| First Author | Zhou N | Year | 2025 |
| Journal | Cell | Volume | 188 |
| Issue | 13 | Pages | 3441-3458.e25 |
| PubMed ID | 40280132 | Mgi Jnum | J:370119 |
| Mgi Id | MGI:8216903 | Doi | 10.1016/j.cell.2025.04.004 |
| Citation | Zhou N, et al. (2025) SLC7A11 is an unconventional H(+) transporter in lysosomes. Cell 188(13):3441-3458.e25 |
| abstractText | 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 alpha-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. |
