2025-06-05 浙江大学 (ZJU)
<関連情報>
- https://www.zju.edu.cn/english/2025/0526/c19573a3055180/page.psp
- https://www.cell.com/cell/fulltext/S0092-8674(25)00406-4
SLC7A11はリソソームにおける非従来型H+トランスポーターである SLC7A11 is an unconventional H+ transporter in lysosomes
Nan Zhou ∙ Jingzhi Chen ∙ Meiqin Hu ∙ … ∙ Fudi Wang ∙ Junsheng Yang ∙ Haoxing Xu
Cell Published:April 23, 2025
DOI:https://doi.org/10.1016/j.cell.2025.04.004
Graphical abstract
Highlights
•Lysosomal SLC7A11 mediates a slow H+ leak via cystine and glutamate flux
•SLC7A11 deficiency causes lysosomal over-acidification and reduced degradation
•Lysosomal pH homeostasis is required to prevent erastin-induced ferroptosis
•SLC7A11 dysfunction facilitates pathological α-synuclein aggregation in neurons
Summary
Lysosomes maintain an acidic pH of 4.5–5.0, optimal for macromolecular degradation. Whereas proton influx is produced by a V-type H+ ATPase, proton efflux is mediated by a fast H+ leak through TMEM175 channels, as well as an unidentified slow pathway. A candidate screen on an orphan lysosome membrane protein (OLMP) library enabled us to discover that SLC7A11, the protein target of the ferroptosis-inducing compound erastin, mediates a slow lysosomal H+ leak through downward flux of cystine and glutamate, two H+ equivalents with uniquely large but opposite concentration gradients across lysosomal membranes. SLC7A11 deficiency or inhibition caused lysosomal over-acidification, reduced degradation, accumulation of storage materials, and ferroptosis, as well as facilitated α-synuclein aggregation in neurons. Correction of abnormal lysosomal acidity restored lysosome homeostasis and prevented ferroptosis. These studies have revealed an unconventional H+ transport conduit that is integral to lysosomal flux of protonatable metabolites to regulate lysosome function, ferroptosis, and Parkinson’s disease (PD) pathology.
