SLC7A11 is an unconventional H+ transporter in lysosomes 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 ISBN 101016/JCELL202504004 instant download

SLC7A11 is an unconventional H+ transporter in lysosomes 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 ISBN 101016/JCELL202504004 instant download

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.