Respiratory complexes

Friedrich, T., Steinmuller, K., Weiss, H. (1995). The proton-pumping respiratory complex I of bacteria and mitochondria and its homologue in chloroplasts. (Review). FEBS Letters 367, 107-111. 

Mitochondria are unique organelles in that they contain their own DNA (mtDNA), which, in addition to ribosomal RN A (rRNA) and transfer RN A (tRNA)-coding sequences, also encodes 13 polypeptides which are components of complexes I, III, IV, and V (Anderson et al., 1981). This fact has important implications for both the genetics and the etiology of the respiratory chain disorders. Since mtDNA is maternally-inherited, a defect of a respiratory complex due to a mtDNA deletion would be expected to show a pattern of maternal transmission. However the situation is complicated by the fact that the majority of the polypeptide subunits of complexes I, III, IV, and V, and all subunits of complex II, are encoded by nuclear DNA. A defect in a nuclear-coded subunit of one of the respiratory complexes would be expected to show classic Mendelian inheritance. A further complication exists in that it is now established that some respiratory chain disorders result from defects of communication between nuclear and mitochondrial genomes (Zeviani et al., 1989). Since many mitochondrial proteins are synthesized in the cytosol and require a sophisticated system of posttranslational processing for transport and assembly, it is apparent that a diversity of genetic errors is to be expected. 

This respiratory complex consists of 13 subunits, of which the three largest are encoded on mtDNA and contain the redox centers. Complex IV is involved in a greater diversity of defects affecting human skeletal muscle than any other respiratory complex. 

In addition to the conditions described above, which involve deficiencies of individual respiratory complexes, there is another important group of mitochondrial disorders which are associated with defects of multiple respiratory complexes. The underlying abnormalities in these disorders are to be found within the mitochondrial genome, which encodes some subunits of all the respiratory complexes except complex II (Figure 12). 

Hosier JP, Eerguson-Miller S, Mills DA. 2006. Energy transduction Proton transfer through the respiratory complexes. Annu Rev Biochem 75 165. 

In the EPR of mammalian cells, we do not see much in addition to the signals from the respiratory complexes. The enzyme aconitase from the citric-acid cycle can be detected, and also the protein cytoplasmic aconitase, later identified as the mRNA translation regulatory factor iron regulatory protein IRP-1, which actually started its career in biochemistry as an EPR signal that could not be assigned to the respiratory chain (Kennedy et al. 1992). 

All disorders except those in group 5 are due to defects of nDNA and are transmitted by Mendelian inheritance. Disorders of the respiratory chain can be due to defects of nDNA or mtDNA. Usually, mutations of nDNA cause isolated, severe defects of individual respiratory complexes, whereas mutations in mtDNA or defects of intergenomic communication cause variably severe, multiple deficiencies of respiratory chain complexes. The description that follows is based on the biochemical classification. 

The (a-SS-a)2 architecture of Robertson et al. has shown wide utility as a basis structure in the systematic design of ever more sophisticated metalloprotein maquettes of the photosynthetic 36) and respiratory complexes toward the goal of testing the fundamentals of biological... 

The presence of multiple different inorganic cofactors in a protein is a common theme in natural metalloproteins, best exemplified by the respiratory complexes, which may contain as many as 10 redox active... 

The oxidation/reduction of redox cofactors in biological systems is often coupled to proton binding/release either at the cofactor itself or at local amino acid residues, which provides the basic mechanochem-ical part of a proton pump such as that foimd in cytochrome c oxidase (95). Despite a thermodynamic cycle that provides that coupling of protonation of amino acids to the reduction process will result in a 60 mV/pH decrease unit in the reduction potential per proton boimd between the pAa values in the Fe(III) and Fe(II) states, the essential pumping of protons in the respiratory complexes has yet to be localized within their three-dimensional structures. 

Brunmair, B. et al. (2004) Fenofibrate impairs rat mitochondrial function by inhibition of respiratory complex I. Journal of Pharmacology and Experimental Therapeutics, 311 (1), 109-114. 

In this pathway the electrons for the drug reduction are generated by the oxidative decarboxylation of malate catalyzed by the NAD-dependent malic enzyme (malate dehydrogenase (decarboxylating)). The NADH produced by this reaction is reoxidized by an enzyme with NADH ferredoxin oxidoreductase activity that has been recently identified as a homologue of the NADH dehydrogenase (NDH) module of the mitochondrial respiratory complex I (Hrdy et al. 2004 and see Hrdy et al., this volume). The... 

Complex III Ubiquinone to Cytochrome c The next respiratory complex, Complex III, also called cytochrome focx complex or ubiquinone icytochrome c oxidoreductase, couples the transfer of electrons from ubiquinol (QH2) to cytochrome c with the vectorial transport of protons from the matrix to the intermembrane space. The determination of the complete structure of this huge complex (Fig. 19-11) and of Complex IV (below) by x-ray crystallography, achieved between 1995 and 1998, were landmarks in the study of mitochondrial electron transfer, providing the structural framework to integrate the many biochemical observations on the functions of the respiratory complexes. 

Brunmair, B., Staniek, K., Gras, F., Scharf, N., Althaym, A., Clara, R., Roden, M., Gnaiger, E., Nohl, H., Waldhausl, W., and Fumsinn, C. 2004. Thiazolidinediones, like metformin, inhibit respiratory complex I a common mechanism contributing to their antidiabetic actions Diabetes 53 1052-1059. 

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,... 

As indicated already, membrane-associated electron transport has not been demonstrated in mitosomes. Neither cytochromes nor haem proteins have been detected by chemical or spectroscopic analyses in anaerobic protozoa and no components of respiratory complexes I-IV have been identified in the genomes of C. parvum, E. cuniculi, E. histolytica and G. intestinalis (Abrahamsen et al. 2004 Katinka et al. 2001 Loftus et al. 2005 McArthur et al. 2000 Muller 2003). However, low levels of ubiquinone have been detected in Giardia and Entamoeba (Ellis et al. 1994). A limited level of membrane-associated electron transport activity in C. parvum is suggested by the presence... 

Enzyme histochemical staining of muscle fibers can identify abnormal levels of respiratory Complexes II, IV, and V, while specific immunohistochemical stains can be used to... 

Electrons enter the ETC at respiratory Complexes I and II. The electrons from NADH enter at respiratory Complex I (RC I, NADH dehydrogenase) with the concomitant oxidation of NADH to NAD+. The electrons carried by FADH2 are transferred to RC II (succinate dehydrogenase) as the FADH2 is oxidized to FAD and succinate is reduced to fumarate. These electrons from RC I and II are transferred to the quinone form of coenzyme Q (CoQ), which delivers them to RC III (UQ-cytochrome c reductase). Cytochrome c then accepts the electrons from RC III, and the reduced cytochrome c is reoxidized as it delivers the electrons to RC IV, cytochrome c oxidase. The electrons are then used by RC IV to reduce molecular oxygen to water. 

As can be seen in Table 8-1, the respiratory complexes of the OXPHOS system are multi-subunit complexes, all except RC II having subunits encoded by both nuclear and mitochondrial genes. 

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