Mitchell loop

P. Mitchell (Nobel Prize for Chemistry, 1978) explained these facts by his chemiosmotic theory. This theory is based on the ordering of successive oxidation processes into reaction sequences called loops. Each loop consists of two basic processes, one of which is oriented in the direction away from the matrix surface of the internal membrane into the intracristal space and connected with the transfer of electrons together with protons. The second process is oriented in the opposite direction and is connected with the transfer of electrons alone. Figure 6.27 depicts the first Mitchell loop, whose first step involves reduction of NAD+ (the oxidized form of nicotinamide adenosine dinucleotide) by the carbonaceous substrate, SH2. In this process, two electrons and two protons are transferred from the matrix space. The protons are accumulated in the intracristal space, while electrons are transferred in the opposite direction by the reduction of the oxidized form of the Fe-S protein. This reduces a further component of the electron transport chain on the matrix side of the membrane and the process is repeated. The final process is the reduction of molecular oxygen with the reduced form of cytochrome oxidase. It would appear that this reaction sequence includes not only loops but also a proton pump, i.e. an enzymatic system that can employ the energy of the redox step in the electron transfer chain for translocation of protons from the matrix space into the intracristal space. 

Fig. 14-5 Mitchell loop mechanism for proton translocation. SH2 = reduced substrate,...

What experimentally testable predictions does the Mitchell loop mechanism make ... 

Fig. 6.27 An example of Mitchell s loops . The substrate SH2 is oxidized by NAD+ (nicotinamideadeninedinucleotide) and the reduced form transports two protons and two electrons, of which two protons remain in the intracristal space and two electrons are transported back by the Fe-S protein to reduce FMN (flavinmononucleotide), the reduced form of which transports two protons and two electrons in the opposite direction...

To explain how H+ transfer occurred across the membrane Mitchell suggested the protons were translocated by redox loops with different reducing equivalents in their two arms. The first loop would be associated with flavoprotein/non-heme iron interaction and the second, more controversially, with CoQ. Redox loops required an ordered arrangement of the components of the electron transport system across the inner mitochondrial membrane, which was substantiated from immunochemical studies with submitochondrial particles. Cytochrome c, for example, was located at the intermembranal face of the inner membrane and cytochrome oxidase was transmembranal. The alternative to redox loops, proton pumping, is now known to be a property of cytochrome oxidase. 

Mirkovitch J, Mirault ME, Laemmli UK (1984) Organization of the higher-order chromatin loop Specific DNA attachment sites on nuclear scaffold. Cell 39(l) 223-232 Mitchell RS, Beitzel BF, Schroder AR, Shinn P, Chen H, Berry CC, Ecker JR, Bushman FD (2004) Retroviral DNA integration ASLV, HIV, and MLV show distinct target site preferences. PLoS Biol 2(8) E234... 

What is the nature of the proton-translocating pumps that link Ap with electron transport In his earliest proposals Mitchell suggested that electron carriers, such as flavins and ubiquinones, each of which accepts two protons as well as two electrons upon reduction, could serve as the proton carriers. Each pump would consist of a pair of oxidoreductases. One, on the inside (matrix side) of the coupling membrane, would deliver two electrons (but no protons) to the carrier (B in Fig. 18-13). The two protons needed for the reduction would be taken from the solvent in the matrix. The second oxidoreductase would be located on the outside of the membrane and would accept two electrons from the reduced carrier (BH2 in Fig. 18-13) leaving the two released protons on the outside of the membrane. To complete a "loop" that would allow the next carrier to be reduced, electrons would have to be transferred through fixed electron carriers embedded in the... 

The flavin of NAD dehydrogenase was an obvious candidate for a carrier, as was ubiquinone. However, the third loop presented a problem. Mitchell s solution was the previously discussed Q cycle, which is shown in Fig. 18-9. This accomplishes the pumping in complex III of 2 H+/ e, the equivalent of two loops.111 However, as we have seen, the magnitude of Ap suggests that 4 H+, rather than 2 H+, may be coupled to synthesis of one ATP. If this is true, mitochondria must pump 12 H+/ O rather than six when dehydrogenating NADH, or eight H+/ O when dehydrogenating succinate. 

In the chemiosmotic model, as first developed by Mitchell in the early 1960 s, proton translocation arises from transfer of electrons from an (H + + e ) carrier (such as FMNH2) to an electron carrier (such as an iron-sulfur protein), with expulsion of protons to the outer compartment of the inner mitochondrial membrane. This process is followed by electron transfer to an (H+ + e ) carrier, with uptake of protons from the matrix. In this model, the electron-transport chain is organized into three such loops, as shown in Fig. 14-5. 

This has been one of the most controversial areas of bioenergetics and is concerned with the role of coenzyme Q. The simplest view of the role of this coenzyme is that it acts as a mobile (2H+ + 2e ) carrier, linking complexes I and II with complex III. However, coenzyme Q may be involved in (H+ + e ) transfer within complex III. One model for this is the proton-motive Q cycle (Fig. 14-6), developed by Mitchell in 1975. This model satisfies prediction (2) of Example 14.10, in that coenzyme Q acts as an (H+ +e ) carrier in two loops. In this model, reduced coenzyme Q (QH2) is linked to oxidized coenzyme Q (Q) via the free-radical semiquinone (QH-) This model provides an explanation for the H+/e stoichiometry. 

Lagerlof KPD, Mitchell TE, Heuer AH (1989) Lattice diffusion kinetics in undoped and impurity-doped sapphire (a-Al203) A dislocation loop annealing stndy. J Am Ceram Soc 72 2159-2179 Lamkin, MA, Riley, FL, Fordham RJ (1992) Oxygen mobility in silicon dioxide and silicate glasses A review. J Eur Ceram Soc 10 347-367... 

However, some of the properties of electron carriers (such as their observed redox potentials) do not fit in such a simple loop model. This has led Mitchell [11] to propose a modified mechanism, the so-called proton-motive Q cycle (Fig. 4B). In this model quinones function in two separate reactions in the QH2/QH- and the Q/QH- couple. These couples have different midpoint redox potentials and would operate at the reducing and the oxidizing site of cytochrome b, respectively. During these reactions proton translocation is supposed to occur by diffusion of the quinones in the fully oxidized (Q) and fully reduced (QH2) forms through the hydrophobic environment between their successive reaction sites at both sides of the membrane. Recently some experimental support for such a role of quinones has been obtained. Alternative models which will not be discussed here, have been postulated by Papa [12] and Williams [13]. Currently there is no conclusive support for a specific model. 

Figure 6.18 Dislocation structure in sapphire deformed 4% by basal glide at 1400°C, consisting of A) glide dislocations, B) edge dipoles, C) faulted dipoles and D, E) dislocation loops. Basal foil, 650 kV. (Micrograph from B. J. Pletka and T. E. Mitchell, Case Western Reserve University, reproduced courtesy of The American Ceramic Society, Westerville, OH.)...

Figure 12.18 Reprinted from Bontinck, W. and Amelinckx, S. (1957) Observation of helicoidal dislocation lines in fluorite crystals, Phil. Mag. 2, 1. With permission from Taylor and Francis, http //www.tandf.co.uk/journals Figure 12.19 Reprinted from Phillips, D.S., Plekta, B. J., Heuer, A.H., and Mitchell, T.E. (1982) An improved model of break-up of dislocation dipoles into loops application to sapphire (a-A Os), Acta Metall. 30,491. Copyright 1982, with permission Elsevier.

Q-cyde a cycle devised by P. Mitchell [FEBS Lett. 56 (1975) 1-6 S9 (1975) 137-139] to overcome the requirement of the redox loop mechanism (see Che-miosmotic hypothesis) for a H electron carrier in the cytochrome hq-containing Complex III of the mitochondrial electron transport chain, the Q.c. proposed that ubiquinone (coenzyme Q), the only mobile, hydrophobic redox component of the chain, participates in electron transfer from cytochrome b to cytochrome c, within Complex III by one-electron steps involving the fully reduced quinol-form (QH2), a stabilized free-radical semiquinone-form (QH ) and the fully oxidized quinone-form (Q). It also made use of the observation that cytochrome b appears to be a dimer composed of b- (b and b (b, which is buried deeply in the membrane with probably on the cytosolic side and by. on the matrix side. In the Hg., outlining the proposed mechanism, it can be seen that two protons are pumped across the membrane (steps 1 9 for uptake from the matrix and steps 3... 

The placement of the components of the respiratory chain in the inner mitochondrial membrane is of considerable importance to the mechanism of the chemiosmotic theory. Mitchell (1967) calls this the "coupling membrane" H+, citric-acid-cycle anions, amino acids, and cations can be transported across this membrane by specific carriers imbedded in it. The respiratory chain is folded into three "loops"... 

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