Organic anion transporters 1 and 3 influence cellular energy metabolism in renal proximal tubule cells.

Autor:	Vriend J; Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, P.O. Box 9101, NL-6500HB, Nijmegen, The Netherlands., Hoogstraten CA; Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, P.O. Box 9101, NL-6500HB, Nijmegen, The Netherlands.; Centre for Systems Biology and Bioenergetics, Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, P.O. Box 9101, NL-6500HB, Nijmegen, The Netherlands., Venrooij KR; Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, P.O. Box 9101, NL-6500HB, Nijmegen, The Netherlands., van den Berge BT; Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, P.O. Box 9101, NL-6500HB, Nijmegen, The Netherlands., Govers LP; Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, P.O. Box 9101, NL-6500HB, Nijmegen, The Netherlands., van Rooij A; Department of Laboratory Medicine, Translational Metabolic Laboratory (TML), Radboud University Medical Center, P.O. Box 9101, NL-6500HB, Nijmegen, The Netherlands., Huigen MCDG; Department of Laboratory Medicine, Translational Metabolic Laboratory (TML), Radboud University Medical Center, P.O. Box 9101, NL-6500HB, Nijmegen, The Netherlands., Schirris TJJ; Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, P.O. Box 9101, NL-6500HB, Nijmegen, The Netherlands.; Centre for Systems Biology and Bioenergetics, Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, P.O. Box 9101, NL-6500HB, Nijmegen, The Netherlands., Russel FGM; Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, P.O. Box 9101, NL-6500HB, Nijmegen, The Netherlands.; Centre for Systems Biology and Bioenergetics, Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, P.O. Box 9101, NL-6500HB, Nijmegen, The Netherlands., Masereeuw R; Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Universiteitsweg 99, NL-3584CG, Utrecht, The Netherlands., Wilmer MJ; Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, P.O. Box 9101, NL-6500HB, Nijmegen, The Netherlands.
Jazyk:	angličtina
Zdroj:	Biological chemistry [Biol Chem] 2019 Sep 25; Vol. 400 (10), pp. 1347-1358.
DOI:	10.1515/hsz-2018-0446
Abstrakt:	Organic anion transporters (OATs) 1 and 3 are, besides being uptake transporters, key in several cellular metabolic pathways. The underlying mechanisms are largely unknown. Hence, we used human conditionally immortalized proximal tubule epithelial cells (ciPTEC) overexpressing OAT1 or OAT3 to gain insight into these mechanisms. In ciPTEC-OAT1 and -OAT3, extracellular lactate levels were decreased (by 77% and 71%, respectively), while intracellular ATP levels remained unchanged, suggesting a shift towards an oxidative phenotype upon OAT1 or OAT3 overexpression. This was confirmed by increased respiration of ciPTEC-OAT1 and -OAT3 (1.4-fold), a decreased sensitivity to respiratory inhibition, and characterized by a higher demand on mitochondrial oxidative capacity. In-depth profiling of tricarboxylic acid (TCA) cycle metabolites revealed reduced levels of intermediates converging into α-ketoglutarate in ciPTEC-OAT1 and -OAT3, which via 2-hydroxyglutarate metabolism explains the increased respiration. These interactions with TCA cycle metabolites were in agreement with metabolomic network modeling studies published earlier. Further studies using OAT or oxidative phosphorylation (OXPHOS) inhibitors confirmed our idea that OATs are responsible for increased use and synthesis of α-ketoglutarate. In conclusion, our results indicate an increased α-ketoglutarate efflux by OAT1 and OAT3, resulting in a metabolic shift towards an oxidative phenotype.
Databáze:	MEDLINE
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