40: Lysosomal SLC7A11 and acidification

Provided PDF (truncated source text) et al., Cell - This episode reviews a study that examines SLC7A11 (7A11) localization to lysosomes and its impact on lysosomal acidification, cystine/cysteine balance, lysosomal function, and cell viability using genetic and pharmacologic tools and isolated lysosome assays. Key terms: SLC7A11, lysosome, lysosomal pH, cystine, ferroptosis. Study Highlights:The authors localize SLC7A11/7A11 to lysosomes (LAMP1 colocalization, tagged knock‑ins/overexpression) and measure juxta‑lysosomal pH changes with genetically encoded and dye‑based pH reporters. Loss, inhibition, or mutation of 7A11 alters lysosomal acidification, cystine/cysteine handling and downstream readouts including cathepsin activity, lipid peroxidation markers, and cell viability under ferroptosis‑related perturbations. Experiments include isolated lysosome assays, pharmacologic modulators (erastin, RSL3, bafilomycin, chloroquine, ferrostatin‑1), multiple cell lines (HT1080, HeLa, HAP1, MEFs), and analyses of patient‑derived neurons from PD cohorts. Conclusion:SLC7A11 associates with lysosomes and modulates lysosomal pH and amino‑acid flux; altering its function changes lysosomal enzyme activity and cellular stress responses in experimental models, suggesting lysosomal amino‑acid handling is an important regulator of lysosomal physiology. Music:Enjoy the music based on this article at the end of the episode. Article title:SLC7A11 is an unconventional H+ transporter in lysosomes First author:Provided PDF (truncated source text) Journal:Cell DOI:10.1016/j.cell.2025.04.004 Reference:Provided PDF (truncated source text) 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/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/base-by-base-40-slc7a11-lysosomes QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-06-09. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited substantive content describing lysosomal localization of SLC7A11, the proposed H+ shuttle/vent mechanism, the pH change from ~4.6 to ~4.2 upon valve disruption, downstream lysosomal dysfunction and ferroptosis, chloroquine rescue at low dose, AAS trafficking mutation validation, and Parkinson's disease relevanc- transcript topics: Lysosomal localization of SLC7A11 and LAMP1 colocalization; Proton shuttle mechanism and lysosomal H+ leak; Effect of SLC7A11 loss on lysosomal pH and enzyme activity; Lipofuscin accumulation and ferroptosis in neurons; Chloroquine low-dose rescue of lysosomal pH and ferroptosis; AAS trafficking mutation confirms lysosomal localization QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 6- claims flagged for review: 0- metadata checks passed: 4- metadata issues found: 0 Metadata Audited:- article_doi- article_title- article_journal- license Factual Items Audited:- SLC7A11 localizes to lysosomes and colocalizes with LAMP1- SLC7A11 modulates lysosomal juxta‑lysosomal pH via a proton shuttle mechanism- Loss/inhibition of SLC7A11 leads to lysosomal overacidification and dysfunction (pH ~4.2; enzymes impaired; lipofuscin accumulation; ferroptosis)- Low-dose chloroqu...