A second mechanism of respiratory control

Kadenbach, Bernhard; Arnold, Susanne

doi:10.1016/s0014-5793(99)00229-x

Cited by 76 publications

(37 citation statements)

References 71 publications

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“…However, it is unclear to what extent solute transport does occur in kidney slices in vitro. Indeed, if little transport is occurring under these conditions, then the ATP/ADP ratio could be high, which may inhibit RC function via a feedback mechanism 35 ; oligomycin would have relatively little effect on ⌬ m in this setting.…”

Section: Discussionmentioning

confidence: 99%

Multiphoton Imaging Reveals Differences in Mitochondrial Function between Nephron Segments

Hall

Unwin

Parker

et al. 2009

Journal of the American Society of Nephrology

131

110

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Mitochondrial dysfunction may play a role in the pathogenesis of several renal diseases. Although functional roles and metabolic demands differ among tubule segments, relatively little is known about the properties of mitochondria in different parts of the nephron. Clinically, the proximal tubule seems particularly vulnerable to mitochondrial toxicity. In this study, we used multiphoton imaging of live rat kidney slices to investigate differences in mitochondrial function along the nephron. The mitochondrial membrane potential was markedly higher in distal than proximal tubules. Inhibition of respiration rapidly collapsed the membrane potential in proximal tubules, but potential was better maintained in distal tubules. Inhibition of the F 1 F o -ATPase abolished this difference, suggesting that maintenance of potential via ATPase activity is more effective in distal than proximal tubules. Immunostaining revealed that the ratio of the expression of ATPase to IF1, an endogenous inhibitor of the mitochondrial ATPase, was lower in proximal tubules than in distal tubules. Production of reactive oxygen species was higher in proximal than distal cells, but inhibition of NADPH oxidase eliminated this difference. Glutathione levels were higher in proximal tubules. Overall, mitochondria in the proximal tubules were in a more oxidized state than those in the distal tubules. In summary, there are axial differences in mitochondrial function along the nephron, which may contribute to the pattern and pathophysiology of some forms of renal injury.

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Section: Discussionmentioning

confidence: 99%

Multiphoton Imaging Reveals Differences in Mitochondrial Function between Nephron Segments

Hall

Unwin

Parker

et al. 2009

Journal of the American Society of Nephrology

131

110

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“…However, the examination of thresholds of cytochrome c oxidase in intact cells (9,10) has raised the critical issue of how accurately the data obtained with isolated mitochondria reflect the in vivo situation. Important complications of the analysis on isolated mitochondria are the possible loss of essential metabolites during the organelle isolation and the disruption of the normal interactions of mitochondria with the cytoskeleton and other organelles, as well as of the possible regulation of enzyme activities by cytoplasmic effectors (11)(12)(13)(14)(15). In this report we have therefore used saponin-permeabilized muscle fibers to determine the reserve capacity of COX in human skeletal muscle.…”

Section: Introductionmentioning

confidence: 99%

Flux Control of Cytochrome c Oxidase in Human Skeletal Muscle

Kunz¹,

Kudin²,

Vielhaber³

et al. 2000

Journal of Biological Chemistry

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SUMMARYIn the present work, by titrating cytochrome c oxidase (COX) with the specific inhibitor KCN the flux control coefficient and the metabolic reserve capacity of COX have been determined in human saponin-permeabilized muscle fibers. In the presence of the substrates glutamate and malate, a 2.3±0.2-fold excess capacity of COX was observed in ADP-stimulated human skeletal muscle fibers. This value was found to be dependent on the mitochondrial substrate supply. In the combined presence of glutamate, malate and succinate, which supported an approximately 1.4-fold higher rate of respiration, only a 1.4±0.2-fold excess capacity of COX was determined. In agreement with these findings, the flux control of COX increased, in the presence of the three substrates, from 0.27±0.03 to 0.36±0.08. These results indicate a tight in vivo control of respiration by COX in human skeletal muscle. This tight control may have significant implications for mitochondrial myopathies. In support of this conclusion, the analysis of skeletal muscle fibers from two patients with chronic progressive external ophthalmoplegia, which carried deletions in 11% and 49% of their mitochondrial DNA, revealed a substantially lowered reserve capacity and increased flux control coefficient of COX, indicating severe rate limitations of oxidative phosphorylation by this enzyme.

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“…Mitochondrial respiration, and thus CcO activity, is also inhibited at high ATP/ADP ratios through high ⌬⌿ m values, known as "respiratory control" (27,28). The allosteric ATP-inhibition represents a second mechanism of respiratory control (29), which is independent of ⌬⌿ m (30). The allosteric ATP-inhibition, however, is lost when the enzyme is dephosphorylated (31,32), possibly at Ser-441 of bovine heart CcO subunit I (23).…”

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confidence: 99%

Phosphorylation and Kinetics of Mammalian Cytochrome c Oxidase

Helling

Vogt

Rhiel

et al. 2008

Molecular & Cellular Proteomics

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The influence of protein phosphorylation on the kinetics of cytochrome c oxidase was investigated by applying Western blotting, mass spectrometry, and kinetic measurements with an oxygen electrode. The isolated enzyme from bovine heart exhibited serine, threonine, and/or tyrosine phosphorylation in various subunits, except subunit I, by using phosphoamino acid-specific antibodies. The kinetics revealed slight inhibition of oxygen uptake in the presence of ATP, as compared with the presence of ADP. Mass spectrometry identified the phosphorylation of Ser-34 at subunit IV and Ser-4 and Thr-35 at subunit Va. Incubation of the isolated enzyme with protein kinase A, cAMP, and ATP resulted in serine and threonine phosphorylation of subunit I, which was correlated with sigmoidal inhibition kinetics in the presence of ATP. This allosteric ATP-inhibition of cytochrome c oxidase was also found in rat heart mitochondria, which had been rapidly prepared in the presence of protein phosphatase inhibitors. The isolated rat heart enzyme, prepared from the mitochondria by blue native gel electrophoresis, showed serine, threonine, and tyrosine phosphorylation of subunit I. It is concluded that the allosteric ATPinhibition of cytochrome c oxidase, previously suggested to keep the mitochondrial membrane potential and thus the reactive oxygen species production in cells at low levels, occurs in living cells and is based on phosphorylation of cytochrome c oxidase subunit I. Molecular & Cellular Proteomics 7:1714 -1724, 2008.Phosphorylation of mitochondrial proteins has become of general interest since the role of mitochondria in apoptosis and degenerative diseases became evident. During the past ten years many protein kinases and phosphatases, mostly known to occur outside of mitochondria, have also been identified in mitochondria or are translocated to mitochondria after activation (1-6). In addition, an increasing number of phosphorylated proteins, including subunits of complexes I-V of the mitochondrial oxidative phosphorylation system, have been identified (7-9). Of particular interest is the phosphorylation of cytochrome c oxidase (CcO) 1 , the terminal, and rate-limiting enzyme of the respiratory chain (complex IV) (10). CcO is composed of three mitochondrial DNA-encoded subunits, forming the catalytic core of the enzyme, and ten nuclear-encoded subunits with regulatory functions. The crystal structure of the bovine heart enzyme forms a dimer (11,12), and supercomplexes of CcO with complex III (cytochrome c reductase) and complex I (NADH dehydrogenase) have been identified in mitochondrial membranes (13-15). The complicated structure of the mammalian enzyme contrasts the bacterial CcO containing only 2-4 subunits (16,17). The additional subunits in eukaryotes are suggested to regulate CcO activity, either by binding effectors or by chemical modification, like glycosylation and phosphorylation. Ten high-affinity binding sites for ADP have been identified in the isolated bovine heart enzyme, seven of which are exchanged by ATP at ...

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A second mechanism of respiratory control

Cited by 76 publications

References 71 publications

Multiphoton Imaging Reveals Differences in Mitochondrial Function between Nephron Segments

Multiphoton Imaging Reveals Differences in Mitochondrial Function between Nephron Segments

Flux Control of Cytochrome c Oxidase in Human Skeletal Muscle

Phosphorylation and Kinetics of Mammalian Cytochrome c Oxidase

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