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Modulation of glucose-related metabolic pathways controls glucose level in airway surface liquid and fight oxidative stress in cystic fibrosis cells

Journal of Bioenergetics and Biomembranes volume 51, pages 203–218 (2019)Cite this article

Abstract

Direct and indirect evidences show that elevated glucose concentrations in airway surface liquid (ASL) promote lung infection by pathogens, playing a role in the progression of the Cystic Fibrosis (CF) disease. The joint action of transporter/s for glucose and of the cellular enzymes is essential in order to try to lower ASL glucose level. Inside the cell, the glycolysis and the pentose phosphate pathway (PPP) compete for the utilization of glucose-6-phosphate (G6P), the product in which glucose, after entry within the cell and phosphorylation, is trapped. The study aims to clarify whether, modulating the activity of enzymatic proteins and/or the level of metabolites/cofactors, involved in intracellular glucose utilization, a lowering of the extracellular glucose level in CF occurs. Biochemical approaches have enabled us to understand i) how G6P is shunted between glycolysis and PPP and ii) that mitochondria, more than enzymes/cofactors participating to the two cell glucose utilization pathways, are protagonists of the scene in counteracting the high ASL glucose level as well as oxidative stress in CF.

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Abbreviations

Aβ :

βeta-amyloid

6AN :

6-aminonicotinamide

ASL :

Airway surface liquid

BP :

3-Bromopyruvate

CF :

cystic Fibrosis

CFBE :

CFBE41o-cells expressing F508del CFTR

CFTR :

cystic fibrosis transmembrane conductance regulator

CITR :

citrate

CN :

potassium-cyanide

DPI :

diphenyliodonium

GI :

glycolytic index

GLU :

glucose

GLUT :

glucose transporter

G6P :

glucose-6-phpsphate

G6PDH :

glucose-6-phosphate dehydrogenase

HK :

hexokinase

L-LAC :

L-lactate

MTT :

3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide

NCEs :

NADPH consuming enzymes

NOX :

NAD(P)H oxidases

NREs :

NADPH-regenerating enzymes

O2 :

molecular oxygen

O2 −• :

superoxide anion radical

OLIGO :

oligomycin

PBS :

phosphate-buffered saline

PFK :

phosphofructokinase

PHLO :

Phloretin

PPP :

pentose phosphate pathway

ROS :

reactive oxygen species

ROT :

rotenone

S.D. :

standard deviation

Wt-CFBE :

CFBE41o-cells stably expressing wildtype CFTR

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Acknowledgements

The present study goes beyond the main objective around which most of the researchers studying Cystic Fibrosis (CF) focuses, ie the mutated CFTR protein. It aims to investigate some of the thousands of metabolic reactions - those related to glucose metabolism and the production of NADPH, which play a primary role in regulating the antioxidant balance to counteract oxidative stress - which develop within the CF cell and have a great value in the specific pathological context. In particular, this study represented a part of the project proposal presented to the FFC (Foundation for Research on Cystic Fibrosis https://www.fibrosicisticaricerca.it/) which found no interest and was therefore not financed. Despite everything, this research was conducted i) thanks to the tenacity and the passion of the researchers who were able to work by borrowing reagents and enzymes from colleagues, therefore the authors thank all the colleagues; ii) asking the Santa Cruz Biotechnology, Inc. company to receive test samples (free of charge) for some of the antibodies used in the study, therefore the authors thank the SCBT for free samples.

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Affiliations

  1. Istituto di Biomembrane, Bioenergetica e Biotecnologie Molecolari (IBIOM) – CNR, Via G. Amendola 122/O, 70126, Bari, Italy

    M. Favia, L. de Bari & Anna Atlante

  2. Dipartimento di Bioscienze, Biotecnologie e Biofarmaceutica, Università di Bari, Via E. Orabona 4, 70126, Bari, Italy

    M. Favia

  3. Istituto di Cristallografia (IC) – CNR, Via G. Amendola 122/O, 70126, Bari, Italy

    R. Lassandro

Authors
  1. M. Favia
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  2. L. de Bari
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  3. R. Lassandro
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  4. Anna Atlante
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Corresponding author

Correspondence to Anna Atlante.

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Favia, M., de Bari, L., Lassandro, R. et al. Modulation of glucose-related metabolic pathways controls glucose level in airway surface liquid and fight oxidative stress in cystic fibrosis cells. J Bioenerg Biomembr 51, 203–218 (2019). https://doi.org/10.1007/s10863-019-09797-5

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  • DOI: https://doi.org/10.1007/s10863-019-09797-5

Keywords

  • Cystic fibrosis
  • Glucose metabolism
  • Glycolysis
  • Pentose phosphate pathway
  • Mitochondria
  • Oxidative stress
  • Lung infection