move into the matrix through the ATP-synthase for each ATP that is synthesized. We see below that one additional proton enters the mitochondrion in connection with the uptake of ADP and Pi and export of ATP, giving a total of four protons per ATP. How does this stoichiometry relate to the P-to-O ratio When mitochondria respire and form ATP at a constant rate, protons must return to the matrix at a rate that just balances the proton efflux driven by the electron-transport reactions. Suppose that 10 protons are pumped out for each pair of electrons that traverse the respiratory chain from NADH to 02, and 4 protons move back in for each ATP molecule that is synthesized. Because the rates of proton efflux and influx must balance, 2.5 molecules of ATP (10/4) should be formed for each pair of electrons that go to 02. The P-to-O ratio thus is given by the ratio of the proton stoichiometries. If oxidation of succinate extrudes six protons per pair of electrons, the P-to-O ratio for this substrate is 6/4, or 1.5. These ratios agree with the measured P-to-O ratios for the two substrates. 

In eukaryotes, most of the reactions of aerobic energy metabolism occur in mitochondria. An inner membrane separates the mitochondrion into two spaces the internal matrix space and the intermembrane space. An electron-transport system in the inner membrane oxidizes NADH and succinate at the expense of 02, generating ATP in the process. The operation of the respiratory chain and its coupling to ATP synthesis can be summarized as follows ... 

Mitchell based his concept on the suggestion that as electron is transported along the respiratory chain, H+ ions are ejected to cytoplasm (the mitochondrion environment). As a consequence, a gradient of H+ ion concentration occurs in external and internal mitochondrial spaces. Of course, this H+ ion concentration gradient is supported by electron transfer free energy decrease and in the case of membrane impermeability for H+ ions. 

Oxidative phosphorylation is ATP synthesis linked to the oxidation of NADH and FADH2 by electron transport through the respiratory chain. This occurs via a mechanism originally proposed as the chemiosmotic hypothesis. Energy liberated by electron transport is used to pump H+ ions out of the mitochondrion to create an electrochemical proton (H+) gradient. The protons flow back into the mitochondrion through the ATP synthase located in the inner mitochondrial membrane, and this drives ATP synthesis. Approximately three ATP molecules are synthesized per NADH oxidized and approximately two ATPs are synthesized per FADH2 oxidized. 

Allen s theory of redox poise, and the evidence supporting it, are discussed in Chap. 3 of this volume. Here, I want to make a few general observations on necessity and workability. Each mitochondrion needs a genome because the speed of electron flow down the respiratory chains depends not just on supply and demand (concentration of NADH, 02, ADP and inorganic phosphate) but also on the number and redox state of respiratory complexes (Allen 1993,... 

Degree of Reduction of Electron Carriers in the Respiratory Chain The degree of reduction of each carrier in the respiratory chain is determined by conditions in the mitochondrion. For example, when NADH and 02 are abundant, the steady-state degree of reduction of the carriers decreases as electrons pass from the substrate to 02. When electron transfer is blocked, the carriers before the block become more reduced and those beyond the block become more oxidized (see Fig. 19-6). For each of the conditions below, predict the state of oxidation of ubiquinone and cytochromes b, clt c, and a + a3. 

These organelles are the sites of energy production of aerobic cells and contain the enzymes of the tricarboxylic acid cycle, the respiratory chain, and the fatty acid oxidation system. The mitochondrion is bounded by a pair of specialized membranes that define the separate mitochondrial compartments, the internal matrix space and an intermembrane space. Molecules of 10,000 daltons or less can penetrate the outer membrane, but most of these molecules cannot pass the selectively permeable inner membrane. By a series of infoldings, the internal membrane forms cristae in the matrix space. The components of the respiratory chain and the enzyme complex that makes ATP are embedded in the inner membrane as well as a number of transport proteins that make it selectively permeable to small molecules that are metabolized by the enzymes in the matrix space. Matrix enzymes include those of the tricarboxylic acid cycle, the fatty acid oxidation system, and others. 

The control of the respiration process and ATP synthesis shifts as the metabolic state of the mitochondria changes. In an isolated mitochondrion, control over the respiration process in state 4 is mainly due to the proton leak through the mitochondrial inner membrane. This type of control decreases from state 4 to state 3, while the control by the adenine nucleotide and the dicarboxylate carriers, cytochrome oxidase, increases. ATP utilizing reactions and transport activities also increase. Therefore, in state 3, most of the control is due to respiratory chain and substrate transport. 

Mine eyes have seen the glory of respiratory chains In every mitochondrion, intrinsic to membranes,... 

The inconsistency between experiment and prediction must lead to the rejection of the model used to describe the system. In the case of oxidative phosphorylation this has led to a refined model, in which the chemiosmotic coupling is visualized as taking place within units of one (or a few) respiratory chain(s) plus ATP synthase, while the pumped protons have only limited access to the bulk phase inside and/or outside the mitochondrion [42]. This more refined model can again be tested by deriving from it flux-force relations according to the MNET approach. A discussion of the refined model can be found in Ref. 43. 

Thus, redox energy is conserved as pmf, which may subsequently be utilised to drive ATP synthesis or other energy-requiring reactions of the mitochondrion, such as ion transport. This principle of respiratory chain function is generally accepted. It... 

The mitochondrion is bounded by two pho-spholipid membranes. The outer membrane is freely permeable to molecules, including water, with a molecular weight of up to about 5000. The inner membrane is rich in membrane-bound proteins and consists, in terms of membrane area, of 50% phospholipid and 50% protein (Lenaz, 1988). Pyruvate dehydn>genase, a mitochondrial enzyme, is water soluble. The proteins of the respiratory chain, as well as ATP synthase, are all bound to the inner mitochondrial membrane. The enzymes of the Krebs cycle are water soluble, with the exception of succinate dehydrogenase. This enzyme is bound to the mitochondrial membrane, where it directly funnels electrons, via HAD, to the respiratory chain. 

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