Futile Cycles Revisited: A Markov Chain Model of Simultaneous Glycolysis and Gluconeogenesis

Jones, Michael E.; Berry, Michael N.; Phillips, John W.

doi:10.1006/jtbi.2002.3042

Cited by 8 publications

(4 citation statements)

References 21 publications

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“…Ishikawa et al (22) showed that acetate induced cytosolic alkalinization that was not affected by H ϩ -ATPase inhibitors and probably was a result of mitochondrial metabolism of acetate to bicarbonate. Studies in the kidney (26,51) have demonstrated the importance of such "futile" cycles of glycolysis and gluconeogenesis, which provide the capacity for rapid changes in glycolytic flux (24,46). Net ATP consumption in futile cycles may be reduced by separation and compartmentalization of the glycolytic and gluconeogenic pathways (24).…”

Section: Discussionmentioning

confidence: 99%

Glucose activates H⁺-ATPase in kidney epithelial cells

Nakamura

2004

American Journal of Physiology-Cell Physiology

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The vacuolar H(+)-ATPase (V-ATPase) acidifies compartments of the vacuolar system of eukaryotic cells. In renal epithelial cells, it resides on the plasma membrane and is essential for bicarbonate transport and acid-base homeostasis. The factors that regulate the H(+)-ATPase remain largely unknown. The present study examines the effect of glucose on H(+)-ATPase activity in the pig kidney epithelial cell line LLC-PK(1). Cellular pH was measured by performing ratiometric fluorescence microscopy using the pH-sensitive indicator BCECF-AM. Intracellular acidification was induced with NH(3)/NH(4)(+) prepulse, and rates of intracellular pH (pH(i)) recovery (after in situ calibration) were determined by the slopes of linear regression lines during the first 3 min of recovery. The solutions contained 1 microM ethylisopropylamiloride and were K(+) free to eliminate Na(+)/H(+) exchange and H(+)-K(+)-ATPase activity. After NH(3)/NH(4)(+)-induced acidification, LLC-PK(1) cells had a significant pH(i) recovery rate that was inhibited entirely by 100 nM of the V-ATPase inhibitor concanamycin A. Acute removal of glucose from medium markedly reduced V-ATPase-dependent pH(i) recovery activity. Readdition of glucose induced concentration-dependent reactivation of V-ATPase pH(i) recovery activity within 2 min. Glucose replacement produced no significant change in cell ATP or ADP content. H(+)-ATPase activity was completely inhibited by the glycolytic inhibitor 2-deoxy-d-glucose (20 mM) but only partially inhibited by the mitochondrial electron transport inhibitor antimycin A (20 microM). The phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin (500 nM) abolished glucose activation of V-ATPase, and activity was restored after wortmannin removal. Glucose activates V-ATPase activity in kidney epithelial cells through the glycolytic pathway by a signaling pathway that requires PI3K activity. These findings represent an entirely new physiological effect of glucose, linking it to cellular proton secretion and vacuolar acidification.

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Section: Discussionmentioning

confidence: 99%

Glucose activates H⁺-ATPase in kidney epithelial cells

Nakamura

2004

American Journal of Physiology-Cell Physiology

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“…In some cases substrate cycles consume up to 70% of the ATP produced by the cell [ 3 – 6 ]. They operate in microorganisms [ 2 ], plants [ 7 , 8 ], yeasts [ 9 ] and animals [ 10 ], playing roles such as heat generation, buffering of metabolite concentrations, improvement of sensitivity in metabolic regulation, and control of the direction of flow in bidirectional pathways [ 1 , 2 ]. In particular, there is a great wealth of genetic, radiotracer, stoichiometric analysis and stable isotope labeling data supporting the occurrence of metabolic cycles resulting from the simultaneous synthesis and breakdown of storage carbohydrates such as trehalose in fungi [ 11 , 12 ], sucrose and starch in heterotrophic organs of plants [ 7 , 13 , 14 ] and glycogen in animals [ 15 – 17 ], yeasts [ 11 ] and bacteria [ 18 – 24 ].…”

Section: Introductionmentioning

confidence: 99%

Genetic and isotope ratio mass spectrometric evidence for the occurrence of starch degradation and cycling in illuminated Arabidopsis leaves

et al. 2017

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Although there is a great wealth of data supporting the occurrence of simultaneous synthesis and breakdown of storage carbohydrate in many organisms, previous 13CO2 pulse-chase based studies indicated that starch degradation does not operate in illuminated Arabidopsis leaves. Here we show that leaves of gwd, sex4, bam4, bam1/bam3 and amy3/isa3/lda starch breakdown mutants accumulate higher levels of starch than wild type (WT) leaves when cultured under continuous light (CL) conditions. We also show that leaves of CL grown dpe1 plants impaired in the plastidic disproportionating enzyme accumulate higher levels of maltotriose than WT leaves, the overall data providing evidence for the occurrence of extensive starch degradation in illuminated leaves. Moreover, we show that leaves of CL grown mex1/pglct plants impaired in the chloroplastic maltose and glucose transporters display a severe dwarf phenotype and accumulate high levels of maltose, strongly indicating that the MEX1 and pGlcT transporters are involved in the export of starch breakdown products to the cytosol to support growth during illumination. To investigate whether starch breakdown products can be recycled back to starch during illumination through a mechanism involving ADP-glucose pyrophosphorylase (AGP) we conducted kinetic analyses of the stable isotope carbon composition (δ13C) in starch of leaves of 13CO2 pulsed-chased WT and AGP lacking aps1 plants. Notably, the rate of increase of δ13C in starch of aps1 leaves during the pulse was exceedingly higher than that of WT leaves. Furthermore, δ13C decline in starch of aps1 leaves during the chase was much faster than that of WT leaves, which provides strong evidence for the occurrence of AGP-mediated cycling of starch breakdown products in illuminated Arabidopsis leaves.

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“…In fact, substrate cycles involving sugars also exist in microorganisms (for review, see Portais and Delort, 2002) and animal cells (Landau, 1999;Jones et al, 2002), and their roles are still a matter of debate. It has been suggested that they could serve to buffer metabolite concentrations, improve sensitivity in metabolic regulation, or rapidly change the direction of net flux (Newsholme et al, 1984;Fell, 1997).…”

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A New Substrate Cycle in Plants. Evidence for a High Glucose-Phosphate-to-Glucose Turnover from in Vivo Steady-State and Pulse-Labeling Experiments with [13C]Glucose and [14C]Glucose

et al. 2005

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Substrate (futile) cycling involving carbohydrate turnover has been widely reported in plant tissues, although its extent, mechanisms, and functions are not well known. In this study, two complementary approaches, short and steady-state labeling experiments, were used to analyze glucose metabolism in maize (Zea mays) root tips. Unidirectional rates of synthesis for storage compounds (starch, Suc, and cell wall polysaccharides) were determined by short labeling experiments using [U-14 C]glucose and compared with net synthesis fluxes to determine the rate of glucose production from these storage compounds. Steady-state labeling with [1-13 C]glucose and [U-13 C]glucose showed that the redistribution of label between carbon C-1 and C-6 in glucose is close to that in cytosolic hexose-P. These results indicate a high resynthesis flux of glucose from hexose-P that is not accounted for by glucose recycling from storage compounds, thus suggesting the occurrence of a direct glucose-P-to-glucose conversion. An enzyme assay confirmed the presence of substantial glucose-6-phosphatase activity in maize root tips. This new glucose-P-to-glucose cycle was shown to consume around 40% of the ATP generated in the cell, whereas Suc cycling consumes at most 3% to 6% of the ATP produced. The rate of glucose-P cycling differs by a factor of 3 between a maize W22 line and the hybrid maize cv Dea, and is significantly decreased by a carbohydrate starvation pretreatment.The development of nonphotosynthetic tissues is closely related to Suc import. Suc is degraded by Suc synthase (SuSy) or invertase to provide UDP-Glc or hexoses for the biosynthesis of structural or storage compounds and for ATP production (Fig. 1). In 1988, Hargreaves and ap Rees used pulse-chase experiments to show the presence of a cycle of synthesis and degradation of Suc in pea roots. This cycle, consuming ATP without any apparent physiological function, was described as a futile cycle, according to Fell's definition (Fell, 1997), and, according to more recent terminology, which refers to a possible role for these processes, it can be described as a substrate cycle (the Suc cycle). Since then, the Suc cycle has been found in many other tissues: chenopodium cells, potato (Solanum tuberosum) tubers, ripening banana (Musa cavendishii), maize (Zea mays) root tips, tomato (Lycopersicon esculentum) cells, and tomato fruit (Hatzfeld and Stitt, 1990;Hill and ap Rees, 1994; DieuaideNoubhani et al., 1995 DieuaideNoubhani et al., , 1997N'tchobo et al., 1999;Rontein et al., 2002). One can estimate that, for the synthesis and degradation of one molecule of Suc, 1.5 to two molecules of ATP are consumed (Fig. 1). Depending on the tissue, this cycle could consume between 5% and 70% of the ATP produced by the cell (Hatzfeld and Stitt, 1990;Hill and ap Rees, 1994;Dieuaide-Noubhani et al., 1995;Fernie et al., 2002;Rontein et al., 2002).Two other substrate cycles related to central carbohydrate metabolism have been described in plants, hexose-P 4 triose-P cycling and the starch synthesi...

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Futile Cycles Revisited: A Markov Chain Model of Simultaneous Glycolysis and Gluconeogenesis

Cited by 8 publications

References 21 publications

Glucose activates H⁺-ATPase in kidney epithelial cells

Glucose activates H⁺-ATPase in kidney epithelial cells

Genetic and isotope ratio mass spectrometric evidence for the occurrence of starch degradation and cycling in illuminated Arabidopsis leaves

A New Substrate Cycle in Plants. Evidence for a High Glucose-Phosphate-to-Glucose Turnover from in Vivo Steady-State and Pulse-Labeling Experiments with [13C]Glucose and [14C]Glucose

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Futile Cycles Revisited: A Markov Chain Model of Simultaneous Glycolysis and Gluconeogenesis

Cited by 8 publications

References 21 publications

Glucose activates H+-ATPase in kidney epithelial cells

Glucose activates H+-ATPase in kidney epithelial cells

Genetic and isotope ratio mass spectrometric evidence for the occurrence of starch degradation and cycling in illuminated Arabidopsis leaves

A New Substrate Cycle in Plants. Evidence for a High Glucose-Phosphate-to-Glucose Turnover from in Vivo Steady-State and Pulse-Labeling Experiments with [13C]Glucose and [14C]Glucose

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Glucose activates H⁺-ATPase in kidney epithelial cells

Glucose activates H⁺-ATPase in kidney epithelial cells