Routes of electron transfer in beef heart cytochrome <i>c</i> oxidase: is there a unique pathway used by all reductants?

Crinson, M.; Nicholls, Peter

doi:10.1139/o92-047

Cited by 11 publications

(9 citation statements)

References 14 publications

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“…The observation that the relative uncoupled respiration rate supported by 0.4 mM TMPD in the presence of antimycin A reached in intact cells of several cell lines a value very close to the COX R max value determined by extrapolation of the KCN inhibition data is in full agreement with the previous finding that, in beef heart submitochondrial particles, the steady-state level of reduction of cytochrome c reached a maximum at Ϸ0.4 mM TMPD (17). Presumably, any increase in O 2 consumption rate occurring in the presence of concentrations of TMPD Ͼ0.4 mM reflects direct electron transfer (16,17) to the cytochrome c oxidase.…”

Section: Kcn Titration Of Cox Activity In Intact Cells As Isolatedsupporting

confidence: 91%

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In vivo control of respiration by cytochrome c oxidase in wild-type and mitochondrial DNA mutation-carrying human cells

Villani

Attardi²

1997

Proc. Natl. Acad. Sci. U.S.A.

184

107

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The metabolic control of respiration is still poorly understood, due mainly to the lack of suitable approaches for studying it in vivo. Experiments on isolated mammalian mitochondria have indicated that a relatively small fraction of each of several components of the electron transport chain is sufficient to sustain a normal O 2 consumption rate. These experiments, however, may not ref lect accurately the in vivo situation, due to the lack in the mitochondrial fraction of essential cytosolic components and to the use of excess of substrates in the in vitro assays. An approach is described here whereby the control of respiration by cytochrome c oxidase (COX; EC 1.9.3.1) was analyzed in intact cultured human osteosarcoma 143B.TK ؊ cells and other wild-type cells and in mitochondrial DNA mutation-carrying human cell lines. Surprisingly, in wild-type cells, only a slightly higher COX capacity was detected than required to support the endogenous respiration rate, pointing to a tighter in vivo control of respiration by COX than generally assumed. Cell lines carrying the MERRF mitochondrial tRNA Lys gene mutation, which causes a pronounced decrease in mitochondrial protein synthesis and respiration rates, revealed, in comparison, a significantly greater COX capacity relative to the residual endogenous respiration rate, and, correspondingly, a higher COX inhibition threshold above which the overall respiratory f lux was affected. The observed relationship between COX respiratory threshold and relative COX capacity and the potential extension of the present analysis to other respiratory complexes have significant general implications for understanding the pathogenetic role of mutations in mtDNA-linked diseases and the tissue specificity of the mutation-associated phenotype.The rapid accumulation of knowledge concerning mitochondrial diseases, especially those caused by mitochondrial DNA (mtDNA) mutations, has stimulated in recent years a strong interest in the metabolic control of oxidative phosphorylation (OXPHOS). In particular, the discovery of threshold effects in the capacity of a mtDNA mutation to produce an OXPHOS defect in the presence of varying amounts of wild-type mtDNA has called attention to the degree of control that a particular step exerts in the OXPHOS pathway. It has been emphasized that application of the metabolic control theory (1, 2) to the study of mitochondrial metabolism can be a valuable approach for determining the level of control exerted by different OXPHOS steps on the rate of mitochondrial respiration (3), and for identifying and quantifying enzymatic defects caused in the OXPHOS machinery by mitochondrial or nuclear DNA mutations (4-7). Recently, this approach has been applied to isolated rat tissue mitochondria, by using increasing concentrations of inhibitors of complex I (rotenone), complex III (myxothiazol or antimycin A), or complex IV (potassium cyanide) to mimic the effects of mutations affecting these complexes (4-7). These experiments have produced results suggesting that ...

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Section: Kcn Titration Of Cox Activity In Intact Cells As Isolatedsupporting

confidence: 91%

“…Sci. USA 94 (1997)chosen, because it supports a rate of respiration very close to the endogenous one in wild-type cells and also minimizes a possible direct electron transfer from TMPD to COX (16,17).…”

Section: Resultsmentioning

confidence: 99%

In vivo control of respiration by cytochrome c oxidase in wild-type and mitochondrial DNA mutation-carrying human cells

Villani

Attardi²

1997

Proc. Natl. Acad. Sci. U.S.A.

184

107

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“…Significant TMPD oxidation generally requires the association of a cytochrome c with the oxidase. For example, at the concentration of TMPD used, the mitochondrial aa 3 -type oxidase exhibits a turnover number of less than 2 s 21 (Crinson & Nicholls, 1992). The purified aa 3 -type oxidase of C. glutamicum, which contains no cytochrome c, oxidizes TMPD at the slow rate of <1 s 21 .…”

Section: Discussionmentioning

confidence: 99%

Evidence for a cytochrome bcc–aa 3 interaction in the respiratory chain of Mycobacterium smegmatis

2006

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Spectroscopic analysis of membranes isolated from Mycobacterium smegmatis, along with analysis of its genome, indicates that the cytochrome c branch of its respiratory pathway consists of a modified bc 1 complex that contains two cytochromes c in its c 1 subunit, similar to other acid-fast bacteria, and an aa 3-type cytochrome c oxidase. A functional association of the cytochrome bcc and aa 3 complexes was indicated by the findings that levels of detergent sufficient to completely disrupt isolated membranes failed to inhibit quinol-driven O2 reduction, but known inhibitors of the bc 1 complex did inhibit quinol-driven O2 reduction. The gene for subunit II of the aa 3-type oxidase indicates the presence of additional charged residues in a predicted extramembrane domain, which could mediate an intercomplex association. However, high concentrations of monovalent salts had no effect on O2 reduction, suggesting that ionic interactions between extramembrane domains do not play the major role in stabilizing the bcc–aa 3 interaction. Divalent cations did inhibit electron transfer, likely by distorting the electron-transfer interface between cytochrome c 1 and subunit II. Soluble cytochrome c cannot donate electrons to the aa 3-type oxidase, even though key cytochrome c-binding residues are conserved, probably because the additional residues of subunit II prevent the binding of soluble cytochrome c. The results indicate that hydrophobic interactions are the primary forces maintaining the bcc–aa 3 interaction, but ionic interactions may assist in aligning the two complexes for efficient electron transfer.

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“…4) and intact cells (Piccoli et al, 2006), respectively. This could be due to the lower Δψ mito elicited by AT as compared with the one measured with NAD-dependent substrates, as well as to the peculiar chemistry of the electron transfer from the primary reductant ascorbate to cytochrome c / COX, via TMPD (Crinson and Nicholls, 1992;Ferguson-Miller et al, 1978). At any event, this observation pinpoints a fundamental limitation to the utilization of the standard KCN-titration technique in the presence of Δψ mito , since this would differentially affect the respiratory fluxes depending on whether COX is analysed as an integrated respiratory chain complex or as an isolated step.…”

Section: Discussionmentioning

confidence: 99%

Tight control of mitochondrial membrane potential by cytochrome c oxidase

et al. 2011

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Routes of electron transfer in beef heart cytochrome c oxidase: is there a unique pathway used by all reductants?

Cited by 11 publications

References 14 publications

In vivo control of respiration by cytochrome c oxidase in wild-type and mitochondrial DNA mutation-carrying human cells

In vivo control of respiration by cytochrome c oxidase in wild-type and mitochondrial DNA mutation-carrying human cells

Evidence for a cytochrome bcc–aa 3 interaction in the respiratory chain of Mycobacterium smegmatis

Tight control of mitochondrial membrane potential by cytochrome c oxidase

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