SLC7A11 is an unconventional H+ transporter in lysosomes
Lysosomes maintain an acidic pH of 4.5-5.0, optimal for macromolecular degradation. Whereas proton influx is produced by a V-type H<sup>+</sup> ATPase, proton efflux is mediated by a fast H<sup>+</sup> 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<sup>+</sup> leak through downward flux of cystine and glutamate, two H<sup>+</sup> 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<sup>+</sup> transport conduit that is integral to lysosomal flux of protonatable metabolites to regulate lysosome function, ferroptosis, and Parkinson's disease (PD) pathology.
Authors
- Yaping Meng (ORCID: https://orcid.org/0009-0000-4787-9778)
- Zikai Jiang
- Hongxu Pan (ORCID: https://orcid.org/0000-0003-4255-5904)
- Cheng Zhao
- Xinghua Feng (ORCID: https://orcid.org/0000-0002-1645-6606)
- Meiqin Hu (ORCID: https://orcid.org/0000-0002-3953-5868)
- Zhidong Cen (ORCID: https://orcid.org/0000-0003-3155-5781)
- Junxia Min (ORCID: https://orcid.org/0000-0001-8099-6327)
- Haoxing Xu (ORCID: https://orcid.org/0000-0003-3561-4654)
- Beisha Tang (ORCID: https://orcid.org/0000-0003-2120-1576)
- Wei Luo (ORCID: https://orcid.org/0000-0003-2826-1723)
- Junsheng Yang (ORCID: https://orcid.org/0000-0002-6425-8495)
- Fangqian Huang (ORCID: https://orcid.org/0009-0000-4058-1282)
- Siyu Liu (ORCID: https://orcid.org/0000-0003-3295-213X)
- Ping Li (ORCID: https://orcid.org/0000-0003-1871-176X)
- Nan Zhou (ORCID: https://orcid.org/0000-0003-0739-9838)
- Fudi Wang (ORCID: https://orcid.org/0000-0001-8730-0003)
- Xiaotong Yang
- Xinhui Chen (ORCID: https://orcid.org/0009-0009-9940-9327)
- Na Wen (ORCID: https://orcid.org/0000-0001-5439-0444)
- Jingzhi Chen (ORCID: https://orcid.org/0000-0002-7884-3177)
- Enjun Xie (ORCID: https://orcid.org/0000-0002-5739-0404)
- Weijie Cai (ORCID: https://orcid.org/0000-0003-4596-5458)
- Liding Zhao (ORCID: https://orcid.org/0000-0003-4862-7294)
- Zhao Dongdong
Institutions
- Central South University (CN)
- Zhejiang Lab (CN)
- National Clinical Research (US)
- Second Affiliated Hospital of Zhejiang University (CN)
- Xiangya Hospital Central South University (CN)
- First Affiliated Hospital Zhejiang University (CN)
- Zhejiang University of Technology (CN)
- Zhejiang University (CN)
Publication Details
- Journal
- Cell
- Published
- 2025-04-23
- DOI
- https://doi.org/10.1016/j.cell.2025.04.004
- Citations
- 28
- Primary Topic
- Amino Acid Enzymes and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 31.13