️ 40: Lysosomal Proton Leak — Uncovering SLC7A11’s Role as an Unconventional H⁺ Transit Pathway

️ Episode 40: Lysosomal Proton Leak — Uncovering SLC7A11’s Role as an Unconventional H⁺ Transit Pathway In this episode of Base by Base, we delve into a revealing study by Zhou et al. (2025) in Cell that identifies SLC7A11—long known for its function in redox homeostasis and ferroptosis—as a slow H⁺ transporter embedded in lysosomal membranes. Through a combination of CRISPR knockouts, pharmacological inhibition, ratiometric pH imaging, and assays on isolated lysosomes, the authors demonstrate that SLC7A11 mediates a constitutive proton efflux by trading luminal cystine for cytosolic glutamate, thereby fine-tuning lysosomal acidity and sustaining degradative capacity. Key highlights of the study:The authors reveal that SLC7A11 operates a distinct, slow H⁺ leak pathway—separate from the fast TMEM175 channel—directly coupling amino-acid exchange with pH regulation. Loss or inhibition of SLC7A11 causes lysosomal over-acidification and diminishes macromolecular degradation, resulting in accumulation of storage materials. Proper SLC7A11 function is shown to be essential for countering erastin-induced ferroptosis and preventing pathological α-synuclein aggregation in neurons. Mechanistic experiments confirm that efflux of cystine from, and influx of glutamate into, lysosomes through SLC7A11 drives its proton leak activity in immuno-isolated organelles. Conclusion:By unveiling SLC7A11 as an unconventional H⁺ transport conduit that integrates metabolite flux with pH homeostasis, this work expands our understanding of lysosomal physiology and suggests new therapeutic avenues for diseases involving ferroptosis, neurodegeneration, and lysosomal storage dysfunction. Reference:Zhou, N., Chen, J., Hu, M., Wen, N., Cai, W., Li, P., Zhao, L., Meng, Y., Zhao, D., Yang, X., Liu, S., Huang, F., Zhao, C., Feng, X., Jiang, Z., Xie, E., Pan, H., Cen, Z., Chen, X., Luo, W., Tang, B., Min, J., Wang, F., Yang, J., & Xu, H. (2025). SLC7A11 is an unconventional H⁺ transporter in lysosomes. Cell, 188(1), 1–18. https://doi.org/10.1016/j.cell.2025.04.004 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International license (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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