The mitochondrial outer membrane is not a major diffusion barrier for ADP in mouse heart skinned fibre bundles

Kongas, Olav; Wagner, Marijke J.; Veld, Frank ter; Nicolay, Klaas; Beek, Hans van; Krab, Klaas

doi:10.1007/s00424-003-1214-9

Cited by 8 publications

(6 citation statements)

References 20 publications

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“…The finding of an adaptive increase in respiratory V max in M-CK -⁄and MiM-CK -⁄gastrocnemius mitochondria is in line with the results of previous studies on muscle homogenate that reported an increase of mitochondrial protein in these genotypes [10,[13][14][15]. Also, the results of polarographic measurements of respiratory V max (but not K ADP 50 ; see [16]) in permeabilized M-CK -⁄gastrocnemius fibres, which can be compared to our results in a straightforward manner, are similar [11,17]. Our present investigations did not provide insight into the exact sites of V max up-regulation in M-CK -⁄and MiM-CK -⁄phenotypes in terms of activities of individual components of the respiratory chain.…”

Section: Fast-twitch Glycolytic Skeletal Musclesupporting

confidence: 91%

Mitochondrial affinity for ADP is twofold lower in creatine kinase knock‐out muscles

2005

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Excitable mammalian cells contain high activities of creatine kinase (CK, EC 2.7.3.2), which catalyses the reversible exchange of a phosphoryl group between phosphocreatine (PCr) and ATP. The tissue-specific CK enzymes are subcellularly compartmentalized and consist of three cytosolic dimers: BB-CK (brain-and smooth muscle-specific), MM-CK (muscle-specific) and MB-CK heterodimers. Furthermore, there is mitochondrial CK (Mi-CK) which is located in the intermembrane space of the mitochondrion and consists mainly of octamers in vivo [1]. Mi-CK and M-CK have been hypothesized to jointly form an energy transport network in which creatine (Cr) and PCr function as diffusible intermediates between sites of ATP synthesis and utilization, thereby buffering fluctuations in the ATP free energy potential, i.e. the ATP ⁄ ADP concentration ratio [2,3]. The roles of Mi-CK and M-CK in this CK ⁄ PCr shuttle model are to maintain a high local ADP ⁄ ATP concentration ratio near the adenine nucleotide translocase (ANT) by transphosphorylation of mitochondrially generated ATP to PCr and a high local ATP ⁄ ADP ratio near extramitochondrial ATPases, respectively [4]. of mitochondria isolated from the MiM-CK -⁄ -phenotype was different (i.e. twofold higher) than that of WT. The implications of these adaptations for striated muscle function were explored by constructing force-flow relations of skeletal muscle respiration. It was found that the identified shift in affinity towards higher ADP concentrations in MiM-CK -⁄ -muscle genotypes may contribute to linear mitochondrial control of the reduced cytosolic ATP free energy potentials in these phenotypes.Abbreviations ACR, acceptor control ratio; AT, atractyloside; CK, creatine kinase; Cr, creatine; CS, citrate synthase; EDL, extensor digitorum longus; FCCP, carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone; LDH, lactate dehydrogenase; PCr, phosphocreatine; RCR, respiratory control ratio; VDAC, voltage-dependent anion channel.

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Section: Fast-twitch Glycolytic Skeletal Musclesupporting

confidence: 91%

Mitochondrial affinity for ADP is twofold lower in creatine kinase knock‐out muscles

2005

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“…The MOM conductance for ADP and ATP is of major importance for theories about the phosphocreatine shuttle and regulation of mitochondrial ATP synthesis, but is apparently not well known, as demonstrated by the considerable differences in its value between various models and experimental results (4,24,25,32,41). The other parameters in the present model were either measured independently in the same experimental model in the same laboratory (CK activities, mitochondrial aerobic capacity, metabolite concentrations), or represent well established literature values for kinetic constants of enzyme processes (MM-CK, Mi-CK, oxidative phosphorylation).…”

Section: Resultsmentioning

confidence: 99%

Adenine nucleotide-creatine-phosphate module in myocardial metabolic system explains fast phase of dynamic regulation of oxidative phosphorylation

Beek¹

2007

American Journal of Physiology-Cell Physiology

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Computational models of a large metabolic system can be assembled from modules that represent a biological function emerging from interaction of a small subset of molecules. A "skeleton model" is tested here for a module that regulates the first phase of dynamic adaptation of oxidative phosphorylation (OxPhos) to demand in heart muscle cells. The model contains only diffusion, mitochondrial outer membrane (MOM) permeation, and two isoforms of creatine kinase (CK), in cytosol and mitochondrial intermembrane space (IMS), respectively. The communication with two neighboring modules occurs via stimulation of mitochondrial ATP production by ADP and P(i) from the IMS and via time-varying cytosolic ATP hydrolysis during contraction. Assuming normal cytosolic diffusion and high MOM permeability for ADP, the response time of OxPhos (t(mito); generalized time constant) to steps in cardiac pacing rate is predicted to be 2.4 s. In contrast, with low MOM permeability, t(mito) is predicted to be 15 s. An optimized MOM permeability of 21 mum/s gives t(mito) = 3.7 s, in agreement with experiments on rabbit heart with blocked glycolytic ATP synthesis. The model correctly predicts a lower t(mito) if CK activity is reduced by 98%. Among others, the following predictions result from the model analysis: 1) CK activity buffers large ADP oscillations; 2) ATP production is pulsatile in beating heart, although it adapts slowly to demand with "time constant" approximately 14 heartbeats; 3) if the muscle isoform of CK is overexpressed, OxPhos reacts slower to changing workload; and 4) if mitochondrial CK is overexpressed, OxPhos reacts faster.

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“…Much higher, sometimes triple-digit micromolar, estimates of KmADP [70] are reported as a simple MM parameter, although proteolytic treatment to remove putative linkages between VDAC and the cytoskeleton reduces KmADP into the double-digit micromolar range, as does the addition of 20 mM creatine [66, 71, 72]. However, diffusional issues related not to mitochondria but rather to the experimental conditions may be confounding the interpretations of this experimental approach [73]. As a technical note it is worth pointing out that permeabilized fiber preparations maintain very high bound CK activity [74], which is largely accounted for by a myofibrillar CK activity that is about 24 times higher than the CK in the mitochondrial intermembrane space [75, 76].…”

Section: Discussionmentioning

confidence: 99%

Dominant and sensitive control of oxidative flux by the ATP-ADP carrier in human skeletal muscle mitochondria: Effect of lysine acetylation

Willis

Miranda-Grandjean

Hudgens

et al. 2018

Archives of Biochemistry and Biophysics

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The adenine nucleotide translocase (ANT) of the mitochondrial inner membrane exchanges ADP for ATP. Mitochondria were isolated from human vastus lateralis muscle (n = 9). Carboxyatractyloside titration of O consumption rate (J) at clamped [ADP] of 21 μM gave ANT abundance of 0.97 ± 0.14 nmol ANT/mg and a flux control coefficient of 82% ± 6%. Flux control fell to 1% ± 1% at saturating (2 mM) [ADP]. The KmADP for J was 32.4 ± 1.8 μM. In terms of the free (-3) ADP anion this KmADP was 12.0 ± 0.7 μM. A novel luciferase-based assay for ATP production gave KmADP of 13.1 ± 1.9 μM in the absence of ATP competition. The free anion KmADP in this case was 2.0 ± 0.3 μM. Targeted proteomic analyses showed significant acetylation of ANT Lysine23 and that ANT1 was the most abundant isoform. Acetylation of Lysine23 correlated positively with KmADP, r = 0.74, P = 0.022. The findings underscore the central role played by ANT in the control of oxidative phosphorylation, particularly at the energy phosphate levels associated with low ATP demand. As predicted by molecular dynamic modeling, ANT Lysine23 acetylation decreased the apparent affinity of ADP for ANT binding.

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The mitochondrial outer membrane is not a major diffusion barrier for ADP in mouse heart skinned fibre bundles

Cited by 8 publications

References 20 publications

Mitochondrial affinity for ADP is twofold lower in creatine kinase knock‐out muscles

Mitochondrial affinity for ADP is twofold lower in creatine kinase knock‐out muscles

Adenine nucleotide-creatine-phosphate module in myocardial metabolic system explains fast phase of dynamic regulation of oxidative phosphorylation

Dominant and sensitive control of oxidative flux by the ATP-ADP carrier in human skeletal muscle mitochondria: Effect of lysine acetylation

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