Abstract
The human equilibrative nucleoside transporter‐3 (hENT3) has been reported as a putative pH‐dependent lysosomal nucleoside transporter. However, our studies on immunolocalization and functional characterization of endogenous hENT3 in several different human cell lines suggest that it is a mitochondrial nucleoside transporter except in placental cells (JAR, JEG3) where endogenous hENT3 is also expressed on cell surface. Tagging the N‐terminus of hENT3 with YFP misdirected the chimeric protein to the lysosomes, while tagging HA at its C‐terminus directed the protein to cell surface and mitochondria with increased uptake of nucleosides via plasma membrane. When expressed in xenopus oocytes, hENT3‐mediated adenosine transport was stimulated by acidic pH (pH 6.5). Taken together with hENT3‐gene silencing data (in JAR cells), our results show that hENT3 transports nucleobases, nucleosides, nucleotides and anti‐HIV dideoxynucleoside drugs into cells as well as mitochondria. Based on these data, we propose that hENT3‐mediated transport of dideoxynucleoside drugs (e.g. didanosine) into cells and subsequently into mitochondria contributes to the mitochondrial toxicity of these drugs. Support by NIH GM054447.
Published Version
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