Abstract
Taurine plays a crucial role in mitochondrial translation. Mammalian cells obtain taurine via exogenous uptake mediated by the plasma membrane transporter SLC6A6 or via cytosolic biosynthesis. However, it remains unclear how taurine enters mitochondria and impacts cellular metabolism. Here we show that SLC6A6, but not exogenous taurine, is essential for mitochondrial metabolism and cancer cell growth. We discover that SLC6A6 also localizes to mitochondria and imports taurine for mitochondrial transfer RNA modifications. SLC6A6 deficiency specifically reduces mitochondrial taurine abundance and abrogates mitochondrial translation and cell proliferation. We identify protein kinase A as a regulator of SLC6A6 subcellular localization, as it promotes SLC6A6 presence at the plasma membrane while inhibiting its mitochondrial localization. Furthermore, we identify NFAT5 as a key regulator of mitochondrial function through SLC6A6 and demonstrate that targeting the NFAT5–SLC6A6 axis markedly impairs mitochondrial translation and tumour growth. Together, these findings suggest that SLC6A6 is a mitochondrial taurine transporter and an exploitable metabolic dependency in cancer.
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Data availability
Original data and images and western blots are available via Zenodo at https://doi.org/10.5281/zenodo.17853672 (ref. 68). The metabolomics data are available from MetaboLights under identifiers MTBLS13422 and MTBLS13424. The proteomics data have been deposited to the ProteomeXchange Consortium via the iProX partner repository with the dataset identifier: PXD071408. All other data supporting the findings of this study are also available from the corresponding authors upon request. Source data are provided with this paper.
Code availability
No custom code was used in this study.
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Acknowledgements
We are grateful to R. Cheng (Core Facility of Metabolomics, Institute of Metabolism and Integrative Biology, Fudan University) and N. Zhu (Core Facility of Molecular Biology, CAS Centre for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology) for technical assistance. This work was supported by the National Key R&D Program of China (grant nos. 2022YFA1103900 to Fuming Li, 2021YFA1300800 to X.-L.Z.), the Strategic Priority Research Program of the Chinese Academy of Sciences (grant no. XDB0570000 to X.-L.Z.); CAS Project for Young Scientists in Basic Research (grant no. YSBR-075) and National Natural Science Foundation of China (grant nos. 82273223 and 82573026 to Fuming Li, 32422048 to Li Chen and 32271300 to X.-L.Z.).
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L.L. and Fuming Li conceived the project and designed the experiments. Fuming Li, Li Chen, X.-L.Z. and P.L. supervised the project. L.L., J.Y., Z.-Q.C., L.W., F.Y., L.Z., W.M., X.X., H.Y. and J.W. performed the experiments. X.C. and Fei Li helped with the bioinformatic analysis. J.Y., X.L., Z.-Q.C., Li Chen and X.-L.Z. performed LC–MS and data analysis. L.L., J.Y., X.L., Z.-Q.C., Li Chen, X.-L.Z. and Fuming Li analysed the data. L.L. and Fuming Li wrote the paper. T.-J.Z., Ligong Chen and H.J. revised the manuscript provided. All authors revised and approved the paper.
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Nature Metabolism thanks Katsuhisa Inoue and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editors: Alfredo Gimenez-Cassina and Jean Nakhle, in collaboration with the Nature Metabolism team.
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Extended data
Extended Data Fig. 1 Exogenous taurine is dispensable for liver and lung cancer cell growth.
a, Relative growth of Hepa1-6 and HepaMP9-1 cells in D10 and D-N2B27 medium for 72 h. n = 4 biological replicates. b, Relative 293 T cell growth in D10 and D-N2B27 medium. c, d, Relative growth of of 293 T (c) and IMR90 (d) cells in DMEM containing indicated supplements for 72 h. n = 4 biological replicates. e, Relative growth of different cancer cells cultured in D10 or D-dFBS medium supplemented with indicated concentrations of taurine. n = 3 biological replicates. f, g, Representative crystal violet staining (f) and quantification (g) of clones from cancer cells cultured in D10 or D-dFBS medium supplemented with indicated concentrations of taurine. n = 3 biological replicates (g). h, Immunoblot analysis of taurine biosynthetic enzymes in different cell lines. HSP90 serves as loading control. All statistical graphs show the mean ± s.e.m. P values were calculated using a two-tailed Student’s t-test (a-c) or one-way ANOVA (d, e, g). Experiments were repeated at least three times independently, with similar results (a-h).
Extended Data Fig. 2 SLC6A6 is required for liver and lung cancer cell growth.
a, qPCR analysis of SLC6A6 mRNA levels from control (shCtrl) and SLC6A6 (sh6A6)/Slc6a6 (sh6a6) knockdown cancer cells. Representative results from three independent experiments are shown. b, c, Representative crystal violet staining (b) and quantification (c) of clonal formation from shCtrl and sh6A6 cancer cells. n = 4 biological replicates (c). d, Representative TMRE staining of shCtrl and sh6A6 cancer cells. Scale bar: 10 µm. e, Immunoblots of indicated mitochondrial proteins from shCtrl and sh6A6 cancer cells cultured in D-N2B27 medium. HSP90 serves as loading control. f, Relative growth of indicated groups of cancer cells cultured in D10 or D-dFBS medium. n = 3 biological replicates. g, Immunoblots of mitochondrial proteins from indicated groups cells cultured in D10 medium. HSP90 serves as loading control. All statistical graphs show the mean ± s.e.m. P values were calculated using one-way ANOVA (a, c, f). Experiments were repeated at least three times independently, with similar results (a-g).
Extended Data Fig. 3 SLC6A6 is required for mitochondrial translation and tRNA modifications.
a, Immunoblot analysis of puromycin incorporation into mitochondrial encoded proteins from In Organello Translation assay. TOM20 serves as loading control. b, Secondary structures of hmtRNATrp with indicated tm5U modification. Arrows indicate specific RNase T1 cleavage sites generating U34‑containing fragments. c, Intensity fractions (%) of U34-containing fragments with different modification states in the indicated A549 cells. Sequences are annotated with their mass-to-charge ratio (m/z), charge state, and relative modification frequencies. Experiments were repeated three times independently, with similar results (a).
Extended Data Fig. 4 SLC6A6 deficiency alters glucose and glutamine metabolism in cancer cells.
a, A scheme of [U-13C] glucose isotope labeling and flux analysis. b, [U-13C] glucose-derived citrate M + 2 labeling percentage (% of total pool) of A549 and Huh7 cells in control and SLC6A6 knockdown groups. n = 3 biological replicates. c, A scheme of [U-13C] glutamine isotope labeling and flux analysis. d, e, [U-13C] glutamine-derived citrate M + 4 (d) and M + 5 (e) labeling percentage (% of total pool) of A549 and Huh7 cells in control and SLC6A6 knockdown groups. n = 3 biological replicates. f, [U-13C] glutamine-derived Malate M + 3 and M + 4 labeling percentage (% of total pool) of A549 and Huh7 cells in control and SLC6A6 knockdown groups. n = 3 biological replicates. All statistical graphs show the mean ± s.e.m. P values were calculated using two-tailed Student’s t-test (b) and one-way ANOVA (d-f). Experiments were repeated three times independently, with similar results (b, d-f).
Extended Data Fig. 5 Mitochondrial localization of SLC6A6.
a, Partial colocalization of SLC6A6-EGFP with PM marker CellMaskTM stain (red) in different cancer cell lines. Scale bar: 10 µm. b, Quantification of colocalization between SLC6A6-EGFP and CellMaskTM stain in (a). c, Colocalization of mouse SLC6A6-EGFP with Mitotracker in HepaMP9-1 cells. Scale bar: 10 µm. d, Quantification of colocalization between mouse SLC6A6-EGFP and Mitotracker. e, Representative IF staining of V5 and COX4 in A549 and Huh7 cells expressing SLC6A6-V5. Scale bar: 10 µm. f, Quantification of colocalization between SLC6A6-5 and COX4 in (e). g, Immunoblots of SLC6A6 from input, PM and mitochondrial lysates isolated from A549 and Huh7 cells and loaded at same percentages. h, Conserved MTS sequence across different species. Positively charged residues and mutated residues in MTS are shown in red. i, j, Representative EGFP and Mitotracker staining (i), and quantification of colocalization (j) in Huh7 cells expressing EGFP (CMV-EGFP), or EGFP fused to wild type (WT) or mutant (MT) SLC6A6 MTS. k, Immunoblots of SLC6A6-HA from input, PM and Mito lysates from Huh7 cells expressing SLC6A6-HA-WT or SLC6A6-HA-MT MTS. l, Relative growth of control (shCtrl) and SLC6A6 knockdown (sh6A6) A549 and Huh7 cells expressing shRNA-resistant SLC6A6-WT or SLC6A6-MT. n = 4 biological replicates. All statistical graphs show the mean ± s.e.m. P values were calculated using one-way ANOVA (l). Experiments were repeated at least three times independently, with similar results (a-g, i-k).
Extended Data Fig. 6 SLC6A6 mediates mitochondrial taurine transport.
a, Relative taurine abundance in control (shCtrl) and SLC6A6 knockdown (sh6A6) A549 and Huh7 cells. n = 3 biological replicates. b, Representative immunofluorescent imaging of CoroNaTM Green and Mitotracker staining in different cancer cells. Scale bar: 10 µm. c, Relative mitochondrial D4 taurine abundance after incubating purified mitochondria with indicated concentrations of D4 taurine, NaCl and P4S for 1 h. n = 3 LC-MS detections. n = 3 biological replicates. d, Relative mitochondrial D4 taurine abundance after incubating purified mitochondria with 10 mM taurine and 10 mM NaCl and indicated concentrations of P4S for 1 h. n = 3 LC-MS detections. All statistical graphs show the mean ± s.e.m. P values were calculated using one-way ANOVA (a, c, d). Experiments were repeated three times independently, with similar results (a-d).
Extended Data Fig. 7 PKA promotes SLC6A6 localization to plasma membrane.
a, Fold change in cell number after culturing A549 and Huh7 cells with indicated concentrations of Fsk for 72 h. n = 4 biological replicates. b, Immunoblots of A549 and Huh7 cells treated with indicated concentrations of Fsk for 72 h. HSP90 serves as loading control. c, A volcano plot showing adjusted p values and fold change in intensities of SLC6A6-binding proteins from proteomic analysis. n = 3 biological replicates. d, KEGG analysis of 589 SLC6A6-binding proteins. e, Immunoblots of input and PM lysates from control (shCtrl) and RAB2A knockdown (shRAB2A) A549 and Huh7 cells. All statistical graphs show the mean ± s.e.m. P values were calculated using one-way ANOVA (a) and two-tailed Student’s t-test (c). Experiments were repeated three times independently, with similar results (a, b, e).
Extended Data Fig. 8 NFAT5 is required for cancer cell growth and mitochondrial function.
a, Kaplan–Meier overall survival plots stratified by SLC6A6 high (red) or low (blue) mRNA levels from TCGA database. b, Kaplan–Meier overall survival plots stratified by NFAT5 high (red) or low (blue) mRNA levels from TCGA database. A log-rank Mantel–Cox test was performed between the groups of each plot (a, b). c, Positive correlation between SLC6A6 and NFAT5 mRNA levels from pan-cancer analysis. d, e, Representative crystal violet staining (d) and quantification (e) of clonal formation from shCtrl and shNFAT5 cancr cells. n = 4 biological replicates (e). f, Quantification of shCtrl and shNFAT5 Huh7 and H1299 cell death (% trypan blue+) in galactose-containing medium (10 mM) for 48 h. n = 4 biological replicates. g, Relative taurine abundance in shCtrl and shNFAT5 A549 and Huh7 cells. n = 3 biological replicates. Data presented as mean ± s.e.m. of three independent experiments; statistical significance was determined by one-way ANOVA (e-g). Experiments were repeated three times independently, with similar results (d-g).
Extended Data Fig. 9 Targeting NFAT5-SLC6A6 axis limits mitochondrial translation and tumour growth.
a, Relative number of cancer cells treated with indicated doses of KRN2 for 72 h. Cell numbers were normalized to vehicle control groups. n = 4 biological replicates. b, Relative cell number of vector control (Vector) and SLC6A6-overexpressing (6A6-OE) A549 and Huh7 cells treated with indicated doses of KRN2 for 72 h. Cell numbers were normalized to corresponding vehicle control groups. n = 3 biological replicates. c, Representative A549 and H1299 xenograft tumour images from vehicle control and KRN2 treatment groups. d, Quantification of A549 and H1299 xenograft tumour weight from vehicle control and KRN2 treatment groups. Ctrl: n = 8 for A549, n = 10 for H1299. KRN2: n = 8 for A549, n = 6 for H1299. e, Representative HepaMP9-1 allograft tumour images from vehicle control and KRN2 treatment groups. f, Quantification of HepaMP9-1 allograft tumour weight from vehicle control (n = 10) and KRN2 (n = 10) treatment groups. g, Q-PCR analysis of HepaMP9-1 allograft tumours from vehicle and KRN2 cohorts. n = 3 tumours. h, Immunoblot analysis of HepaMP9-1 allograft tumours from vehicle and KRN2 cohorts. n = 3 tumours. i, Quantification of relative mouse body weight change from vehicle and KRN2 treatment cohorts. n = 5 mice for each cohort. j, Representative HE staining of liver, lung and kidney sections from vehicle control and KRN2 treated mice. Scale bar: 10 µm. Data presented as mean ± s.e.m. of three independent experiments; statistical significance was determined by one-way ANOVA (a, b) and a two-tailed Student’s t-test (d, f, g, i). Experiments were repeated three times independently, with similar results (a, b, g, h, j).
Supplementary information
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Quantitative reverse transcription PCR primer sequences.
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shRNA/sgRNA oligo sequences.
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Proteomics data analysis.
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Li, L., You, J., Chai, ZQ. et al. SLC6A6 imports taurine into mitochondria to sustain mitochondrial translation and tumour growth. Nat Metab (2026). https://doi.org/10.1038/s42255-026-01455-6
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DOI: https://doi.org/10.1038/s42255-026-01455-6
