Mitochondrial complex

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. 

Motoyuki T, Kaoru K, Hironori N, Akira T, Hajime I, Hideto M. Definition of crucial structural factors of acetogenins, potent inhibitors of mitochondrial complex I. Biochim Biophys Acta 2000 1460 302-310. 

Similarly, abnormalities in the mitochondrial machinery and resulting oxidative stress may also intervene in Parkinson s disease (PD) [31, 32]. The decreased activity of mitochondrial complex I in PD patients [33], and the preferential toxicity of the complex I inhibitor rotenone [34] and MPP+ (the active metabolite of MPTP)... 

Colquhoun and Schumacher [98] have shown that y-linolcnic acid and eicosapentaenoic acid, which inhibit Walker tumor growth in vivo, decreased proliferation and apoptotic index in these cells. Development of apoptosis was characterized by the enhancement of the formation of reactive oxygen species and products of lipid peroxidation and was accompanied by a decrease in the activities of mitochondrial complexes I, III, and IV, and the release of cytochrome c and caspase 3-like activation of DNA fragmentation. Earlier, a similar apoptotic mechanism of antitumor activity has been shown for the flavonoid quercetin [99], Kamp et al. [100] suggested that the asbestos-induced apoptosis in alveolar epithelial cells was mediated by iron-derived oxygen species, although authors did not hypothesize about the nature of these species (hydroxyl radicals, hydrogen peroxide, or iron complexes ). 

D. Washo-Stultz, C. L. Crowley-Weber, K. Dvorakova, C. Bernstein, H. Bernstein, K. Kunke, C. N. Waltmire, H. Garewal and C. M. Payne, Role of mitochondrial complexes I and II, reactive oxygen species and arachidonic acid metabolism in deoxycholate-induced apoptosis. Cancer Lett., 2002, 177(2), 129. 

MPTP is a protoxin that is converted by monoamine oxidase to /V-methyl-4-phenylpyridinium (MPP+). MPP+ is selectively taken up by cells in the substantia nigra through an active mechanism normally responsible for dopamine reuptake. MPP+ inhibits mitochondrial complex I, thereby inhibiting oxidative phosphorylation. The interaction of MPP+ with complex I probably leads to cell death and thus to striatal dopamine depletion and parkinsonism. 

Non-mitochondrial complex I proteins in a hydrogenosomal oxidoreductase complex. Nature 431 1103-1107... 

Horner DS, Heil , Happe T, Embley TM (2002) Iron hydrogenases - ancient enzymes in modern eukaryotes. Trends Biochem Sci 27 148-153 Hrdy I, Hirt RP, Dolezal P, Bardonova L, Foster PG, Tachezy J, Embley TM (2004) Trichomonas hydrogenosomes contain the NADH dehydrogenase module of mitochondrial complex I. Nature 432 618-622 Hurtgen MT (2003) Ancient oceans and oxygen. Nature 423 592-593 Javaux EJ, Knoll AH, Walter MR (2001) Morphological and ecological complexity in early eukaryotic ecosystems. Nature 412 66-69... 

Dyall SD et al. (2004b) Non-mitochondrial complex I proteins in a hydrogenosomal oxi-doreductase complex. Nature 431 1103-1107 Eddy SR (1996) Hidden Markov models. Curr Opin Struct Biol 6 361-365 Eddy SR (1998) Profile hidden Markov models. Bioinformatics 14 755-763 Embley TM (2006) Multiple secondary origins of the anaerobic lifestyle in eukaryotes. 

Hrdf I, Hirt RP, Dolezal P, Bardoiiovd L, Foster PG, Tachezy J, Embley TM (2004) Trichomonas hydrogenosomes contain the NADH dehydrogenase module of mitochondrial complex I. Nature 432 618-622... 

Figure 7.47 The mechanism of cardiotoxicity of doxorubicin. The drug can acquire electrons from mitochondrial complex I. The quinone thus produced can donate the electron to oxygen, and the superoxide produced damages heart tissues and mtDNA. Abbreviation mtDNA, mitochondrial DNA.

Ahammadsahib, K.I., Hollingworth, R.M., McGovren, P.J., Hui, Y.-H., and McLaughlin, J.L. Inhibition of NADH ubiquinone reductase (mitochondrial complex I) by bullatacin, a potent antitumor and pesticidal Annonaceous acetogenin. Life Sci., 53, 1113, 1993. 

Miyoshi, H., Ohshima, M., Shimada, H., Akagi, T., Iwamura, H., and McLaughlin, J.L. Essential structural factors of acetogenins as potent inhibitors of mitochondrial complex I. Biochim. Bio-phys. Acta, 1365, 443, 1998. 

FIGURE 19-33 Bacterial respiratory chain, (a) Shown here are the respiratory carriers of the inner membrane of E. coli. Eubacteria contain a minimal form of Complex I, containing all the prosthetic groups normally associated with the mitochondrial complex but only 14 polypeptides. This plasma membrane complex transfers electrons from NADH to ubiquinone or to (b) menaquinone, the bacterial equivalent of ubiquinone, while pumping protons outward and creating an electrochemical potential that drives ATP synthesis. 

Like the homologous Complex III in mitochondria, the cytochrome bci complex of purple bacteria carries electrons from a quinol donor (QH2) to an electron acceptor, using the energy of electron transfer to pump protons across the membrane, producing a proton-motive force. The path of electron flow through this complex is believed to be very similar to that through mitochondrial Complex III, involving a Q cycle (Fig. 19-12) in which protons are consumed on one side of the membrane and released on the other. The ultimate... 

Complex III (ubiquinol-cytochrome c oxido-reductase or cytochrome bct complex). Mitochondrial complex III is a dimeric complex, each subunit of which contains 11 different subunits with a total molecular mass of 240 kDa per monomer.104-107 However, in many bacteria the complex consists of only three subunits, cytochrome b, cytochrome c , and the high potential ( 0.3 V) Rieske iron-sulfur protein, which is discussed in Chapter 16, Section A,7. These three proteins are present in all bc1 complexes. 

The simpler cytochrome bc] complexes of bacteria such as E. coli,102 Paracoccus dentrificans,116 and the photosynthetic Rhodobacter capsulatus117 all appear to function in a manner similar to that of the large mitochondrial complex. The bc] complex of Bacillus subtilis oxidizes reduced menaquinone (Fig. 15-24) rather than ubiquinol.118 In chloroplasts of green plants photochemically reduced plastoquinone is oxidized by a similar complex of cytochrome b, c-type cytochrome /, and a Rieske Fe-S protein.119 120a This cytochrome b6f complex delivers electrons to the copper protein plastocyanin (Fig. 23-18). 

Complex IV. Cytochrome c oxidase (ubiquinol-cytochrome c oxidoreductase). Complex IV from mammalian mitochondria contains 13 subunits. All of them have been sequenced, and the three-dimensional structure of the complete complex is known (Fig. 18-10).125-127 The simpler cytochrome c oxidase from Paracoccus denitrificans is similar but consists of only three subunits. These are homologous in sequence to those of the large subunits I, II, and III of the mitochondrial complex. The three-dimensional structure of the Paracoccus complex is also known. Its basic structure is nearly identical to that of the catalytic core of subunits I, II, and III of the mitochondrial complex (Fig. 18-10,A).128 All three subunits have transmembrane helices. Subunit III seems to be structural in function, while subunits I and II contain the oxidoreductase centers two hemes a (a and a3) and two different copper centers, CuA (which contains two Cu2+) and a third Cu2+ (CuB) which exists in an EPR-silent exchange coupled pair with a3. Bound Mg2+ and Zn2+ are also present in the locations indicated in Fig. 18-10. 

Figure 18-9 Proposed routes of electron transfer in mitochondrial complex III according to Peter Mitchell s Q cycle. Ubiquinone (Q) is reduced to QH2 by complex I (left side of diagram) using two H+ taken up from the matrix (leaving negative charges on the inner membrane surface). After diffusing across the bilayer (dashed line) the QH2 is oxidized in the two steps with release of the two protons per QH2...

---