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Impact of hexavalent chromium on mammalian cell bioenergetics: phenotypic changes, molecular basis and potential relevance to chromate-induced lung cancer

Abstract

Occupational exposure to hexavalent chromium [Cr(VI)] has been firmly associated with the development of several pathologies, notably lung cancer. According to the current paradigm, the evolution of normal cells to a neoplastic state is accompanied by extensive metabolic reprogramming, namely at the level of energy-transducing processes. Thus, a complete understanding of the molecular basis of Cr(VI)-induced lung cancer must encompass the elucidation of the impact of Cr(VI) on metabolism. Research in this area is still in its infancy. Nonetheless, Cr(VI)-induced metabolic phenotypes are beginning to emerge. Specifically, it is now well documented that Cr(VI) exposure inhibits respiration and negatively affects the cellular energy status. Furthermore, preliminary results suggest that it also upregulates glucose uptake and lactic acid fermentation. From a mechanistic point of view, there is evidence that Cr(VI) exposure can interfere with energy transducing pathways at different levels, namely gene expression, intracellular protein levels and/or protein function. Loss of thiol redox control likely plays a key role in these processes. The transcriptional networks that control energy transduction can likewise be affected. Data also suggest that Cr(VI) exposure might compromise energy transducing processes through changes in the intracellular pools of their substrates. This article reviews, for the first time, the information available on Cr(VI) impact on mammalian cell bioenergetics. It aims to provide a framework for the understanding of the role played by bioenergetics in Cr(VI)-induced carcinogenesis and is also intended as a guide for future research efforts in this area.

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Notes

  1. EC = ([ATP] + ½[ADP])/[ATP] + [ADP] + [AMP]).

Abbreviations

BDH:

β-Hydroxybutyrate dehydrogenase

Cr(III):

Trivalent chromium

Cr(IV):

Tetravalent chromium

Cr(V):

Pentavalent chromium

Cr(VI):

Hexavalent chromium

DCFH:

Dichlorodihydrofluorescein

DHR:

Dihydrorhodamine

EC:

Energy charge

ETC:

Electron transport chain

FDG-PET:

18-Fluorodeoxyglucose positron emission tomography

G6PDH:

Glucose-6-phosphate dehydrogenase

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

GPx:

Glutathione peroxidase

GSH:

Reduced glutathione

GSR:

Glutathione reductase

GST:

Glutathione S-transferase

KGDH:

α-Ketoglutarate dehydrogenase

LDH:

Lactate dehydrogenase NHBE Normal human bronchial epithelial

MCAD:

Medium-chain acyl-CoA dehydrogenase

MDH:

Malate dehydrogenase

NADPH:

Nicotinamide adenine dinucleotide phosphate

OCR:

Oxygen consumption rate

OXPHOS:

Oxidative phosphorylation

PDH:

Pyruvate dehydrogenase

PDK2:

Pyruvate dehydrogenase kinase isoform 2

3-PGK:

3-Phosphoglycerate kinase

PGM:

Phosphoglucomutase

PK:

Pyruvate kinase

PPP:

Pentose phosphate pathway

Prx:

Peroxiredoxin

ROS:

Reactive oxygen species

SCO2:

Synthesis of cytochrome c oxidase 2

SOD:

Superoxide dismutase

TCA:

Tricarboxylic acid

TPI:

Triosephosphate isomerase

Trx:

Thioredoxin

Trx1:

Cytosolic thioredoxin

Trx2:

Mitochondrial thioredoxin

TrxR:

Thioredoxin reductase

TrxR1:

Cytosolic thioredoxin reductase

TrxR2:

Mitochondrial thioredoxin reductase

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Acknowledgments

Investigations from the authors’ laboratories described here were supported by Centro de Investigação em Meio Ambiente, Genética e Oncobiologia (CIMAGO), Portugal (Grants 26/07, to AMU, and 16/06, to MCA) and by Fundação para a Ciência e a Tecnologia, Portugal (Grant PEst-OE/QUI/UI0070/2011, to Unidade de Química Física Molecular). The authors apologize to all colleagues whose relevant work could not be mentioned and/or cited owing to space limitations.

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Abreu, P.L., Ferreira, L.M.R., Alpoim, M.C. et al. Impact of hexavalent chromium on mammalian cell bioenergetics: phenotypic changes, molecular basis and potential relevance to chromate-induced lung cancer. Biometals 27, 409–443 (2014). https://doi.org/10.1007/s10534-014-9726-7

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  • DOI: https://doi.org/10.1007/s10534-014-9726-7

Keywords

  • Hexavalent chromium
  • Chromate-induced lung cancer
  • Energy metabolism
  • Warburg effect
  • Oxidative stress