2. Academic Validation
  3. SLC7A11 is an unconventional H+ transporter in lysosomes

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.
Nan Zhou 1,  Jingzhi Chen 1,  Meiqin Hu 2,  Na Wen 1,  Weijie Cai 3,  Ping Li 3,  Liding Zhao 4,  Yaping Meng 3,  Dongdong Zhao 3,  Xiaotong Yang 3,  Siyu Liu 3,  Fangqian Huang 3,  Cheng Zhao 3,  Xinghua Feng 3,  Zikai Jiang 5,  Enjun Xie 6,  Hongxu Pan 7,  Zhidong Cen 8,  Xinhui Chen 8,  Wei Luo 8,  Beisha Tang 7,  Junxia Min 6,  Fudi Wang 6,  Junsheng Yang 5,  Haoxing Xu 9
Affiliations

Affiliations

  • 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: meiqinh@zju.edu.cn.
  • 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: haoxingx@zju.edu.cn.
PMID: 40280132 DOI: 10.1016/j.cell.2025.04.004
Abstract

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.

Keywords

acidification; cystine; ferroptosis; lysosome; pH optimum.

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