Slc7a11 Is An Unconventional H Transporter In Lysosomes Nan Zhou by Nan Zhou, 1, 2, 9 Jingzhi Chen, 1, 2, 9 Meiqin Hu, 1, 9, * Na Wen, 1, Dongdong Zhao, 1 Xiaotong Yang, 1 Siyu Liu, 1 Fangqian Hhongxu Pan, 5 Zhidong Cen, 6 Xinhui Chen, 6 Wei Luo, 6 Beind Haoxing Xu1, 7, 8, 10, * New Cornerstone Science Laboratory And Liangzhu Laboratory, T 101016/JCELL202504004 instant download after payment.

SUMMARYLysosomes maintain an acidic pH of 4.5–5.0, optimal for macromolecular degradation. Whereas protoninflux is produced by a V-type H+ ATPase, proton efflux is mediated by a fast H+ leak throughTMEM175 channels, as well as an unidentified slow pathway. A candidate screen on an orphan lysosomemembrane 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 cystineand glutamate, two H+ equivalents with uniquely large but opposite concentration gradients across lysosomal membranes. SLC7A11 deficiency or inhibition caused lysosomal over-acidification, reduceddegradation, 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 integralto lysosomal flux of protonatable metabolites to regulate lysosome function, ferroptosis, and Parkinson’sdisease (PD) pathology.