SLC7A11 is an unconventional H+ transporter in lysosomes
- Cell. 2025 Jun 26;188(13):3441-3458.e25. doi: 10.1016/j.cell.2025.04.004.
- 1. New Cornerstone Science Laboratory and Liangzhu Laboratory, the Second Affiliated Hospital and School of Basic Medical Sciences, Zhejiang University, Hangzhou, China; Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China.
- 2. New Cornerstone Science Laboratory and Liangzhu Laboratory, the Second Affiliated Hospital and School of Basic Medical Sciences, Zhejiang University, Hangzhou, China. Electronic address: [email protected].
- 3. New Cornerstone Science Laboratory and Liangzhu Laboratory, the Second Affiliated Hospital and School of Basic Medical Sciences, Zhejiang University, Hangzhou, China.
- 4. New Cornerstone Science Laboratory and Liangzhu Laboratory, the Second Affiliated Hospital and School of Basic Medical Sciences, Zhejiang University, Hangzhou, China; Department of Cardiology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
- 5. Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China.
- 6. The Second Affiliated Hospital & the First Affiliated Hospital, Institute of Translational Medicine, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou, China.
- 7. Department of Neurology & National Clinical Research Centre for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
- 8. Department of Neurology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
- 9. New Cornerstone Science Laboratory and Liangzhu Laboratory, the Second Affiliated Hospital and School of Basic Medical Sciences, Zhejiang University, Hangzhou, China; Institute of Fundamental and Transdisciplinary Research and The State Key Lab of Brain-Machine Intelligence, Zhejiang University, Hangzhou, China; Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: [email protected].
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.