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Facilitated mitochondrial import of antiviral and anticancer nucleoside drugs by human equilibrative nucleoside transporter-3.
Govindarajan R
,
Leung GP
,
Zhou M
,
Tse CM
,
Wang J
,
Unadkat JD
.
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Human equilibrative nucleoside transporter-3 (hENT3) was recently reported as a pH-dependent, intracellular (lysosomal) transporter capable of transporting anti-human immunodeficiency virus (HIV) dideoxynucleosides (ddNs). Because most anti-HIV ddNs (e.g., zidovudine, AZT) exhibit clinical mitochondrial toxicity, we investigated whether hENT3 facilitates transport of anti-HIV ddNs into the mitochondria. Cellular fractionation and immunofluorescence microscopy studies in several human cell lines identified a substantial presence of hENT3 in the mitochondria, with additional presence at the cell surface of two placental cell lines (JAR, JEG3). Mitochondrial or cell surface hENT3 expression was confirmed in human hepatocytes and placental tissues, respectively. Unlike endogenous hENT3, yellow fluorescent protein (YFP)-tagged hENT3 was partially directed to the lysosomes. Xenopus oocytes expressing NH2-terminal-deleted hENT3 (expressed at the cell surface) showed pH-dependent interaction with several classes of nucleosides (anti-HIV ddNs, gemcitabine, fialuridine, ribavirin) that produce mitochondrial toxicity. Transport studies in hENT3 gene-silenced JAR cells showed significant reduction in mitochondrial transport of nucleosides and nucleoside drugs. Our data suggest that cellular localization of hENT3 is cell type dependent and the native transporter is substantially expressed in mitochondria and/or cell surface. hENT3-mediated mitochondrial transport may play an important role in mediating clinically observed mitochondrial toxicity of nucleoside drugs. In addition, our finding that hENT3 is a mitochondrial transporter is consistent with the recent finding that mutations in the hENT3 gene cause an autosomal recessive disorder in humans called the H syndrome.
Addanki,
Determination of intramitochondrial pH and intramitochondrial-extramitochondrial pH gradient of isolated heart mitochondria by the use of 5,5-dimethyl-2,4-oxazolidinedione. I. Changes during respiration and adenosine triphosphate-dependent transport of Ca++, Mg++, and Zn++.
1968, Pubmed
Addanki,
Determination of intramitochondrial pH and intramitochondrial-extramitochondrial pH gradient of isolated heart mitochondria by the use of 5,5-dimethyl-2,4-oxazolidinedione. I. Changes during respiration and adenosine triphosphate-dependent transport of Ca++, Mg++, and Zn++.
1968,
Pubmed
Addanki,
Reliability of the quantitation of intramitochondrial pH and pH gradient of heart mitochondria.
1968,
Pubmed
Arnér,
Mammalian deoxyribonucleoside kinases.
1995,
Pubmed
Baldwin,
The equilibrative nucleoside transporter family, SLC29.
2004,
Pubmed
Baldwin,
Functional characterization of novel human and mouse equilibrative nucleoside transporters (hENT3 and mENT3) located in intracellular membranes.
2005,
Pubmed
,
Xenbase
Barnes,
Distribution and functional characterization of equilibrative nucleoside transporter-4, a novel cardiac adenosine transporter activated at acidic pH.
2006,
Pubmed
,
Xenbase
Carr,
Adverse effects of antiretroviral therapy.
2000,
Pubmed
Chang,
Molecular requirements of the human nucleoside transporters hCNT1, hCNT2, and hENT1.
2004,
Pubmed
Divi,
Transplacentally exposed human and monkey newborn infants show similar evidence of nucleoside reverse transcriptase inhibitor-induced mitochondrial toxicity.
2007,
Pubmed
Dragovic,
Nucleoside reverse transcriptase inhibitor usage and the incidence of peripheral neuropathy in HIV/AIDS patients.
2003,
Pubmed
Engel,
Identification and characterization of a novel monoamine transporter in the human brain.
2004,
Pubmed
,
Xenbase
Govindarajan,
In situ hybridization and immunolocalization of concentrative and equilibrative nucleoside transporters in the human intestine, liver, kidneys, and placenta.
2007,
Pubmed
Govindarajan,
Expression and hepatobiliary transport characteristics of the concentrative and equilibrative nucleoside transporters in sandwich-cultured human hepatocytes.
2008,
Pubmed
Haines,
Cardiolipin: a proton trap for oxidative phosphorylation.
2002,
Pubmed
Honkoop,
Mitochondrial injury. Lessons from the fialuridine trial.
1997,
Pubmed
Hyde,
The ENT family of eukaryote nucleoside and nucleobase transporters: recent advances in the investigation of structure/function relationships and the identification of novel isoforms.
2001,
Pubmed
Igamberdiev,
Equilibration of adenylates in the mitochondrial intermembrane space maintains respiration and regulates cytosolic metabolism.
2006,
Pubmed
John,
Chronic hyperlactatemia in HIV-infected patients taking antiretroviral therapy.
2001,
Pubmed
Khalifat,
Membrane deformation under local pH gradient: mimicking mitochondrial cristae dynamics.
2008,
Pubmed
Kohler,
A brief overview of mechanisms of mitochondrial toxicity from NRTIs.
2007,
Pubmed
Lai,
Mitochondrial expression of the human equilibrative nucleoside transporter 1 (hENT1) results in enhanced mitochondrial toxicity of antiviral drugs.
2004,
Pubmed
Lee,
Identification of the mitochondrial targeting signal of the human equilibrative nucleoside transporter 1 (hENT1): implications for interspecies differences in mitochondrial toxicity of fialuridine.
2006,
Pubmed
Lewis,
Mitochondrial toxicity of antiviral drugs.
1995,
Pubmed
Lewis,
Nucleoside reverse transcriptase inhibitors, mitochondrial DNA and AIDS therapy.
2005,
Pubmed
Lum,
Human intestinal es nucleoside transporter: molecular characterization and nucleoside inhibitory profiles.
2000,
Pubmed
,
Xenbase
McKenzie,
Hepatic failure and lactic acidosis due to fialuridine (FIAU), an investigational nucleoside analogue for chronic hepatitis B.
1995,
Pubmed
Molho-Pessach,
The H syndrome is caused by mutations in the nucleoside transporter hENT3.
2008,
Pubmed
Nakamura,
Targeting and assembly of rat mitochondrial translocase of outer membrane 22 (TOM22) into the TOM complex.
2004,
Pubmed
Nantel,
Localization of endogenous Grb10 to the mitochondria and its interaction with the mitochondrial-associated Raf-1 pool.
1999,
Pubmed
Neve,
Identification and characterization of a mitochondrial targeting signal in rat cytochrome P450 2E1 (CYP2E1).
2001,
Pubmed
Pfanner,
Versatility of the mitochondrial protein import machinery.
2001,
Pubmed
Pisoni,
Detection and characterization of a nucleoside transport system in human fibroblast lysosomes.
1989,
Pubmed
Pujol,
How can organellar protein N-terminal sequences be dual targeting signals? In silico analysis and mutagenesis approach.
2007,
Pubmed
Robin,
Bimodal targeting of microsomal CYP2E1 to mitochondria through activation of an N-terminal chimeric signal by cAMP-mediated phosphorylation.
2002,
Pubmed
Shayeghi,
Nucleobase transport in opossum kidney epithelial cells and Xenopus laevis oocytes: the characterisation, structure-activity relationship of uracil analogues and oocyte expression studies of sodium-dependent and -independent hypoxanthine uptake.
1999,
Pubmed
,
Xenbase
Su,
Large-scale analysis of the human and mouse transcriptomes.
2002,
Pubmed
Wang,
Characterization of a bioengineered chimeric Na+-nucleoside transporter.
1999,
Pubmed
,
Xenbase
Yao,
Transport of antiviral 3'-deoxy-nucleoside drugs by recombinant human and rat equilibrative, nitrobenzylthioinosine (NBMPR)-insensitive (ENT2) nucleoside transporter proteins produced in Xenopus oocytes.
2001,
Pubmed
,
Xenbase
